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The importance of drug scheduling and recovery phases in determining drug activity. Improving etoposide efficacy in BCR-ABL-positive CML cells.

K562 leukaemic cells are known to be less sensitive to etoposide than other cell lines, despite having similar topo II mRNA levels and cleavable complex formation. We have investigated the effect of etoposide schedule on cell cycle distribution, apoptosis and p21(waf1) and cdk1(p34) status in two bcr-abl-positive chronic myeloid leukaemia (CML) cell lines (K562 and KU812) and two small cell lung cancer (SCLC) cell lines (H69 and GLC4). During a continuous 5-day exposure, the SCLC cell lines showed a time and concentration-dependent loss of cell viability, with an initial block in the G2/M phase of the cell cycle followed by apoptosis. In contrast, the two CML cell lines showed no significant apoptosis or loss of viability after a similar block in G2/M. However, when K562 or KU812 cells were placed in drug-free medium following a 3-day drug exposure there was marked, concentration-dependent apoptosis (% apoptosis after release at 1 microM etoposide in K562, 10% at 24 h, 30% at 48 h). Our data also show that p21(waf1) does not increase after etoposide treatment in either H69 or GLC4 (both with mutated-p53). Although K562 and KU812 cells are null-p53, the arrest in G2/M during drug exposure was associated with increased p21(waf1) and a decrease in cdk1 (both P<0.001 compared with controls). Upon release of these cells from drug-medium, p21(waf1) gradually returned to control levels, which was associated with an easing of the block at G2/M and an induction of apoptosis. This study highlights the importance of cell cycle regulatory proteins in drug sensitivity and resistance, and suggests that in cells such as K562 and KU812, a pulsed schedule may be more active than a single prolonged exposure.

CDC2 Protein Kinase↗

Use of cluster analysis for gait pattern classification of patients in the early and late recovery phases following stroke.

The mixture of gait deviations seen in patients following a stroke is remarkably variable. An objective system for classification of gait patterns for this population could be used to guide treatment planning. Quantitated gait analysis was conducted for 47 individuals at admission to in-patient rehabilitation and again at 6 months post-stroke for 42 subjects. Non-hierarchical cluster analysis was used to classify the gait patterns of patients based on the temporal-spatial and kinematic parameters of walking. Four clusters of patients were identified at both assessment intervals. At the admission test walking velocity, peak knee extension in mid stance and peak dorsiflexion in swing were the three factors that best characterized the groups. At 6 months the explanatory variables were velocity, knee extension in terminal stance, and knee flexion in pre swing. Differences in muscle strength and muscle activation patterns during walking were identified between groups.

Adult↗

Left ventricular volumes in the recovery phase after myocardial infarction: relation to infarct location, left ventricular function and one-year cardiac mortality.

Absolute left ventricular volumes, normalized to body surface area, were determined by a count-based radionuclide technique in 189 patients with myocardial infarction (MI). All examinations were performed in the second week after MI. Fifty-three percent of the patients had an increased end-diastolic volume index (EDVI) and 72% an increased end-systolic volume index (ESVI). Patients with anterior MI had the same median EDVI as patients with inferoposterior MI, but significantly higher median ESVI and significantly lower median stroke volume index (SVI). SVI was subnormal in 19% of the 189 patients and left ventricular ejection fraction (LVEF) was subnormal in 67%. A non-linear, inverse relationship was present between EDVI and LVEF and between ESVI and LVEF, but LVEF varied greatly for any degree of ventricular dilatation. During a 1-year follow-up period, death from cardiac causes occurred in 29 patients. A strong relationship was present between the degree of ventricular dilatation and 1-year mortality, as well as between the degree of SVI or LVEF reduction and 1-year mortality but, next to clinical heart failure, LVEF was the single most powerful predictor of cardiac death, and various combinations of EDVI, ESVI and SVI did not add more prognostic information to that obtained by heart failure than did LVEF.

Aged↗

Persistent ionized hypocalcemia in patients during resuscitation and recovery phases of body burns.

