Aged monkeys as a partial model for Parkinson's disease.

Parkinson's Disease (PD) and the natural aging process share a number of biochemical mechanisms, including reduced function of dopaminergic systems. The present study aims to determine the extent that motor and behavioral changes in aged monkeys resemble parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The behavioral and physiological changes in PD are believed to result largely from selective depletion of dopamine in the nigrostriatal system. In the present study, ten aged female monkeys were compared with three groups: 9 untreated young adult female monkeys, 10 young adult male monkeys and 13 older male monkeys that had been exposed to MPTP. Trained observers, blind as to age and drug condition and without knowledge of the hypotheses, scored the monkeys using the Parkinson's factor score (Parkscore), which has been validated by a high correlation with post mortem striatal dopamine (DA) concentrations. The aged animals had higher scores on the Parkscore compared with the young adults, with most of its component behavioral items showing significance (tremor, Eating Problems, Delayed initiation of movement, and Poverty of Movement). L-Dopa and DA-agonists did not clearly reverse the principal measure of parkinsonism. DA concentrations post mortem were 63% lower in 3 aged monkeys in the ventral putamen compared with 4 young adults, with greater reductions in putamen than in caudate (45%). We conclude that aged monkeys, unexposed to MPTP, show a similar profile of parkinsonism to that seen after the neurotoxin exposure to MPTP in young adult monkeys. The pattern of greater DA depletion in putamen than in caudate in aged monkeys is the same as in human Parkinson's disease and contrasts with the greater depletion in caudate seen after MPTP. Aged monkeys of this species reflect many facets of Parkinson's disease, but like older humans do not improve with standard dopamine replacement pharmacotherapies.

Existing technologies to reduce specific toxicant emissions in cigarette smoke.

BACKGROUND: The World Health Organization Tobacco Product Regulation (TobReg) study group has proposed emissions level performance standards for nine toxicants (NNN, NNK, acetaldehyde, acrolein, 1,3-butadiene, CO, BaP, benzene and formaldehyde, all expressed as micrograms per milligram nicotine as measured under the Canadian intensive method) in cigarette smoke for parties to the FCTC in conjunction with regular monitoring of emissions of nine other toxicants of interest, nicotine and nicotine-free dry particulate matter (NFDPM, or "tar"). METHODS: We examined the published literature and publicly available tobacco industry documents to determine the extent to which existing available technologies can be applied to reduce the emissions of the specified toxicants in cigarette smoke. RESULTS: Agricultural practices (for example, fertilisers, curing), plant characteristics (for example, protein content, nicotine content), tobacco blending (for example, American blend vs Virginia blend) and cigarette design (for example, additives, filters, paper) issues all have roles in the generation and reduction of specific smoke toxicants. The tobacco industry has explored a number of technologies, including selective filtration, changes to curing practices and rod additives to reduce specific toxicants. CONCLUSIONS: Technologies exist to reduce the toxicants identified by TobReg. The extent to which the industry is able to simultaneously reduce toxicants, however, is unknown.

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation.

The vast majority of cancer cells have defective checkpoints that permit the cell cycle to progress in the presence of double-strand DNA breaks (DSBs) caused by ionizing radiation (IR) and radiomimetic drugs. ATR (ataxia telangiectasia-mutated and Rad3-related) has recently been shown to be activated by DSBs, although the consequences of this activity are largely unknown. In this report, we use advanced gene targeting methods to generate biallelic hypomorphic ATR mutations in human colorectal cancer cells and demonstrate that progression of the cancer cell cycle after IR treatment requires ATR. Cells with mutant ATR accumulated at a defined point at the beginning of the S phase after IR treatment and were unable to progress beyond that point, whereas cells at later stages of the S phase during the time of irradiation progressed and completed DNA replication. The prolonged arrest of ATR mutant cancer cells did not involve the ataxia telangiectasia mutated-dependent S-phase checkpoint, but rather closely resembled a previously characterized form of cell cycle arrest termed S-phase stasis. As ATR strongly contributed to clonogenic survival after IR treatment, these data suggest that blocking ATR activity might be a useful strategy for inducing S-phase stasis and promoting the radiosensitization of checkpoint-deficient cancer cells.

