IN VIVO ESTIMATION OF CHANGES IN DISTAL TUBULE FLOW AND THEIR ROLE IN DEXAMETHASONE-INDUCED KALIURESIS IN CONTROL AND POTASSIUM-ADAPTED RATS

The aim of this study was to determine whether the kaliuresis associated with glucocorticoids is due to a direct tubular action or is secondary to effects of glucocorticoids on distal tubule flow. A whole kidney technique was used to avoid the problem, inherent in microperfusion and micropuncture studies, of deciding whether (all) the appropriate nephron segment(s) are being studied. The method used was to determine the best whole kidney measure of distal tubule flow (the independent variable) by correlating this with the dependent variable (potassium excretion, corrected for differences in plasma potassium, UkV/PIK+) in conscious intact and adrenalectomized control and potassium-adapted rats. After an intragastric potassium chloride load, the correlation of UkV/PIK+ with UkV + UNaV was better than with either UNaV or UV, as measures of distal tubule flow. From the relationship a measure of potassium excretion independent of distal tubule flow can thus be calculated as UkV/PIK+ divided by (UkV + UNaV), defined as UK#. Measurement of UK# clearly demonstrates decreases in potassium excretion with adrenalectomy and increases in potassium excretion with aldosterone and in the potassium-adapted rat, consistent with described changes in potassium secretion. In contrast, with dexamethasone treatment, whilst there was an increase in UkV and UkV/PIK+, there was no change in UK# either in the control of potassium-adapted rats. These results suggest that the kaliuretic effect of dexamethasone cannot be attributed to direct tubular effects of glucocorticoids but rather can be explained by its effect on distal tubule flow.     

Effect of filming on tooth brushing performance in uninstructed adults in north-east England

Video recordings were obtained of 90 adults aged 18-22 yr brushing their teeth. Thirty subjects were unaware they were being filmed and 60 subjects had been informed that they would be filmed while they brushed their teeth. From repeated viewing of the tapes the areas of the mouth that were brushed, the total brushing time and the proportion of time spent brushing each of 16 areas of the mouth were obtained for each subject. Subjects who knew they were being filmed brushed significantly more mandibular occlusal surfaces, and lingual areas in both arches than subjects who were unaware they were being filmed. There was no significant difference in the mean toothbrushing time between the two groups. The informed group spent proportionally less time brushing posterior buccal areas and more time on occlusal and lingual areas than the group who were unaware they were being filmed, the difference being statistically significant for the mandibular arch areas. It was concluded that knowledge of filming alters toothbrushing behaviour to a small extent so that care should be taken when interpreting behavioural changes in future intervention studies.     

Airway Protection Following Simulated Gastro-Oesophageal Reflux In Sedated And Sleeping Neonatal Piglets During Active Sleep

1. In infants, promethazine has been implicated in the pathogenesis of sleep apnoea, apparent life threatening events (ALTE) and the Sudden Infant Death syndrome (SIDS). The aim of the present study was to investigate, in a neonatal animal, the effects of a commonly used promethazine-containing medication on airway protective mechanisms and cardiorespiratory reflexes following simulated gastro-oesophageal reflux (GER) to different levels in the oesophagus and pharynx. 2. Physiological and radiographic recordings were made in 21 naturally sleeping (controls) and 21 sedated (1.5 mg/kg, p.o., promethazine) piglets. On 3 consecutive days physiological recordings were made in all piglets during active sleep. Gastro-oesophageal reflux was simulated by the injection of boluses of 0.5 mL HCl, pH 2 or 3, or NaCl (0.9%) at 37 degrees C into the pharynx, upper or lower oesophagus. 3. In healthy neonatal piglets, minimal sedation with promethazine, which did not affect behaviour during wakefulness, revealed previously unreported findings during active sleep. 4. The most significant effects were observed following simulated GER to the pharynx, with no effect observed in the lower oesophagus. In sedated piglets, compared with naturally sleeping piglets, there was a significant reduction in swallowing (P < 0.01), delayed radiological clearance of fluid (P < 0.05), a reduction in breathing rate, oxygen saturation and heart rate and an increase in apnoea. 5. These findings are consistent with a low dose of promethazine producing a significant attenuation of airway protective mechanisms and, thus, stimulation of the laryngeal chemoreflex. The results suggest a mechanism for the association observed between promethazine use and the occurrence of ALTE and SIDS. The results support continued caution and suggest the need for greater regulation of promethazine-containing medications in infants.     

The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse

Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose–response study with AZA gavaged daily for 10 days at 40–120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.     

Cardioprotective Effect of Propranolol From Alcohol-Induced Heart Muscle Damage as Assessed by Plasma Cardiac Troponin-T

