Trimethoprim/sulfamethoxazole and renal function in transplant patients.

Twenty-two patients with functioning renal allografts took part in a double-blind crossover trial during which placebo, sulfamethoxazole, and trimethoprim/sulfamethoxazole were given for periods of 14 days. The patients were divided into 2 groups. The first group consisting of 12 patients had serum creatinine levels less than 0.18 mmol/L and the second group of 10 patients had serum creatinine levels between 0.18 mmol/L and 0.35 mmol/L. Renal function at the end of each period was assessed by clearance of inulin (CIn), p-aminohippurate (CPAH) and endogenous creatinine (CCr). The second group also had a pitressin concentration test as a measure of distal tubule function. There was no change in inulin or creatinine clearance or in maximum concentration after pitressin in any of the patients in any of the phases. In the first group there was an increase in PAH clearance during the sulfonamide and trimethroprim/sulfamethoxazole phases. This change was not seen in the second group of patients with significantly impaired renal function.

The effectiveness of a soluble calcium preparation as a gut phosphate binder.

We determined the phosphate binding capacity of a soluble commercial calcium preparation by carrying out metabolic balances on four normal subjects and by administering it for 4 weeks to six patients treated by maintenance hemodialysis. Each tablet of Sandocal 1000 (Sandoz, Australia) contained 1 g of elemental calcium as calcium lactate-gluconate 5.23 g and calcium carbonate 0.8 g. The metabolic balance study was performed over two consecutive nine-day periods. A constant, normal diet was consumed throughout, but in the second period one Sandocal 1000 tablet was added to each of the three major daily meals. Each period consisted of four days of equilibrium, then five days of collection of urine and feces. Polyethylene glycol 4,000 was used as a continuous fecal marker and carmine red was used to indicate gut transit time. Calcium supplementation increased fecal phosphate excretion by 11.2 +/- 2.3 mmol/d (SD), and decreased urinary phosphate by 8.4 +/- 2.6 mmol/d. Plasma calcium levels were unchanged, while plasma phosphate levels rose slightly. The increase in fecal phosphate was similar to that previously reported when calcium carbonate 8 g/d or aluminum hydroxide 6.4 g/d were administered. In the patients treated by maintenance hemodialysis, the reduction in plasma phosphate induced by Sandocal 1000, three tablets daily, was similar to that obtained with aluminum hydroxide 1.8 +/- 1.2 g/d. Hence, this calcium preparation appears to have a phosphate binding capacity similar to that of standard doses of aluminum hydroxide.

Influence of lung volume on oxygen cost of resistive breathing.

We examined the relationship between the O2 cost of breathing (VO2 resp) and lung volume at constant load, ventilation, work rate, and pressure-time product in five trained normal subjects breathing through an inspiratory resistance at functional residual capacity (FRC) and when lung volume (VL) was increased to 37 +/- 2% (mean +/- SE) of inspiratory capacity (high VL). High VL was maintained using continuous positive airway pressure of 9 +/- 2 cmH2O and with the subjects coached to relax during expiration to minimize respiratory muscle activity. Six paired runs were performed in each subject at constant tidal volume (0.62 +/- 0.2 liters), frequency (23 +/- 1 breaths/min), inspiratory flow rate (0.45 +/- 0.1 l/s), and inspiratory muscle pressure (45 +/- 2% of maximum static pressure at FRC). VO2 resp increased from 109 +/- 15 ml/min at FRC by 41 +/- 11% at high VL (P less than 0.05). Thus the efficiency of breathing at high VL (3.9 +/- 0.2%) was less than that at FRC (5.2 +/- 0.3%, P less than 0.01). The decrease in inspiratory muscle efficiency at high VL may be due to changes in mechanical coupling, in the pattern of recruitment of the respiratory muscles, or in the intrinsic properties of the inspiratory muscles at shorter length. When the work of breathing at high VL was normalized for the decrease in maximum inspiratory muscle pressure with VL, efficiency at high VL (5.2 +/- 0.3%) did not differ from that at FRC (P less than 0.7), suggesting that the fall in efficiency may have been related to the fall in inspiratory muscle strength. During acute hyperinflation the decreased efficiency contributes to the increased O2 cost of breathing and may contribute to the diminished inspiratory muscle endurance.

Pressure-time product, flow, and oxygen cost of resistive breathing in humans.