A study of recrystallization in single-phase aluminium using in-situ annealing in the scanning electron microscope.

In-situ annealing experiments were performed in the scanning electron microscope on a single-phase Al-0.13Mg alloy cold rolled to different strain levels. Once the validity of the technique had been verified by comparison of the recrystallization kinetics and final grain size with bulk annealed samples, the method was used in combination with electron back-scattered diffraction (EBSD) to study the potential mechanisms for recrystallization in this alloy. During annealing of material rolled to moderate strains (epsilont < 0.7), the primary mechanism was strain-induced boundary migration (SIBM). In material rolled to higher true strains (epsilont > 1.4), recrystallization occurred extensively along pre-existing cube bands and EBSD measurements showed that the mean size of cells within the cube bands was larger than for all other orientations measured, suggesting a size advantage was responsible for the strengthening of cube texture during recrystallization. SIBM was shown to occur concurrently with the nucleation along cube bands but this contributed a lower proportion of nucleation sites during recrystallization.

Characterizing the deformed state in Al-0.1 Mg alloy using high-resolution electron backscattered diffraction.

The application of high resolution electron backscatter diffraction (EBSD) in a field emission gun scanning electron microscope to the characterization of a deformed aluminium alloy is discussed and the results are compared with those obtained by transmission electron microscopy. It is shown that the adequate spatial resolution, accompanied by the improvement in angular resolution to approximately 0.5 degrees that can be achieved by data processing, together with the extensive quantitative data obtainable, make EBSD a suitable method for characterizing the cell or subgrain structures in deformed aluminium. The various methods of analysing EBSD data to obtain subgrain sizes are discussed and it is concluded that absolute subgrain reconstruction is the most accurate.

Orientation averaging of electron backscattered diffraction data.

The use of data averaging to improve the angular precision of electron backscattered diffraction (EBSD) maps is discussed. It is shown that orientations may be conveniently and rapidly averaged using the four Euler-symmetric parameters which are coefficients of a quaternion representation. The processing of EBSD data requires the use of an edge preserving filter and a modified Kuwahara filter has been successfully implemented and tested. Three passes of such a filter have been shown to reduce orientation noise by a factor of approximately 10. Application of the method to deformed and recovered aluminium alloys has shown that such data processing enables small subgrain misorientation (< 0.5 degrees ) to be detected reliably.

Photosynthesis and Stomatal Conductance of Potato Clones (Solanum tuberosum L.) : Comparative Differences in Diurnal Patterns, Response to Light Levels, and Assimilation through Upper and Lower Leaf Surfaces.

A few potato clones, such as A6948-4, had higher rates of photosynthesis in the field than the Russet Burbank and were able to maintain higher rates not only during mid-day but also in the early morning and late evening hours. In addition, they maintained higher carbon assimilation rates over a range of photosynthetic photon flux density from 400 to 2,000 microeinsteins per square meter per second.Stomatal conductance increased linearly as irradiance increased from 500 to 2,000 microeinsteins per square meter per second with all four potato clones that were examined. Obviously, comparative measurements of stomatal conductance or diffusive resistance with potato must be taken at a known and constant photosynthetic photon flux density.The upper (adaxial) leaf surface of some potato clones provided a surprising contribution to total carbon assimilation. Neither stomatal conductance, number of stomata per unit area, total area of the stomatal apparatus, nor chlorophyll content appear to account for differences in carbon assimilation rates among clones.

99Tcm-diphosphonate scanning as an aid to diagnosis of infection in total hip joint replacements.

Local infection following total hip joint replacement is often difficult to diagnose. Bone scanning with 99Tcm-diphosphonate has been used in an attempt to detect such infection by assessing uptake of 99Tcm in the hip. Posterior view dot scans of patients with total hip joint replacements were analysed quantitatively to determine the ratios of dots in regions around the acetabular, trochanteric and femoral parts of the prosthesis compared with normal bone. The scans were also assessed visually. Patients with definite evidence of infection showed higher uptake than control patients. The clearest distinction in uptake between the two groups was in the femoral shaft region. The data from these two groups of patients were used to propose diagnostic criteria for detecting abnormalities on scans. These criteria were applied to scans of a third test group of patients who had painful hips, but no definite evidence of infection. The numerical method of analysis is less subjective and may therefore be preferable as a means of providing evidence for or against a diagnosis of infection in patients with painful hip replacements.

