Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model.

BACKGROUND: This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia. METHODS: Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules. RESULTS: The combined model accurately predicted observed nadir timing (r=0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients (r=0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 µg m(-2) tri-weekly, is G-CSF, 300 µg, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m(-2), is optimally supported by the slightly less cost-effective G-CSF 300 µg, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per µl) under Doc, 100-150 mg m(-2) tri-weekly. CONCLUSIONS: The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.

Effects of percutaneous transluminal coronary angioplasty on cardiopulmonary responses during exercise.

AIM: The aim of this study was to examine by means of percutaneous transluminal coronary angioplasty (PTCA) whether dilating blocked coronary arteries in patients with coronary heart disease will improve relevant attributes measured during cardiopulmonary exercise testing (CPET). METHODS: Fourteen myocardial ischemia patients (13 male, 1 female; age range: 42-72 years), who were referred for cardiac catheterization, participated in the study. Eight patients underwent PTCA (experimental group) and 6 did not (control group). All subjects performed CPET about 2 weeks before and 3 weeks after cardiac catheterization. RESULTS: The results of electrocardiogram (ECG) analysis reveal a very low predictive accuracy (36%) for identifying coronary heart disease and/or anatomical changes caused by the PTCA. However, selected CPET parameters in the experimental group only showed significant post-PTCA changes from baseline. Peak oxygen uptake (VO(2)) increased from 17.49 to 20.75 mL x kg(1) x min(1), ventilatory anaerobic threshold from 12.15 to 14.39 mL x kg(1) x min(1), peak oxygen pulse (O(2)pulse) from 11.76 to 13.27 mL x beat(1), and O(2)pulse slope from 7.05 to 9.25, slope category. No significant inter- or intra-group differences were found in peak exercise heart rate, respiratory exchange ratio, subjective rating of perceived exertion, or systolic and diastolic blood pressure. CONCLUSIONS: This study suggests that selected CPET parameters seem to be highly sensitive to changes in cardiac function caused by the PTCA, significantly more than with conventional stress ECG. These findings merit further investigation.

Homology search and choice of homologous partner during mitotic recombination.

Homologous recombination is an important DNA repair mechanism in vegetative cells. During the repair of double-strand breaks, genetic information is transferred between the interacting DNA sequences (gene conversion). This event is often accompanied by a reciprocal exchange between the homologous molecules, resulting in crossing over. The repair of DNA damage by homologous recombination with repeated sequences dispersed throughout the genome might result in chromosomal aberrations or in the inactivation of genes. It is therefore important to understand how the suitable homologous partner for recombination is chosen. We have developed a system in the yeast Saccharomyces cerevisiae that can monitor the fate of a chromosomal double-strand break without the need to select for recombinants. The broken chromosome is efficiently repaired by recombination with one of two potential partners located elsewhere in the genome. One of the partners has homology to the broken ends of the chromosome, whereas the other is homologous to sequences distant from the break. Surprisingly, a large proportion of the repair is carried out by recombination involving the sequences distant from the broken ends. This repair is very efficient, despite the fact that it requires the processing of a large chromosomal region flanking the break. Our results imply that the homology search involves extensive regions of the broken chromosome and is not carried out exclusively by sequences adjacent to the double-strand break. We show that the mechanism that governs the choice of homologous partners is affected by the length and sequence divergence of the interacting partners, as well as by mutations in the mismatch repair genes. We present a model to explain how the suitable homologous partner is chosen during recombinational repair. The model provides a mechanism that may guard the integrity of the genome by preventing recombination between dispersed repeated sequences.

Recombination of Ty elements in yeast can be induced by a double-strand break.

