Local structure investigation of Co-Fe-Si-B ribbons by extended X-ray absorption fine-structure spectroscopy.

In the present work, extended X-ray absorption fine-structure (EXAFS) investigations of Co69FexSi21-xB10 (x = 3, 5, 7) glassy ribbons were performed at the Co K-edge. The magnitude of the first peak of the Fourier transforms of the EXAFS signals is found to increase monotonically with increasing Si concentrations indicating the formation of the localized ordered structure at the atomic scale. The Co-Si coordination number (CN) increases at the expense of the CN of Co/Fe. Smaller interatomic distances are observed in the glassy phase compared with that in the crystalline phase which promotes the stability of the glassy phase. Calculations of the thermodynamic parameter (PHSS), cohesive energy (EC) and the atomic radius difference (δ) parameter show that the alloy composition Co69Fe3Si18B10 has a good glass-forming ability (GFA) with the highest CN of Si compared with other compositions. A linear correlation of CN with that of the GFA parameter (PHSS) exists and the CN also plays a crucial role in the GFA of the glassy alloys. This parameter should be considered in developing different GFA criteria.

Caloric restriction mimetic 2-deoxyglucose maintains cytoarchitecture and reduces tau phosphorylation in primary culture of mouse hippocampal pyramidal neurons.

Typical form of neurons is crucially important for their functions. This is maintained by microtubules and associated proteins like tau. Hyperphosphorylation of tau is a major concern in neurodegenerative diseases. Glycogen synthase kinase3ß (GSK3ß) and cyclin-dependent protein kinase 5 (Cdk5) are the enzymes that govern tau phosphorylation. Currently, efforts are being made to target GSK3ß and Cdk5 as possible therapeutic avenues to control tau phosphorylation and treat neurodegenerative diseases related to taupathies. In a number of studies, caloric restriction mimetic 2-deoxyglucose (C6H12O5) was found to be beneficial in improving the brain functions. However, no reports are available on the effect of 2-deoxyglucose 2-DG on tau phosphorylation. In the present study, hippocampal pyramidal neurons from E17 mouse embryos were isolated and cultured on poly-L-lysine-coated coverslips. Neurons from the experimental group were treated with 10 mM 2-deoxyglucose. The treatment of 2-DG resulted in healthier neuronal morphology in terms of significantly lower number of cytoplasmic vacuoles, little or no membrane blebbings, maintained axon hillock and intact neurites. There were decreased immunofluorescence signals for GSK3ß, pTau at Ser262, Cdk5 and pTau at Ser235 suggesting decreased tau phosphorylation, which was further confirmed by Western blotting. The results indicate the beneficial effects of 2-DG in controlling the tau phosphorylation and maintaining the healthy neuronal cytoarchitecture.

Developing a strategic marketing plan for physical and occupational therapy services: a collaborative project between a critical access hospital and a graduate program in health care management.

The purpose of this study was to develop a marketing plan for the Physical and Occupational Therapy (PT/OT) department at a Critical Access Hospital (CAH). We took the approach of understanding and analyzing the rural community and health care environment, problems faced by the PT/OT department, and developing a strategic marketing plan to resolve those problems. We used hospital admissions data, public and physician surveys, a SWOT analysis, and tools to evaluate alternative strategies. Lack of awareness and negative perception were key issues. Recommended strategies included building relationships with physicians, partnering with the school district, and enhancing the wellness program.

Patient compliance with prolonged low-dose oral etoposide for small cell lung cancer.

Using an 'intelligent' tablet bottle which, unknown to the patient, electronically records the times of opening we have assessed the compliance of patients with prescribed oral medication. The compliance pattern of 12 patients receiving low dose etoposide for small cell lung cancer was monitored over 25 treatment periods, representing a total of 298 days. The data were expressed as overall compliance (OC), defined as the observed number of bottle openings as a percentage of the prescribed number of doses, and as two indices representing daily and hourly irregularities in the times of opening. The OC had a mean (+/- s.d.) value of 93.2% (+/- 12%) over the 25 treatment periods, and is similar to that which we have reported in a group of lymphoma patients (Lee et al., 1992). By means of a self assessed diary card we monitored the physical and mental state of the patients. Although we found significant associations between the compliance measures and some of the diary card measures, the magnitude of the observed effects would be of little practical consequence. We conclude that, in our group of patients, inadequate compliance with oral chemotherapy would not account for any significant lack of clinical response.

Patient compliance with oral chemotherapy as assessed by a novel electronic technique.