We examined the relationship between the pressure-time product (Pdt) of the inspiratory muscles and the O2 cost of breathing (VO2 resp) in five normal subjects breathing through an external inspiratory resistance with a tidal volume of 800 ml at a constant end-expiratory lung volume [functional residual capacity, (FRC)]. Each subject performed 30-40 runs, each of approximately 30 breaths, with inspiratory flow rates ranging from 0.26 +/- 0.01 to 0.89 +/- 0.04 l/s (means +/- SE) and inspiratory mouth pressures ranging from 10 +/- 1 to 68 +/- 4% of the maximum inspiratory pressure at FRC. In all subjects VO2 resp was linearly related to Pdt when mean inspiratory flow (VI) was constant, but the slope of this relationship increased with increasing VI. Therefore, Pdt is an accurate index of VO2 resp only when VI is constant. There was a linear relationship between the VO2 resp and the work rate across the external resistance (W) for all runs in each subject over the range of W 10 +/- 1 to 137 +/- 21 J/min. Thus, at a constant tidal volume the VO2 resp was related to the mean inspiratory pressure, independent of flow or inspiratory duration. If the VO2 resp were determined mainly during inspiration, then for a given rate of external work or O2 consumption, VI would be inversely related to mean inspiratory pressure. Efficiency (E) was 2.1 +/- 0.2% and constant over a large range of VI, pressure, work rate, or resistance and was not altered by the presence of a potentially fatiguing load. The constant E over such a wide range of conditions implies a complex integration of the recruitment, mechanical function, and energy consumption of the muscles utilized in breathing.

Influence of inspiratory flow rate and frequency on O2 cost of resistive breathing in humans.

We examined the combined effect of an increase in inspiratory flow rate and frequency on the O2 cost of inspiratory resistive breathing (VO2 resp). In each of three to six pairs of runs we measured VO2 resp in six normal subjects breathing through an inspiratory resistance with a constant tidal volume (VT). One of each pair of runs was performed at an inspiratory muscle contraction frequency of approximately 10/min and the other at approximately 30/min. Inspiratory mouth pressure was 45 +/- 2% (SE) of maximum at the lower contraction frequency and 43 +/- 2% at the higher frequency. Duty cycle (the ratio of contraction time to total cycle time) was constant at 0.51 +/- 0.01. However, during the higher frequency runs, two of every three contractions were against an occluded airway. Because VT and duty cycle were kept constant, mean inspiratory flow rate increased with frequency. Careful selection of appropriate parameters allowed the pairs of runs to be matched both for work rate and pressure-time product. The VO2 resp did not increase, despite approximately threefold increases in both inspiratory flow rate and contraction frequency. On the contrary, there was a trend toward lower values for VO2 resp during the higher frequency runs. Because these were performed at a slightly lower mean lung volume, a second study was designed to measure the VO2 resp of generating the same inspiratory pressure (45% maximum static inspiratory mouth pressure at functional residual capacity) at the same frequency but at two different lung volumes. This was achieved with a negligibly small work rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressure-time product, work rate, and endurance during resistive breathing in humans.

We examined the effect of increasing work rate, without a corresponding increase in the pressure-time product, on energy cost and inspiratory muscle endurance (Tlim) in five normal subjects during inspiratory resistive breathing. Tidal volume, mean inspiratory mouth pressure, duty cycle, and hence the pressure-time product were kept constant, whereas work rate was varied by changing the frequency of breathing. There was a linear decrease in Tlim of -2.1 +/- 0.5 s.J-1.min-1 (r = 0.87 +/- 0.06) with increasing work rate. The data satisfied a model of energy balance during fatiguing runs (Monod and Scherrer. Ergonomics 8: 329-337, 1965) and were consistent with the hypothesis that the rate of energy supply, or respiratory muscle blood flow, is fixed when the pressure-time product is constant. Our results indicate that during inspiratory resistive breathing against fatiguing loads, work rate determines endurance independently of the pressure-time product. On the basis of the model, our results lead to estimates of respiratory muscle blood flow and available energy stores under the conditions of our experiment.

Relationship among EMG and contractile responses of the diaphragm elicited by hypotension.