The Ty retrotransposons are the main family of dispersed repeated sequences in the yeast Saccharomyces cerevisiae. These elements are flanked by a pair of long terminal direct repeats (LTRs). Previous experiments have shown that Ty elements recombine at low frequencies, despite the fact that they are present in 30 copies per genome. This frequency is not highly increased by treatments that cause DNA damage, such as UV irradiation. In this study, we show that it is possible to increase the recombination level of a genetically marked Ty by creating a double-strand break in it. This break is repaired by two competing mechanisms: one of them leaves a single LTR in place of the Ty, and the other is a gene conversion event in which the marked Ty is replaced by an ectopically located one. In a strain in which the marked Ty has only one LTR, the double-strand break is repaired by conversion. We have also measured the efficiency of repair and monitored the progression of the cells through the cell-cycle. We found that in the presence of a double-strand break in the marked Ty, a proportion of the cells is unable to resume growth.

Prenatal ultrasound diagnosis of club foot: outcome and recommendations for counselling and follow-up.

Club foot was diagnosed by ultrasonography in 91 feet (52 fetuses) at a mean gestational age of 22.1 weeks (14 to 35.6). Outcome was obtained by chart review in 26 women or telephone interview in 26. Feet were classified as normal, positional deformity, isolated club foot or complex club foot. At initial diagnosis, 69 feet (40 fetuses) were classified as isolated club foot and 22 feet (12 fetuses) as complex club foot. The diagnosis was changed after follow-up ultrasound scan in 13 fetuses (25%), and the final ultrasound diagnosis was normal in one fetus, isolated club foot in 31 fetuses, and complex club foot in 20 fetuses. At birth, club foot was found in 79 feet in 43 infants for a positive predictive value of 83%. Accuracy of the specific diagnosis of isolated club foot or complex club foot was lower; 63% at the initial ultrasound scan and 73% at the final scan. The difference in diagnostic accuracy between isolated and complex club foot was not statistically significant. In no case was postnatal complex club foot undiagnosed on fetal ultrasound and all inaccuracies were overdiagnoses. Karyotyping was performed in 25 cases. Abnormalities were noted in three fetuses, all with complex club foot and with additional findings on ultrasound.

The effect of body posture on exercise- and hyperventilation-induced asthma.

Recent studies have shown that swimming is of relatively low asthmogenicity, even under conditions of high respiratory heat (and/or water) loss (RHL). It has been suggested that the horizontal body position may contribute to swimming's low asthmogenicity. We studied the effects of upright and prone body postures on pulmonary function following exercise (EIA) and after nonexercise hyperventilation (HIA). Twelve asthmatic boys (aged 12 to 16 years) underwent two 8-min exercise sessions of shoulder flexion-extension and two 8-min isocapnic hyperventilation treatments, in a counterbalanced order, either while lying prone or standing upright. All tests were carried out in a climatic chamber at 10 +/- 1 degree C and 31 +/- 2 percent relative humidity. Minute ventilation (VE) was kept constant at a predetermined individual level during all treatments. No differences were observed in pulmonary functions between the prone and upright postures following either exercise (FEV1 = -20.5 +/- 18.7 percent vs -22.2 +/- 18.7 percent, respectively) or hyperventilation (FEV1 = -29.6 +/- 19.0 percent vs -29.7 +/- 20.2 percent). We conclude that body posture on land has no meaningful effect on the severity of bronchoconstriction in asthmatic children; however, in view of some conceivable physiologic benefits of the prone position in water, an interactive effect on swimming-induced asthma (SIA) of body posture and water immersion cannot be ruled out.

Interleukin-3-like activity levels in pregnant women: possible modulation by progesterone.

Human interleukin-3-like activity (IL-3-LA), a factor possessing similar characteristics to interleukin-3 and having clony stimulating factor (CSF) activity, has recently been defined. In the present study, IL-3-LA levels in the sera of women before and after delivery were examined. The results indicate a significant increase in IL-3-LA levels in women before delivery as compared to IL-3-LA levels after delivery or to non-pregnant healthy women. The ability of mononuclear cells from women before and after delivery to produce IL-3-LA was similar to that of mononuclear cells from cord blood. In addition, the effect of progesterone on in vitro IL-3-LA production was examined and a stimulatory dose-dependent effect was observed. These observations point to the hypothesis that during pregnancy IL-3-LA levels are modulated by progesterone. With placental loss, the IL-3-LA in the sera decreases, although the mononuclear cells previously affected by the hormone continue to produce cytokines.