Serum digoxin levels in neonates, infants and children with heart disease.

Serum digoxin levels were measured in 53 neonates and infants receiving 18-22 microgram/kg/day (high dose) oral maintenance digoxin, and 44 neonates, infants and children receiving less than 18 microgram/kg/day (low dose) oral maintenance digoxin. In both groups, patients under four months of age had significantly higher serum digoxin levels than older patients, in the high dose group 2.6 ng/ml compared with 1.4 ng/ml and in the low dose group 2.2 ng/ml compared with 1.0 ng/ml. Correlation between digoxin dosage and serum level was weak and unaffected by blood urea level. Only two patients in the entire series showed toxic manifestations. Sixteen patients had serum digoxin levels measured before and after corrective cardiac surgery while receiving comparable dosages of digoxin. Despite lower serum digoxin levels postoperatively pulse rates fell significantly, illustrating the influence of changing haemodynamic status on the inter-relationships of digoxin dosage, serum levels and clinical response. Recommended dosage regimens are outlined.

The effect of verapamil on experimental myocardial ischaemia with a particular reference to regional myocardial blood flow and metabolism.

The effects of verapamil on epicardial ST segment elevation, regional myocardial metabolism and collateral blood flow were studied in open-chest anesthetized dogs following left anterior descending coronary artery occlusion. Collateral blood flow was measured by radioactive microspheres (15 +/- 5 micron diameter) and regional metabolism was studied by measuring lactate concentration in venous blood draining the infarcting myocardium. Verapamil (0-2 mg/kg intravenously) produced a significant reduction (50-60%) in the epicardial ST elevation when it was given before coronary occlusion; when administered 15 minutes after coronary occlusion and infusion continued for two hours, it minimized (30-40%) ST segment elevation, and prevented the fall in cardiac index and rise in systemic resistance found in the untreated animals in which the ST segment remained persistently elevated. Changes in epicardial ST segment occurred without alterations in the QRS duration. Verapamil had no effect on either the total collateral blood flow or the relative distribution of flow to the endocardial and epicardial halves of the ischemic ventricular myocardium. No significant differences were found between the levels of lactate in blood sampled from small epicardial veins at the center of the infarct when the control animals were compared with those treated with verapamil.

Distribution of yttrium 90 ferric hydroxide colloid and gold 198 colloid after injection into knee.

Thirteen knees were injected with yttrium 90(90Y) ferric hydroxide colloid, and 12 with gold 198(198Au) colloid for treatment of persistent synovitis. Retention in the knee and uptake in lymph nodes and liver were measured by a quantitative scanning technique. There was no significant difference in the retention in the knee of the two different colloids. A tendency towards higher lymph node uptake was observed with 198Au compared with 90y. The inflammatory activity of the knee at the time of treatment may have influenced the subsequent lymph node uptake of 198Au, but not that of the 90Y, nor the overall leakage of either from the knee. 90Yferric hydroxide colloid was retained in the treated knee at least as well as other colloids which have been used for this purpose.

The effects of isoprenaline on epicardial ST-segment elevation, lactate production, and myocardial blood flow following coronary artery ligation.

Isoprenaline was infused at low and high rates into anaesthetized dogs after ligation of the left anterior descending coronary artery, the resultant changes in epicardial ST-segment elevation being compared with lactate production and myocardial blood flow in the infarcting myocardium. Although ST elevation was increased at both infusion rates, there was no change in the arterial-local coronary venous difference of lactate concentration nor in myocardial blood flow at the centre of the infarct. The results suggest that the relationship between epicardial ST-segment elevation and other indices of ischaemic myocardial injury is complex and requires further evaluation.

Effects of amiodarone on thyroid function in patients with ischaemic heart disease.