Despite important physiological functions, the fluctuations in plasma ionized calcium concentrations [Ca++] after major thermal injury have not been defined. Measurements of [Ca++] were undertaken in 25 patients of age ranging from 6-75 years, with body surface area burns of 25-85%. Plasma total calcium [Ca], inorganic phosphorus [Pi] and magnesium [Mg++] were also followed. Urinary excretion of the same ions was quantified in nine patients for the first 6 days postburn. The control group consisted of 12 patients who had sustained a similar injury at least 16 months earlier. Significantly low [Ca++] persisted throughout the observation period, despite an average replacement of 0.2 mM/kg.day of CaCl2. The initial hypophosphatemia and hypermagnesemia tended toward normal during the latter phase of the injury. Urinary excretion of the of the cations was not significantly elevated in the first 6 days postburn. The usual reciprocal relationship between [Ca] and [pi] was not evident, and there was no correlation between [Ca++] and the size of burn. The use of McLean-Hastings nomogram poorly predicted the [Ca++] from [Ca]. Our data indicate that marked alterations in [Ca++] homeostasis occur after thermal injury. The etiology of hypocalcemia remains to be elucidated; the physiological consequences in terms of hemodynamic function deserve further study.

Adolescent↗

Distribution of 137Cs in soils due to the Goiânia accident and decisions for remedial action during the recovery phase.

In September 1987, a powder radioactive source was removed from a teletherapy machine in Goiânia, Brazil. Subsequently, it was ruptured in a residential garden causing the dissemination of 137Cs throughout the city. Soil resuspension processes and burial of contaminated house waste in unused gardens were the major contributors to the Cs dissemination in soils at the secondary contaminated sites. Only locations within a radius of 50 m from the primary contaminated sites presented the need for remedial action. The radiation dose-rate measurements and the soil profiles were good indicators of the extent of the secondary contamination and were fundamental for the decisions taken regarding decontamination procedures. In cases of surface contamination, 60% on average of the total activity remained in the upper 1.5-cm layer over the first 5 mo after the accident, and topsoil removal proved to be an effective procedure for decontamination.

Accidents↗

The role of extreme events in the impacts of selective tropical forestry on erosion during harvesting and recovery phases at Danum Valley, Sabah.

Ten years' hydrological investigations at Danum have provided strong evidence of the effects of extremes of drought, as in the April 1992 El Niño southern oscillation event, and flood, as in January 1996. The 1.5 km2 undisturbed forest control catchment experienced a complete drying out of the stream for the whole 1.5 km of defined channel above the gauging station in 1992, but concentrated surface flow along every declivity from within a few metres of the catchment divide after the exceptional rains of 19 January 1996. Under these natural conditions, erosion is episodic. Sediment is discharged in pulses caused by storm events, collapse of debris dams and occasional landslips. Disturbance by logging accentuates this irregular regime. In the first few months following disturbance, a wave of sediment is moved by each storm, but over subsequent years, rare events scour sediment from bare areas, gullies and channel deposits. The spatial distribution of sediment sources changes with time after logging, as bare areas on slopes are revegetated and small gullies are filled with debris. Extreme storm events, as in January 1996, cause logging roads to collapse, with landslides leading to surges of sediment into channels, reactivating the pulsed sediment delivery by every storm that happened immediately after logging. These effects are not dampened out with increasing catchment scale. Even the 721 km2 Sungai Segama has a sediment yield regime dominated by extreme events, the sediment yield in that single day on 19 January 1996 exceeding the annual sediment load in several previous years. In a large disturbed catchment, such road failures and logging-activity-induced mass movements increase the mud and silt in floodwaters affecting settlements downstream. Management systems require long-term sediment reduction strategies. This implies careful road design and good water movement regulation and erosion control throughout the logging process.

Ecosystem↗

Significance of ventricular ectopic activity in the early recovery phase of acute myocardial infarction.