PURPOSE: Previous reports have suggested low rates of compliance with the oral component of cancer chemotherapy, which, if confirmed, would have serious implications on treatment. Because of the uncertainties in the methodology used in previous studies, we have assessed compliance with a novel technique. PATIENTS AND METHODS: An "intelligent" tablet bottle was used, which, unknown to the patient, electronically records the times of opening over a period of weeks. The records were scored for overall compliance (total number of bottle openings as a percentage of the prescribed number) and for daily and hourly irregularity indices. Twenty-one patients undergoing treatment for Hodgkin's or non-Hodgkin's lymphoma were monitored for a total of 65 treatment periods, each of up to 2 weeks (852 days in total). Eight measures of side effects and quality of life were self-assessed daily by the patients using a diary card. RESULTS: The overall compliance was 100.6% +/- 20.6% (mean +/- SD). Overall compliance was lower (mean reduction, 10%) in treatment periods with drugs prescribed to be taken three times a day. It was not possible to demonstrate convincingly any relationship between compliance and any of the following: drug type, monitoring period sequence, the diary card scores of side effects and quality of life, number of relapses, and time since initial diagnosis. CONCLUSION: These results are reassuring, but further work is in progress to measure compliance in other treatment regimens in which the side effects are more severe and the prognosis is worse.

Effect of captopril on functional, physiological and biochemical outcome criteria in aged heart failure patients.

1. Captopril was evaluated as an adjuvant to diuretic and digoxin therapy in heart failure in old age, using walking ability, minute ventilation and oxygen consumption and plasma atrial natriuretic factor (ANF) concentration as measures of outcome. 2. Twenty patients, mean (s.d.) age 81 (6) years, entered a double-blind, randomised, crossover study of three treatments, a twice daily regimen of captopril (AA), at a dosage established by titration against serum angiotensin converting enzyme (ACE) activity, the same dosage in the morning with placebo at night (AP), and twice daily placebo (PP). Each treatment lasted 3 weeks. A 2 week run-in period on triple therapy, with AA captopril, was used to assess stability and compliance. Seventeen completed all treatments: three completed two. 3. Any benefit of captopril was modest and there was deterioration in gait on the titrated dosage 3 months afterwards (P = 0.04). Efficacy in the old may be greatest when the titrated dose (25 or 50 mg) is given once daily: the multiple daily doses recommended may be unnecessarily demanding. 4. Walking performance was measured by gait analysis (GA) at free walking speed and by a simple walking test (SWT), in which patients stopped at the first relevant symptom. There was a consistent tendency for four measures of performance (GA: speed, stride length and double support time; SWT distance) to be best on the AP treatment, next best on AA, and worst on PP but for the fifth, SWT speed, AP and AA were similar. The trend appeared most marked for SWT distance, mean (s.e. mean) values for AP, AA and PP being 123 (15), 94 (16) and 75 (16) m, respectively. However, the treatment effect did not reach statistical significance at the 0.05 level. 5. There was no significant difference between treatments in minute ventilation, minute oxygen consumption, or their ratio, either at rest or on exercise. 6. Resting ANF concentrations were nearly four times higher (P = 0.0001) in the patients than those, mean (s.e. mean) 66 (5) pmol l-1, in eleven healthy volunteers of mean age 80 (6) years, and the increase on exercise, seen in the controls (P less than 0.01), was absent. In the patients the resting plasma ANF concentration was significantly affected by treatment (P = 0.03), being less on both AP, 245 (9), and AA, 214 (9) than on PP, 264 (10) pmol l-1 (P = 0.02 and 0.03, respectively). 7. Baseline serum ACE activity was induced on active treatment. The change in ACE activity at 3 h post an active dose was significantly greater on AP than AA (P = 0.005). The increased sensitivity to inhibition during once daily administration was reflected in mean arterial pressure. The pre-dose standing pressure was less on AP than on PP (P less than 0.05), and the change in postural fall (pre-dose minus 2 h post), was greater (P = 0.004), but AA and PP were similar in these respects.(ABSTRACT TRUNCATED AT 400 WORDS)

Objective outcome criteria in trials of anti-parkinsonian therapy in the elderly: sensitivity, specificity and reliability of measures of brady- and hypo-kinesia.