Thyroid function was evaluated clinically and biochemically in 12 patients with ischaemic heart disease receiving 200 mg oral amiodarone three times daily for periods up to 6 weeks. During drug administration, no patient developed clinical or laboratory evidence of hypothyroidism, but serum levels of T3 tended to fall and those of T4 increased but not to levels outside the normal range. Amiodarone produced a significant reduction in heart rate with prolongation of the QTc interval of the electrocardiogram without altering either the PR interval or the QRS duration. These effects of the drug were still present 4 weeks after cessation of treatment. In spite of the high iodine content, amiodarone does not, therefore, depress thyroid function to any important degree during chronic administration and its antianginal action does not appear to be caused by the production of generalized hypothyroidism.

Cobalt chloride in the treatment of refractory anaemia in patients undergoing long-term haemodialysis.

The effect of oral cobalt chloride on the anaemia of patients undergoing long-term haemodialysis therapy was investigated in 14 patients taking 25 mg then 50 mg daily. After eight weeks of treatment the mean haematocrit increase in 11 patients completing the trial was 23% of the original level and the 51Cr-red cell volume had increased by 20%. The 51Cr red half-life lengthened after treatment in six patients and the 59Fe plasma half-time shortened in ten patients. After treatment, evidence of increased erythropoietic activity was seen in the bone marrow of five patients. No evidence was found of thyroid of liver dysfunction but three patients developed transient loss of hearing demonstrated by audiometry. Cobalt chloride appears to be helpful in the management of some uraemic patients with refractory anaemia.

Changes in myocardial blood flow and S-T segment elevation following coronary artery occlusion in dogs.

The relationship between regional blood flow and epicardial S-T segment elevation was studied in 26 open-chest anesthetized dogs with left anterior coronary artery ligations. Changes in myocardial blood flow, measured with 15 plus or minus 5mu (diameter) microspheres labeled with 141-Ce, 85-Sr, and 169-Yb, were correlated with summated S-T segment elevations 15 minutes, 1 hour, and 2 hours after coronary artery occlusion. In normal areas, myocardial blood flow was 113 plus or minus 5 ml/min 100 g- minus 1 and summated S-T segment elevation was 0.3 plus or minus 0.2 mv. Fifteen minutes after coronary artery occlusion in 26 dogs, S-T segment elevation was 5.7 plus or minus 0.7 mv over the center of the infarct and myocardial blood flow was 10 plus or minus 1 ml/min 100 g- minus 1; over the border zone, myocardial blood flow was 63 plus or minus 4 ml/min 100 g- minus 1 and S-T segment elevation was 3.1 plus or minus 0.1 mv. One third of the areas with a myocardial blood flow of 10 ml/min 100 g- minus 1 or less had no S-T segment elevation. In the center and border zones of the infarct in 9 dogs, myocardial blood flow increased from 11 plus or minus 2 and 67 plus or minus 8 ml/min 100 g- minus 1 15 minutes after occlusion to 20 plus or minus 4 and 84 plus or minus 12 ml/min 100 g- minus 1, respectively, 2 hours after coronary artery occlusion. These increases were not associated with a significant reduction in summated S-T segment elevation. The results do not suggest a simple quantitative relationship between epicardial S-T segment elevation and myocardial blood flow following acute coronary artery occlusion.

Red cell and plasma volumes in normal adults.

Despite numerous published methods for predicting normal red cell and plasma volumes, little is known of the range of normal in subjects of given body dimensions. In this study, reported results of red cell and plasma volumes in 481 normal men and 303 normal women have been used to calculate mean volumes and standard deviations (s.d.) for any given body surface area (male and female results being kept separate). All of these mean volumes, each plus or minus 2 s.d., have been plotted against body surface area. The resulting graphs of means and 95% confidence limits have tended to be curvilinear. Standard deviations have increased with increasing mean volumes, but coefficients of variation (s.d./mean) have shown considerable constancy at 11-12%. The mean values observed in this series have often differed substantially from those predicted from published formulas. Use of the presently observed means with the 11-12% coefficients of variation allows compilation for any surface area of a range of normal against which a clinically obtained volume can be compared.