Cerebral lateral ventricular asymmetry: is this a normal ultrasonographic finding in the fetal brain?

OBJECTIVE: To evaluate the clinical significance of in utero detection of fetal cerebral lateral ventricular asymmetry. METHODS: We used high resolution ultrasonography to study asymmetries of the fetal lateral ventricles in the human brain. A retrospective survey was conducted on 7200 pregnant women who presented at two large district hospitals in Israel. Only fetuses with a difference of greater than 2.4 mm (two standard deviations) in the width of the lateral ventricles, with no known brain pathology, were included in the study. Index cases were evaluated regarding maternal complications, prenatal ultrasound examinations, postnatal imaging studies, and neonatal outcome up to 6 months of age. RESULTS: Lateral ventricular asymmetry was found in 21 subjects, all with available clinical data. In 15 fetuses (71%), the body or the occipital horn of the left lateral ventricle was larger than the right, whereas in six fetuses (29%), the right was larger than the left. In four cases (20%), serial scans noted resolution of asymmetry; in 15 (75%), it was persistent; and in one (5%), asymmetry increased. In one case, termination of pregnancy was performed; however, pathologic examination of the fetal brain failed to detect any structural abnormality. Underlying cerebral pathology was later found only in three fetuses (14%); one had subclinical cytomegalovirus ventriculitis, one had insidious periventricular hemorrhage, and in one fetus with increased asymmetry, trisomy 21 was verified. All the remaining 17 cases had normal neurologic development. CONCLUSIONS: Some degree of asymmetry of the lateral ventricles exists in the human fetal brain and is detectable in utero. Lateral ventricular asymmetry alone is probably not clinically significant, and it may be considered as a normal variant, rather than a pathologic finding.

Induction of cadmium tolerance in Escherichia coli K-12.

Cadmium ions are bacteriocidal, resulting in exponential killing that starts immediately after exposure. We have shown that pretreatment with sublethal concentrations of cadmium induces cadmium tolerance. Protection against cadmium killing can also be obtained by preincubation at elevated temperatures, known to induce the heat-shock response. However, in contrast to pretreatment at elevated temperatures, exposure to sublethal cadmium concentrations does not induce thermotolerance.

Ischemic stroke due to induction of ovulation with clomiphene citrate and menotropins without evidence of ovarian hyperstimulation syndrome.

Cerebral infarction due to menotropin therapy without evidence of ovarian hyperstimulation is presented. The patient was successfully treated with aspirin and anticonvulsive agents and was discharged without residual neurologic symptoms.

Swimming and asthma. Benefits and deleterious effects.

Swimming is a common pastime activity and competitive sport for patients with asthma. One reason for such popularity may be the low asthmogenicity of swimming compared with landbased activities. Review of available evidence suggests that swimming induces less severe bronchoconstriction than other sports. The mechanisms for this protective effect of swimming are not clear, but there is some experimental evidence intimating that it results in part from the high humidity of inspired air at water level, which reduces respiratory heat loss (and possibly osmolarity of airways mucus). Beneficial roles of horizontal posture and of water immersion have been tested but not confirmed. Swimming poses two potentially deleterious effects to the patient with asthma. One is the exaggerated parasympathetic tone due to the 'diving reflex', that has been shown to trigger bronchoconstriction. The other is airway irritation because of chlorine and its derivatives. Swimming as a training modality has definite benefits for the patient with asthma. These include an increase in aerobic fitness and a decrease in asthma morbidity. There is no conclusive evidence, however, that swim training causes a decrease in the severity or frequency of exercise-induced bronchoconstriction.

Anaerobic characteristics in male children and adolescents.