In a canine model, we investigated the effects of severe hypotension on the indexes of diaphragmatic failure. We measured 1) the transdiaphragmatic pressure obtained in response to 20- and 100-Hz stimulation of phrenic nerves (Pdi20 and Pdi100), 2) the power spectrum of diaphragmatic electromyogram (EMG), 3) the ratio of integrated diaphragmatic EMG to Pdi (Edi/Pdi), and 4) the rate of relaxation of Pdi100 and Pdi20. Arterial blood pressure (Pa) was reduced to 40-50 mmHg by a balloon inflated in the inferior vena cava and was maintained at this level until Pdi100 declined to 75% of the control value (100% shock time, ST). A recovery period of 60 min at normal Pa was allowed. During hypotension, Pdi100 and Pdi20 declined only at 100% ST [95.0 +/- 13.0 (SE) min]; however, only Pdi100 recovered within 15 min. The power spectrum shifted to low frequencies early and progressively during shock period. Edi/Pdi rose significantly at 80 and 100% ST and recovered within 15 min. The relaxation rate of Pdi20 and Pdi100 increased significantly at 100% ST only. We conclude that 1) diaphragmatic contractility is depressed during severe hypotension, 2) changes in the power spectrum occurred first in the shock state, followed by alterations in Edi/Pdi, and subsequently both changes in the frequency-pressure curve and relaxation rate occurred last.

Effect of expiratory loading on glottic dimensions in humans.

We examined the effects of external mechanical loading on glottic dimensions in 13 normal subjects. When flow-resistive loads of 7, 27, and 48 cmH2O X l-1 X s, measured at 0.2 l/s, were applied during expiration, glottic width at the mid-tidal volume point in expiration (dge) was 2.3 +/- 12, 37.9 +/- 7.5, and 38.3 +/- 8.9% (means +/- SE) less than the control dge, respectively. Simultaneously, mouth pressure (Pm) increased by 2.5 +/- 4, 3.0 +/- 0.4, and 4.6 +/- 0.6 cmH2O, respectively. When subjects were switched from a resistance to a positive end-expiratory pressure at comparable values of Pm, both dge and expiratory flow returned to control values, whereas the level of hyperinflation remained constant. Glottic width during inspiration (unloaded) did not change on any of the resistive loads. There was a slight inverse relationship between the ratio of expiratory to inspiratory glottic width and the ratio of expiratory to inspiratory duration. Our results show noncompensatory glottic narrowing when subjects breathe against an expiratory resistance and suggest that the glottic dimensions are influenced by the time course of lung emptying during expiration. We speculate that the glottic constriction is related to the increased activity of expiratory medullary neurons during loaded expiration and, by increasing the internal impedance of the respiratory system, may have a stabilizing function.

T cell leukaemia in the rat: stable marker chromosome in leukaemic cells.

The karyotype of a transplantable T cell leukaemia which arose originally in a PVG strain rat undergoing chronic internal beta irradiation of the spleen was examined and a marker chromosome was found. Although the leukaemia progressively became more acute during 4 years of continuous passage the marker did not change. Cytogenetic analysis of normal rats given an acute exposure to external irradiation revealed, among other abnormalities, a marked of the same morphology indicating that the original marker was probably radiation induced. This is the first description of a stable marker chromosome in an experimental animal leukaemia.

Spasmodic croup in the adult.

Recurrent inspiratory stridor, for which there appears to be no organic basis, can present a serious medical problem. We measured the changes in cross-sectional area of the glottic aperture during the respiratory cycle in a patient with recurrent inspiratory stridor when she was well, during a spontaneous attack, and during one induced with histamine aerosol. The glottis was visualized using a fiberoptic bronchoscope passed transnasally and attached to a video camera and tape recorder. During stridor there was marked constriction of the glottis on inspiration and phase reversal of the normal movements of the vocal cords with respect to respiration. Intermittent positive pressure ventilation (IPPV) and continuous positive airway pressure (CPAP) applied during stridor, in the absence of inspiratory effort, reversed the glottic narrowing. Pulmonary resistance (RL) on inspiration was elevated during stridor and returned to normal during IPPV and CPAP. Expiratory RL was normal throughout. Our results show that stridor in this patient was due to dynamic inspiratory constriction of the vocal cords. Glottic constriction could be induced by histamine aerosol and reversed when lung inflation was unaccompanied by inspiratory effort during IPPV and CPAP. Recognition and appropriate management of this condition may avoid potentially dangerous therapeutic interventions.

Respiratory movements of the vocal cords.