BACKGROUND: Heavy alcohol consumption from either long-term misuse or binge drinking is associated with poor cardiac contractility, mitochondrial dysfunction, and ventricular arrhythmias. The aim of this study was to measure circulating cardiac troponin-T as a marker for myocardial damage following acute and chronic alcohol administration. METHODS: In acute studies, male Wistar rats were treated with alcohol (75 mmol/kg body weight, intraperitoneal) and plasma was collected 2.5 hr after alcohol administration for analysis of rat cardiac troponin-T. In addition, rats were pretreated with cyanamide (an inhibitor of acetaldehyde dehydrogenase), various beta-blockers, xanthine oxidase inhibitors, or lisinopril before acute alcohol dosing. In chronic studies, rats were fed alcohol (as 35% of total dietary calories) for 6 weeks. RESULTS: The results of the time course study showed that acute alcohol administration significantly raised plasma cardiac troponin-T levels after 2.5 hr and 6 hr, but not after 24 hr. The effects of alcohol on cardiac troponin-T were potentiated with cyanamide pretreatment. Acute ethanol, alone or with cyanamide pretreatment, decreased systolic blood pressure and increased heart rates. Beta-blocker pretreatment with propranolol reduced the alcohol-induced increase in plasma troponin-T, whereas lisinopril potentiated this effect. The beta-blockers, atenolol and metoprolol, and the xanthine oxidase inhibitors, allopurinol and oxypurinol, were unable to reduce elevated troponin-T. However, pretreatment with the beta-blocker timolol moderated the acute alcohol-induced increase in troponin-T. In the chronic alcohol rat model, no differences were observed between alcohol and control pair-fed rats, suggesting the inducement of tolerance. CONCLUSIONS: In conditions of acute exposure, ethanol-induced lesions are characterized by raised plasma cardiac troponin-T possibly due to beta1 and/or beta2 adrenergic activation.     

Integration of conservative surgery, radiotherapy, and chemotherapy for the treatment of early-stage, node-positive breast cancer: sequencing, timing, and outcome

The optimal means of combining breast-conserving surgery, radiation therapy, and chemotherapy for the treatment of patients with early-stage, node-positive breast cancer is not known. We reviewed the results in 295 patients treated at the Joint Center for Radiation Therapy and affiliated institutions from 1976 to 1985. All patients had positive axillary nodes on dissection, had no gross residual disease in the breast or axilla after surgery, and received breast irradiation (with or without nodal irradiation) and three or more cycles of a cyclophosphamide, methotrexate, and fluorouracil (CMF)-based or doxorubicin-containing regimen. Median follow-up in patients without any failure was 78 months. Breast failure rates were assessed in relation to the sequencing of radiotherapy and chemotherapy. The different sequences were not randomly assigned, and the characteristics of the sequence groups differed. The actuarial 5-year breast failure rate was 4% in 99 patients receiving radiotherapy before chemotherapy; 8% in 54 patients sequentially receiving some chemotherapy, then radiotherapy without concurrent chemotherapy, then further chemotherapy; and 6% in 116 patients receiving concurrent chemotherapy and radiotherapy. However, the failure rate was 41% in 26 patients who received all chemotherapy before radiotherapy. The crude incidences of local failure within 4 years of treatment in these groups were 3%, 2%, 4%, and 15%, respectively (P = .065 for all four groups not being the same). The actuarial 5-year local failure rate was 5% for 252 patients irradiated within 16 weeks after surgery compared with 35% for 34 patients irradiated more than 16 weeks after surgery. The 4-year crude incidences were 4% and 12% for the two groups, respectively (P = .06). These results suggest that delaying the initiation of radiotherapy may result in an increased likelihood of local failure. Formal randomized controlled trials will be needed to confirm these results and to improve the integration of these treatment modalities.     

Assessment of adjuvant trials in breast cancer

In this paper, we discuss the analytic problems associated with the evaluation of overall survival for breast cancer adjuvant studies and results of pooling data from the published literature to determine if there is evidence showing an overall survival advantage to adjuvant therapy. An investigation of the effect of competing causes of death shows that trials on older patients have low statistical power. Hence many of the current trials have low statistical power and may fail to find overall survival advantage for adjuvant therapy even when a benefit exists. The implications of the assessment of short-term follow-up are discussed in the context of the heterogeneous distribution of residual disease after primary treatment. Short-term follow-up (less than 5 yr) precludes anyone from making any conclusions about benefit for patients with small residual tumor burdens who constitute the patient subgroup most likely to benefit from adjuvant therapy. We reviewed 15 published randomized trials (each having a control group receiving no systemic therapy) to determine if overall survival has been increased by adjuvant therapy. We conclude that there is a benefit from some chemotherapy regimens given to node-positive premenopausal women. However, the published data for tamoxifen are mixed, with some trials showing benefit and others not. As more follow-up time is accumulated, this matter should be settled.     

The relationships between patients'' related variables in asthma: Implications for asthma management

OBJECTIVE: Understanding patients' personal characteristics is essential for better asthma management. This study assessed the relationships between patients' related variables in asthma and identified key associations relevant to asthma management. METHODOLOGY: Subjects were recruited from the Alfred Hospital Asthma and Allergy Clinic (Melbourne, Victoria, Australia) and general practices. Their clinical and demographic characteristics, asthma knowledge, impact of asthma on their quality of life, their self-management skills and attitudes to asthma were assessed. RESULTS: One hundred and sixty-nine subjects participated in the study. Fifty-seven per cent had one or more previous hospital admissions, 94% had either moderate or severe asthma, and 51% reported nocturnal symptoms in the last 6 weeks. Patients who spoke only English, had been admitted to an intensive care unit, had a peak flow meter, and an asthma action plan had significantly better asthma knowledge than those who did not. The impact of asthma was greatest in patients who had a peak flow meter, used oral steroids, had exercise limitation, and developed asthma between the ages of 31-45 years. Female patients had better self-management skills than males. Patients with asthma-related distress were more likely to use oral steroids or theophylline and to have a history of previous hospital admissions. Patient self-confidence was negatively correlated with age. CONCLUSIONS: There are significant relationships between many of patients' variables related to asthma, including their personal clinical, demographic and psychological characteristics. The findings have implications for optimizing asthma management.