Only sparse information has been published on the effects of growth, development, and maturation on the ability to perform high intensity, short-term "anaerobic" tasks. Cross-sectional studies on Italian, African, British, and American females and males have indicated an age-related progression in the performance of the Margaria step-running test. Children had a distinctly lower mechanical power output than adolescents and young adults, both in absolute terms and when divided by body weight, or by fat-free mass. Data are presented on some 300 10- to 45-yr-old Israeli males who performed the Wingate anaerobic test by cycling or by arm cranking. Both the peak power at any 5-s period and the mean power throughout the test were lowest in the children, whether expressed in absolute power units or corrected for body weight. Performance progressed with age and reached the highest values at the end of the third decade for cycling and at the end of the second decade for arm cranking. This pattern is unlike that described for maximal O2 uptake per kg body weight which, in males, remains virtually unchanged from childhood to young adulthood. In females, maximal O2 uptake per kg is even higher in children than among adolescents or adults. Biochemical correlates of such a low anaerobic performance in children are their lower maximal lactate concentration in muscle and blood, lower rate of anaerobic glycolysis, and lower levels of acidosis at maximal exercise. The mechanisms for the relatively deficient anaerobic characteristics of children are not clear.

Specific inspiratory muscle training in well-trained endurance athletes.

PURPOSE: It has been reported that arterial O2 desaturation occurs during maximal aerobic exercise in elite endurance athletes and that it might be associated with respiratory muscle fatigue and relative hypoventilation. We hypothesized that specific inspiratory muscle training (SIMT) will result in improvement in respiratory muscle function and thereupon in aerobic capacity in well-trained endurance athletes. METHODS: Twenty well-trained endurance athletes volunteered to the study and were randomized into two groups: 10 athletes comprised the training group and received SIMT, and 10 athletes were assigned to a control group and received sham training. Inspiratory training was performed using a threshold inspiratory muscle trainer, for 0.5 h x d(-1) six times a week for 10 wk. Subjects in the control group received sham training with the same device, but with no resistance. RESULTS: Inspiratory muscle strength (PImax) increased significantly from 142.2 +/- 24.8 to 177.2 +/- 32.9 cm H2O (P < 0.005) in the training but remained unchanged in the control group. Inspiratory muscle endurance (PmPeak) also increased significantly, from 121.6 +/- 13.7 to 154.4 +/- 22.1 cm H2O (P < 0.005), in the training group, but not in the control group. The improvement in the inspiratory muscle performance in the training group was not associated with improvement in peak VEmax, VO2max breathing reserve (BR). or arterial O2 saturation (%SaO2), measured during or at the peak of the exercise test. CONCLUSIONS: It may be concluded that 10 wk of SIMT can increase the inspiratory muscle performance in well-trained athletes. However, this increase was not associated with improvement in aerobic capacity, as determined by VO2max, or in arterial O2 desaturation during maximal graded exercise challenge. The significance of such results is uncertain and further studies are needed to elucidate the role of respiratory muscle training in the improvement of aerobic-type exercise capacity.

Physiological responses to incremental exercise in patients with chronic fatigue syndrome.

PURPOSE: The purpose of this investigation was to characterize the physiological response profiles of patients with chronic fatigue syndrome (CFS), to an incremental exercise test, performed to the limit of tolerance. METHODS: Fifteen patients (12 women and three men) who fulfilled the case definition for chronic fatigue syndrome, and 15 healthy, sedentary, age- and sex-matched controls, performed an incremental progressive all-out treadmill test (cardiopulmonary exercise test). RESULTS: As a group, the CFS patients demonstrated significantly lower cardiovascular as well as ventilatory values at peak exercise, compared with the control group. At similar relative submaximal exercise levels (% peak VO(2)), the CFS patients portrayed response patterns (trending phenomenon) characterized, in most parameters, by similar intercepts, but either lower (VCO(2), HR, O(2pulse), V(E), V(T), PETCO(2)) or higher (B(f), V(E)/VCO(2)) trending kinetics in the CFS compared with the control group. It was found that the primary exercise-related physiological difference between the CFS and the control group was their significantly lower heart rate at any equal relative and at maximal work level. Assuming maximal effort by all (indicated by RER, PETCO(2), and subjective exhaustion), these results could indicate either cardiac or peripheral insufficiency embedded in the pathology of CFS patients. CONCLUSION: We conclude that indexes from cardiopulmonary exercise testing may be used as objective discriminatory indicators for evaluation of patients complaining of chronic fatigue syndrome.