We examined the movements of the vocal cords during tidal breathing, panting, and large changes in lung volume in 12 normal subjects. The glottis was observed with a fiber-optic bronchoscope, and the glottic image was recorded together with flow, volume, and a time marker onto videotape. Phasic respiratory swings in glottic width (dg) and glottic area (Ag) were reproducible in all subjects but differed substantially between subjects. In the group as a whole dg and Ag increased during inspiration to 10.1 +/- 5.6 mm and 126 +/- 8 mm2 (mean +/- SE), respectively, whereas during expiration the lowest values were 5.7 +/- 0.5 mm and 70 +/- 7 mm2, respectively. These extreme dimensions corresponded closely to the midtidal volume points in the respiratory cycle. Glottic width during vital capacity (VC) expirations was nearly 30% greater at a flow of 1.2 l/s than at 0.5 l/s, but the relationship between dg and lung volume differed between subjects. When swings in dg were minimized by panting, there was no difference in dg between functional residual capacity (FRC) and a volume corresponding to midinspiratory capacity. However, tidal breathing at this lung volume was associated with a 20% decrease in dg compared with breathing at FRC. Our observations indicate a tight coupling between the pattern of glottic movement and the respiratory volume cycle. The results suggest that during voluntary respiratory maneuvers both intrinsic laryngeal and respiratory muscles are recruited, participating as effector organs in ventilatory and respiratory control.

Upper airway dimensions and movements in bronchial asthma.

We measured the diameter and vertical displacement of the laryngeal and oropharyngeal airways in 8 seated asymptomatic asthmatic subjects (31 to 60 yr of age) before and after bronchoconstriction (BC) induced by histamine phosphate aerosol. An image of the airways was obtained in 2 planes using an X-ray fluoroscope attached to a videotape recorder, onto which signals of flow and volume at the mouth were recorded simultaneously. We calculated real dimensions from the video image using size markers included in the picture. During BC, when FEV1 fell to 35 +/- 4% (mean +/- SE) of control, the lateral diameter (DLAT) of the larynx at mid-expiration narrowed over approximately 10 mm vertical height above the glottis. Lateral diameter of the glottis during mid-expiration fell from 6.5 +/- 1.5 mm by 46 +/- 12% (p less than 0.05), but that during inspiration was unchanged. In the 3 subjects with the greatest glottic narrowing, anteroposterior diameter (DAP) and DLAT of the larynx at the level of the corniculate cartilages narrowed by 28 and 27%, respectively. There was inspiratory dilatation of the oropharynx during BC. The DAP during inspiration at the level of the hyoid increased from 15.0 +/- 1.5 to 17.5 +/- 1.5 mm (p less than 0.05), while that at the level of the third cervical vertebra (C3) increased from 12.5 +/- 1.5 to 17.0 +/- 2.0 mm (p less than 0.05). The diameters during mid-expiration were unchanged so that the difference between inspiration and mid-expiration increased at both levels. Higher in the oropharynx (20 mm above C3), expiratory DAP decreased in 6 of 8 subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the glottic aperture during bronchial asthma.

We measured the cross-sectional area of the glottis in 12 asymptomatic asthmatic subjects before and after bronchoconstriction (BC) induced by histamine or ultrasonically nebulized water aerosol. The glottis was visualized using a fiberoptic bronchoscope attached to a video camera and tape recorder onto which flow and volume were simultaneously recorded. During induced asthma, measurements of forced expiratory flow fell to 36 +/- 3% (mean +/- SE) of control. Glottic area at mid-expiration (Age) fell from 75 +/- 14 mm2 by 45 +/- 8% (p less than 0.005). In some subjects, expiratory constriction of the supraglottic portion of the larynx and pharynx was also noted. Five subjects showed mild constriction (13 to 32%) of the glottis during inspiration. The administration of 10 cm H2O of continuous positive airway pressure (CPAP) during the induced asthma temporarily abolished expiratory constriction of the glottis and supraglottic structures; Age increased from 45 +/- 15 to 79 +/- 11 mm2 (p less than 0.01). The constriction returned when CPAP was stopped. After reversal of BC by salbutamol Age returned to values similar to those before BC. Although the mechanism for the expiratory glottic constriction is not known, it may be related to the different pattern of respiratory muscle activity seen in asthma. We speculate that the glottic constriction may contribute to hyperinflation by slowing expiratory flow and/or allowing a reduction in the persistent inspiratory muscle activity during expiration.

Diaphragmatic fatigue produced by constant or modulated electric currents.

In anesthetized rabbits the efficiency of phrenic nerve stimulation with trains of electric current was studied either when ventilation was effected entirely by bilateral nerve stimulation (electrophrenic ventilation) or during unilateral nerve stimulation when animals were ventilated with a pump and open chest. Trains of rectangular electric pulses (RPT) with constant amplitude and frequency or sine waves, both the amplitude and frequency of which were modulated and controlled by a computer (MSWT), were used with each animal. MSWT closely reproduced the physiological shape of transdiaphragmatic pressure waves. Diaphragm fatigue, as determined from the decrease in the maximal relaxation rate of twitches, occurred after 20 minutes of bilateral or unilateral nerve stimulation with RPT, but only after 60 min (unilateral stimulation) or 98 min (bilateral stimulation) with MSWT. These data show the importance of the motor signal pattern in long-lasting nerve stimulation.