1. We compare the sensitivity and specificity of chosen outcome criteria in a placebo-controlled, randomised cross-over study of the efficacy of maintenance therapy with the levodopa/carbidopa combination (Sinemet Plus) alone. Patients were characterised by having idiopathic Parkinsonism with no overt fluctuations in control in relation to individual doses of medication. 2. The effect of omission of a morning dose of maintenance therapy on simple timed tests of mobility and manual dexterity, and on distance/time parameters of gait was studied in fourteen patients (aged 64 to 88 years). Measurements made 2, 4 and 6 h after morning active and placebo treatments were standardised by taking the pre-treatment measurement on that day as baseline. 3. In a linear model, which allowed for the structure of the study, neither the total time taken by each patient to get up from a chair, walk an individually set distance, turn, return to and sit in the chair, nor the rate of progress at fastening the same set of buttons, was sensitive to the treatment effect. 4. Three of the gait parameters, free walking speed, mean stride length and mean double support time, were sensitive to the treatment effect. Correction for the speed of each walk, caused some reduction in the sensitivity of stride length to treatment effect, but that of double support time remained. Speed, and double support time or stride length, appeared to be complementary in defining the treatment effect. 5. The linear modelling revealed the complexity of the treatment effect. Although active treatment, by comparison with placebo, increased free walking speed (P = 0.019), the more levodopa found in the plasma following treatment, (P = 0.0005) and the greater the increment in the concentration of its peripheral metabolite, 3-O-methyldopa (P = 0.006), the less the beneficial effect. This model may reflect reduced uptake into the brain and/or an adverse effect of parent drug or a metabolite. 6. The specificity of free walking speed for the treatment effect was good, as was that of mean stride length, after it had been corrected for speed of each walk, and of mean double support time, after correction for speed and incorporation of the change in lying blood pressure accompanying treatment into the model. 7. The measurements of gait parameters were ranked according to reliability.(ABSTRACT TRUNCATED AT 400 WORDS)

Capsules for frozen sectioning of small specimens.

It was necessary to make sections of small unfixed specimens which had been frozen while still immersed in their normal culture medium. The principal difficulty stemmed from the poor sectioning quality of the frozen culture medium. A capsule is described which has a narrow well in which the tissue specimen fits snugly within a small amount of culture medium. After freezing, the whole capsule is sectioned and the resulting sections, being nearly devoid of culture medium, are of good quality.

Effect of duration of levodopa/decarboxylase inhibitor therapy on the pharmacokinetic handling of levodopa in elderly patients with idiopathic Parkinson's disease.

We address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinson's disease experience a fall off in benefit from levodopa maintenance therapy. Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after. There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30 MD]/AUC, did so at the 0.01 level. The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of gait in the elderly parkinsonian on maintenance levodopa/carbidopa therapy.

1. We have used gait analysis to investigate the efficacy of maintenance therapy with a levodopa/carbidopa combination in patients with idiopathic Parkinsonism, who do not have overt fluctuations in control in relation to administration of medication. 2. Fourteen patients (aged 64 to 88 years) receiving maintenance therapy with levodopa and carbidopa (Sinemet Plus) entered a placebo-controlled, randomised cross-over study of the effect of omission of a morning dose of active treatment on distance/time parameters of gait. Measurements made 2, 4 and 6 h after the morning treatment were standardised by taking the pre-treatment measurement on that day as baseline. 3. The mean increase in stride length (7%) and decrease in double support time (20%) on active treatment were small but statistically significant (P less than 0.0001, in each case), there being no significant placebo effect on either gait parameter (P = 0.69 and 0.08 respectively). Neither active nor placebo treatments had any significant (P greater than 0.45 in each case) effect on the lying, standing or postural fall in mean arterial pressure, measurements being made in the same temporal relation to the treatments as was gait. 4. In a generalised linear model, after allowing for the effect (P less than 0.0001) of intrinsic variability in pre-treatment speed as well as for structure of the study, nature of treatment had an effect on stride length over the whole walk, significant at P = 0.002. 5. Pre-treatment postural fall in mean arterial pressure was nearly as significant (P = 0.003) as the nature of treatment in the context of such a model: the greater the fall, the greater the increment in stride length seen following active or placebo treatment. This was probably explained by an acquired tolerance to the fall as the day progressed. 6. The major determinant (P less than 0.0001) of the change in double support time over the whole walk, after allowing for the structure of the study, appeared to be the post treatment mean arterial standing blood pressure. The lower the pressure, the shorter the double support time, and hence, the greater the tendency to a hurried gait. 7. Nature of treatment, when added into the models described in summary points 5 and 6, had no significant effect (P greater than 0.25, in each case).(ABSTRACT TRUNCATED AT 400 WORDS)

Screening for aminoglycoside auditory toxicity in the old.