The effect of prone immersion on bronchial responsiveness in children with asthma.

We studied the effects of prone immersion on pulmonary function in children with asthma. Twelve children with asthma were subjected to prone immersion (WET) and standing upright on land (DRY) under controlled conditions regarding temperature and relative humidity of the inhaled air, minute ventilation, respiratory frequency, tidal volume, and the concentration of carbon dioxide in the exhaled air. Eight minutes of isocapnic hyperpnea was performed in random order either in the swimming pool (prone) or on land (upright), with the temperature and relative humidity of the inhaled air kept at 20 +/- 2 degrees C and 10 +/- 2%, respectively. The average accumulated ventilation for the 8 min of hyperpnea was 3151 for the WET treatment and 3101 for the DRY (P > 0.1). Average heart rates were 101 +/- 11 and 115 +/- 17 beats.min-1 for the WET and DRY treatments, respectively (P < 0.05). The decrease in FEV1 (delta FEV1) was 26.3 +/- 16.7% after the WET treatment (compared with pretreatment FEV1), and 26.4 +/- 11.3% after the DRY treatment (P > 0.1 between WET and DRY delta FEV1), with similar trend (insignificant differences between treatments), for delta FVC, delta PEF 50%, and delta PEF 25-75%. It is concluded that airway hyperactivity is not alleviated by whole body prone immersion.

Exaggerated systolic blood pressure response to exercise in a water polo team.

Twenty-three top-level water polo players (WP) were examined for blood pressure (BP) response to graded and continuous cycle ergometry. Testing also included resting muscle biopsy for fiber typing, exercise ECG recording for heart rate (HR), exercise concentrations of blood lactate (LA), measured VO2max, and ratings of perceived exertion (RPE). A control group (C), whose subjects were physically active in endurance sports, but were older and less fit than the experimental subjects, was tested by an identical protocol. The BP response to exercise was significantly higher in the WP group at all comparison criteria including onset of blood lactate accumulation, absolute HR, percent of HRmax, and power loads (including loadless pedaling). To date, we are unaware of other reports on whole groups of sportsmen showing an exaggerated BP response to exercise. While it would appear from previous studies that normotensive individuals showing such a response are at a greater risk of developing hypertension, the significance of this BP response in highly-trained athletes in a specific sport remains unclear.

Reexamination of Stewart's quantitative analysis of acid-base status.

To provide experimental verification to Stewart's quantitative approach to acid-base analysis, the effects of acute maximal treadmill exercise (VO2max test) on venous acid base status were studied in 17 male subjects aged 18-23 yr. Venous CO2 tension (PCO2) total plasma proteins ([PTOT]), [H+], and concentrations of strong ions [( Na+], [K+], [Cl-] and lactate ion concentration ([La-]) were measured before and within 1 min post-exercise. Mean post-exercise PCO2, [PTOT], [K+], and [La-] were significantly higher than the corresponding pre-exercise values (P less than 0.05), there was a strong tendency for a significant change in [Na+] (P less than 0.056), and no changes were found in [Cl-]. Changes in venous acid-base status were analyzed quantitatively by applying relevant physicochemical theory. Altered values measured in the independent variables ([PTOT], PCO2, and net strong ion difference, [SID]) were used to calculate the corresponding changes in the dependent quantities. Comparison of individual measured and calculated values for the only one of these that is normally measured, ([H+]), yielded the theoretically expected agreement. PCO2 and [SID] changes accounted for most [H+] changes. These results demonstrate the usefulness of the quantitative approach (i.e., [H+]-PCO2 diagram) in the analysis and in understanding of plasma acid base changes with exercise and in clinical situations.