Holter monitoring of 51 patients on the 4th to 6th day after acute myocardial infarction (AMI) disclosed complex ventricular ectopic beats in 17 (35%), nine of whom (53%) died in the following 26 months. Of the remaining patients with no or only non-complex ectopic beats, five (15%) died. The difference was significant using Gehan's test of censored data (p less than 0.01). Multivariate analysis demonstrated a significant increase of death risk associated with complex ventricular ectopic beats as well as with heart failure (relative risk 3.6 and 5.9, respectively). Age, gender, number of ventricular ectopic beats, cardiac enlargement on X-ray and angina pectoris had no significant effect on mortality. The prevalence of ventricular ectopy was 84% (n = 43) irrespective of age and sex and equal to the finding in the late hospital phase reported by other investigators, and in healthy subjects. Complex ventricular ectopic beats appeared in 35% (n = 17). The prevalence increased significantly with age and was significantly higher in post-infarction patients (38%) than in healthy individuals (8%). The present results indicate that a subgroup containing most of the high-risk patients may be identified early after AMI by detecting complex premature ventricular beats in continuous electrocardiographic recordings.

Adult↗

Severe illness in older patients: the association between depressive disorders and functional dependency during the recovery phase.

An association between depression and physical dependency arising from a recent illness has been generally accepted. To clarify this relationship over time, 30 medical rehabilitation patients aged 54 to 94 years were assessed 1 week after admission and at discharge to quantify symptoms of depression, physical dependency, and cognitive functioning using the Hamilton Depression Scale (HAM-D), the Geriatric Depression Scale (GDS), the Barthel Index for physical function, and the Mini-Mental State Examination (MMSE). Significant depressive symptomatology was found by HAM-D in 25 patients on admission and 14 on discharge. No significant associations were present between either admission or discharge depression scores and all other variables. The HAM-D change score was significantly correlated with the Barthel change score (r = 0.57, P less than 0.001) and with the MMSE change score (r = 0.48, P = 0.01). All patients whose mood improved also improved in physical functioning, whereas 75% of those whose mood did not improve failed to make headway in physical functioning. This implies that it is not the degree of physical incapacity but rather the failure to regain prior abilities which is strongly associated with persisting depression following a catastrophic illness. Furthermore, characteristics found commonly in the group whose mood did not improve included physicians' failure to diagnose and treat depression or a setback from a significant medical or surgical complication.

Aged↗

Dietary effects in the early recovery phase of kwashiorkor. Plasma levels of triglycerides, FFA, D-beta-hydroxybutyrate, glycerol, postheparin lipoprotein lipase (LPL), glucose and insulin.

The fatty liver often found in untreated kwashiorkor has been associated with highly variable concentration of circulating lipids. The effect on lipid metabolism of two isocaloric diets--one synthetic monomolecular (Vivonex) and one standard (Casilan)--which both initiated satisfactory clinical improvement was studied in 21 Ethiopian children with kwashiorkor during the first weeks of rehabilitation. Before treatment mean fasting values of all biochemical parameters were within normal ranges except for moderately elevated triglycerides--an unexpected finding-and low insulin. Individual values varied greatly; triglyceride between 0.39 and 3.49 mmol/1. FFA correlated both to glycerol, D-beta-hydroxybutyrate and triglyceride values. During treatment insulin, glucose and glycerol remained essentially unchanged and were similar in both dietary groups. In the Vivonex group only there was an initial marked, parallel fall of FFA and D-beta-hydroxybutyrate suggesting greater availability of carbohydrate and enhanced glucose utilization. This pattern of response seemed to occur without comparable inhibition of lipolysis. Triglycerides--like serum albumin--increased faster in the Casilan group. The highest mean triglyceride value was reached by day 8 in the Casilan group and by day 15 in the Vivonex group. Ten minutes following heparin injection triglycerides declined, FFA and glycerol increased indicating release of in vivo active lipase. LPL activity assayed in vitro was similar and unaffected by 2 weeks of dietary treatment in both groups. LPL activity was inversely correlated to triglycerides providing--beside the type of diet--another possible explanation for the wide variations seen in circulatory triglycerides.

Blood Glucose↗