1. We have investigated 22 patients receiving gentamicin, mean (s.d.) age 78 (6) years for auditory toxicity, using a standard audiometric technique in a sound-treated room (Study 1). 2. Use of a portable audiometer might allow a larger and more representative proportion of patients treated with aminoglycosides to be screened for ototoxicity. A method for detecting high frequency loss suitable for use in the ward was evaluated in 12 volunteers aged 27 (4) years (Study 2). 3. The error inherent in taking hearing at the start of treatment as a reference point was measured in 16 patients, aged 81 (8) years, prescribed non-ototoxic antibacterials (Study 3). 4. A significant (P = 0.05) reduction in hearing threshold was detected in Study 1, although psychometric tests revealed unchanged or improved ability to co-operate. This occurred only at 4000 Hz, the highest frequency used. The magnitude of this loss, mean 2.5 dB, was similar to that of the improvement in threshold detected (P = 0.0004) early in the course of treatment in Study 3. Thus, underestimation of ototoxicity is likely. 5. If a change of threshold of 10 dB or more is taken arbitrarily to represent a real change in hearing, then there was a significant excess of patients in Study 1 with losses at 4000 Hz only (P = 0.032). The six with such losses at this frequency were older than the rest. However, there was a significant (P less than 0.02) positive correlation between log mean predose serum gentamicin concentration and age. Thus, it remains to be determined whether presbyacusis sensitizes those hair cells which it does not destroy to toxic damage. 6. The cumulative dose of gentamicin (for a course of the duration given) was calculated according to published prescribing aids. There was no systematic reduction in the ratio of the dose recommended by a given aid to the dose prescribed in the six with hearing losses as defined above. 7. In Study 2, thresholds obtained at 6000 Hz in the open ward were, on average, 0.9 dB higher than in the sound treated room, but the effect of venue did not reach statistical significance. In the morning thresholds were marginally, but significantly (P = 0.04), lower than in the afternoon. Precision, as measured by the standard deviation of replicate determination, was independent of test conditions. Using multiple (ten) threshold determinations appeared to improve resolution.(ABSTRACT TRUNCATED AT 400 WORDS)

Parkinsonian abnormality of foot strike: a phenomenon of ageing and/or one responsive to levodopa therapy?

1. Normally during walking, the heel strikes the ground before the forefoot. Abnormalities of foot strike in idiopathic Parkinson's disease may be amenable to therapy: objective measurements may reveal response which is not clinically apparent. Occult changes in foot strike leading to instability may parallel the normal, age-related loss of striatal dopamine. 2. The nature of foot strike was studied using pedobarography in 160 healthy volunteers, aged 15 to 91 years. Although 16% of strikes were made simultaneously by heel and forefoot, there were no instances of the forefoot preceding the heel. No significant effect of age on an index of normality of foot strikes was detected (P greater than 0.3). 3. The effect on foot strike of substituting placebo for a morning dose of a levodopa/carbidopa combination was studied in a double-blind, cross-over trial in 14 patients, aged 64 to 88 years, with no overt fluctuations in control of their idiopathic Parkinson's disease in relation to dosing. On placebo treatment there was a highly significant (P = 0.004) reduction in the number of more normal strikes, i.e. heel strikes plus simultaneous heel and forefoot strikes. The effect appeared unrelated to the corresponding difference between active and placebo treatments in plasma concentration of levodopa or a metabolite of long half-time, 3-O-methyldopa (3OMD). However, it correlated negatively (P less than 0.05) with the mean of the 3OMD concentrations. 4. It appears that some abnormalities of foot strike due to Parkinson's disease are reversible. Employing test conditions, designed to provoke abnormalities of foot strike, might be useful in screening for pre-clinical Parkinson's disease.

The paradox of using a 7 day antibacterial course to treat urinary tract infections in the community.

1. We have studied determinants of outcome of 7 day courses of treatment in 77 middle aged and elderly patients, in whom the general practitioner's diagnosis of urinary tract infections had been confirmed microbiologically. Bacteria were sensitive to cephalexin or trimethoprim. Where there was no preference, treatments were allocated randomly. Compliance was monitored using a pill box with a concealed electronic device which recorded openings of the box. 2. Prescribing trimethoprim, 200 mg twice daily, was more effective than cephalexin, 250 mg four times daily (cure rates 93 and 67%) (P less than 0.006). Those cured and not cured were not distinguished by age, gender, genitourinary history, or infecting organism. 3. Compliance as measured by box openings was worse for cephalexin than for trimethopim (P = 0.01). However, both totality and pattern of compliance were similar in patients cured and not cured by cephalexin. Thus rigid adherence to a conventional course did not promote cure: fewer doses could have been prescribed. 4. Estimating compliance is essential to clinical trials where medication is self-administered. Poor compliance may establish over exacting regimens. Counting box openings did overestimate compliance, but counting residual tablets overestimated it grossly: given the number of openings less than the ideal, there should have been 171 residual tablets, only 55 were found.