Normal cardiopulmonary responses during incremental exercise in 20- to 70-yr-old men.

Healthy men (N = 1424, age 20-70 yr) underwent a progressive incremental treadmill exercise test to volitional maximum. Cardiopulmonary variables were measured breath-by-breath. The aerobic power (VO2max) declined at an average yearly rate of 0.33 ml.kg.-1min-1, HRmax declined 0.685 beats.min-1.yr-1, and max O2 pulse declined at an annual rate of 0.115 ml.beat-1.kg-1*100. Gas exchange threshold (GET) expressed as percentage of VO2max was 58% and 69% in the youngest (20-30 yr) and oldest (61-70 yr) decades, respectively. The average decline in VE, Vt, f, and PETCO2 over the entire age range was 29%, 10%, 21%, and 7%, respectively. There were increases in VE/VO2, and VE/VECO2, from age 20-70 yr of 13% and 14%, respectively, but no changes across 5 decades in PETO2. Physical (height and weight) as well as life-style characteristics (leisure time activity, place of residency, smoking), were found to be potent predictors in most of the cardiopulmonary values at maximal exercise and therefore should be incorporated in the predictive equations for such variables. Normal response patterns of most cardiopulmonary variables throughout the range of exercise intensities were shown to be age-affected and thus should be standardized for age decades.

Changes in muscle metabolites in females with 30-s exhaustive exercise.

The purpose of this study was to quantify the changes in selected intramuscular metabolites associated with non-oxidative energy metabolism after performance of the Wingate Test (WT), a widely used, exhaustive, 30-s cycle test of short-time muscular power. Muscle biopsies were taken from the m. vastus lateralis of nine female physical education students at rest and immediately after performance of the WT. The concentrations of adenosine triphosphate (ATP), creatine phosphate (CP), lactate, and glycogen were determined. The ATP decreased from 20.9 to 13.8; CP decreased from 62.7 to 25.1; lactate increased from 9.0 to 60.5; and glycogen decreased from 360 to 278 (all concentrations are mmol X kg-1 dry muscle). The absolute changes in CP and lactate were not as large as those reported in other exercise studies. Based on the metabolite changes, it was concluded that the WT is a satisfactory test of the maximal muscular power that can be generated from non-oxidative metabolism, but that the 30-s duration of the test probably does not tax the maximal capacity of such energy metabolism.

Binding of 125I-labeled endotoxin to bovine, canine, and equine platelets and endotoxin-induced agglutination of canine platelets.

Endotoxin from Escherichia coli O127:B8, Salmonella abortus-equi and S minnesota induced clumping of some canine platelets (PLT) at a final endotoxin concentration of 1 microgram/ml. Endotoxin-induced clumping of canine PLT was independent of PLT energy-requiring processes, because clumping was observed with canine PLT incubated with 2-deoxy-D-glucose and antimycin A. The PLT responded to adenosine diphosphate before, but not after, incubation with the metabolic inhibitors. Endotoxin induced a slight and inconsistant clumping of bovine and equine PLT at high (mg/ml) endotoxin concentration. High-affinity binding sites could not be demonstrated on canine, bovine, and equine PLT, using 125I-labeled E coli O127:B8 endotoxin. Nonspecific binding was observed and appeared to be due primarily to an extraneous coat on the PLT surface that was removed by gel filtration. The endotoxin that was bound to PLT did not appear to modify PLT function. An attempt to identify plasma proteins that bound physiologically relevant amounts of endotoxin was not successful. The significance of the endotoxin-induced clumping or lack of it on the pathophysiology of endotoxemia is discussed.