Pressure sores: effect of Parkinson's disease and cognitive function on spontaneous movement in bed.

It has previously been shown that the incidence of pressure sores is related inversely to the amount of movement made during the night. The present study of 30 in-patients of geriatric units suggests that the measurement of mean lateral displacement of the centre of gravity may better characterize those at risk than the total amount of movement. The mean displacement was reduced in Parkinson's disease and in dementia. The prevalence of pressure sores was markedly increased where Parkinson's disease and dementia coexisted.

Compliance with anti-tuberculous therapy: a field trial of a pill-box with a concealed electronic recording device.

We have conducted a field trial of a pill-box containing a concealed electronic device for monitoring compliance in 23 consecutive adult out patients taking a rifampicin/isoniazid combination once daily. In 22 cases, the times when the box was opened were successfully recorded for the entire period (mean (SD) 26 (5) days) between successive clinic visits. In the other patient the record terminated after one week, a broken box being returned. Both totality of compliance (as assessed by box openings) and consistency of compliance (the proportion of the total number of intervals between openings which were of 22 to 26 h in length) were significantly greater in those studied in the intensive than in the maintenance phase of therapy. Patients may have taken the reduction in medication at the end of the intensive phase as signalling cure. A computer program has been developed to display the recorded data. This allowed the physician responsible to assimilate at a glance the patient's tablet-taking habits. In routine practice knowledge of the presence of the device may improve compliance and a discussion of the graphical display may prove of value in counselling.

Prescribing digoxin in geriatric units--exercise and redistribution of drug.

In subjects capable of normal everyday activity, exercise has been shown to lower the serum digoxin concentration by increasing uptake into skeletal muscle. A randomized cross-over study of the effect on the serum digoxin concentration of treatments consisting of rest for, or exercise during, 30 min was carried out in 20 elderly patients undergoing rehabilitation. In one patient exercise was associated with a marked (40%) reduction in the serum digoxin concentration. In the remainder there was a very small, but statistically significant, fall in concentration in the exercise as compared with the rest period. Unexpectedly low serum digoxin concentrations in in-patients of geriatric units, may occasionally be an artefact due to temporary redistribution of digoxin.

Parkinson's disease in the elderly: response to and optimal spacing of night time dosing with levodopa.

1. Insomnia is an even more frequent complaint in elderly patients with Parkinson's disease than might be expected from the effect of age alone on sleep. 2. A double-blind, placebo-controlled trial in eleven patients with Parkinson's disease of mean (s.d.) age 80(5) years, showed that nocturnal dosing with levodopa produced a clinically significant improvement in sleep both as assessed subjectively and by measurement of number of spontaneous moves in bed. 3. Despite the long interval between tablet administration and morning assessment, walking time was faster on mornings following active treatment.

Prescribing digoxin in geriatric units: the unexplained variability in dosage requirements.

Some physicians regard patients of Geriatric Units as a homogeneous population with respect to digoxin dosage requirements. Others advocate the use of pharmacokinetic models in prescribing digoxin for the elderly. Sixty in-patients of Geriatric Units were studied and the results compared with those previously obtained from 129 patients of other adult Units; all were receiving maintenance digoxin. For each patient the dose required to achieve a mean steady-state serum digoxin concentration of 1.6 nmol X l-1, the standardized dose, was calculated, assuming proportionality between the dose given and the concentration achieved. A mean of four estimates of standardized dose for each individual was used in the analysis. Threefold ranges of standardized dose covered the requirements of approximately 85% of patients both of Geriatric Units (62.5 to 187.5 micrograms per day) and of other adult Units (125 to 375 micrograms per day). The variables, serum creatinine concentration, sex, age, and body weight were of relatively little value in predicting the standardized dose for the patients in Geriatric Units. There was a sub-group of these in-patients for whom the standardized dose was extremely large.

Evaluation of medigoxin in outpatients.

We compared our ability to predict the dose of medigoxin and of digoxin required to achieve a fixed serum concentration (the dose requirement) in 33 outpatients. Preliminary work supported the assumptions that the steady state glycoside concentration achieved was proportional to the daily dose given to an individual, and that the bioavailability of the different tablet presentations was similar for either glycoside. We were not able to predict the dose requirement from patient characteristics with any more certainty for medigoxin than for digoxin. Not only the between-patient variability in dose requirement, but also the within-patient variability, was similar for the two glycosides. However the digoxin used had a dissolution rate of over 90% in 1 h. When comparing medigoxin with digoxin of lower, or more variable dissolution rate, medigoxin may be preferable.