Labetalol and bendrofluazide: comparison of their antihypertensive effects.

A randomized double-blind crossover trial of labetalol, bendrofluazide and placebo was carried out in 18 patients with mild to moderate hypertension. The reduction in blood pressure observed with labetalol and bendrofluazide was similar. The plasma levels of labetalol showed a significant correlation with changes in blood pressure (r = 0.07; P less than 0.021); and plasma level determinations of this drug may be of value in the management of patients who receive antihypertensive agents.

Effects of erythropoietin therapy on the lipid profile in end-stage renal failure.

To evaluate the effects of erythropoietin (EPO) therapy on the lipid profile in end-stage renal failure, we undertook a prospective study in patients on both hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). One hundred and twelve patients (81 HD, 31 CAPD) were enrolled into the study. Lipid parameters [that is, total cholesterol and the LDL and HDL subfractions, triglycerides, lipoprotein (a), apoproteins A and B], full blood count, iron studies, B12, folate, blood urea, aluminium and serum parathyroid hormone were measured prior to commencement of EPO therapy. Ninety-five patients were reassessed 5.2 +/- 0.3 (mean +/- SEM) months later and 53 patients underwent a further assessment 13.1 +/- 0.6 months after the commencement of EPO, giving an overall follow-up of 10.0 +/- 0.6 months in 95 patients. As expected, EPO treatment was associated with an increase in hemoglobin (7.7 +/- 0.1 vs. 9.9 +/- 0.2 g/dl; P < 0.001) and a decrease in ferritin (687 +/- 99 vs. 399 +/- 69 micrograms/liter; P < 0.01). A significant fall in total cholesterol occurred (5.8 +/- 0.1 vs. 5.4 +/- 0.2 mmol/liter; P < 0.05) in association with a fall in apoprotein B (1.15 +/- 0.04 vs. 1.04 +/- 0.06; P < 0.05) and serum triglycerides (2.26 +/- 0.14 vs. 1.99 +/- 0.21; P < 0.05) during the course of the study. Other lipid parameters did not change, although there was a trend towards improvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Thin-membrane nephropathy--a common cause of glomerular haematuria.

Thin-membrane nephropathy recently has been described as a cause of glomerular haematuria. The prognosis of the condition is unclear but it generally is considered to be benign. In a series of 92 patients with glomerular haematuria, thin-membrane nephropathy was found to be a common cause, occurring in 26 (28%) patients. Sixteen patients were women. The mean age was 42 years. Four patients had a family history of renal disease or haematuria and no patient was deaf. Haematuria had been present from six days to 30 years. Loin pain occurred in 31% of patients. Hypertension was not a feature and mild renal impairment was present in one case only, while a further three cases showed proteinuria at a level of greater than 500 mg of protein per day. Glomerular basement membranes in patients with thin-membrane nephropathy gave a mean (+/- standard deviation) width of 319 + 37 nm which was significantly (P less than 0.002) less than the control value of 394 +/- 61 nm. On the basis of clinical features and serological parameters, thin-membrane nephropathy could not be separated from other renal causes of haematuria but required careful electronmicroscopic examination of renal biopsy material to establish the diagnosis. Limited follow-up has confirmed the good prognosis of the condition.

Treatment of hemodialysis bone disease with 24,25-(OH)2D3 and 1,25-(OH)2D3 alone or in combination.

We studied the effects of vitamin D metabolites in 29 patients established on chronic hemodialysis. The patients were divided into four groups; one was treated with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] 0.5 microgram/day, one with 24R,25-dihydroxyvitamin D3 [24,25-(OH)2D3] 10 micrograms/day, and one with both metabolites. The control group was not given vitamin D. Plasma levels of both metabolites were low before treatment. 1,25-(OH)2D3 levels became normal, and 24,25-(OH)2D3 increased to supranormal levels after administration of the corresponding metabolite. Combined treatment produced still higher plasma levels of 24,25-(OH)2D3, suggesting an interaction between the two metabolites. Patients receiving 1,25-(OH)2D3 alone had a greater increase in plasma calcium than those receiving both metabolites. In control patients, hyperparathyroid bone disease worsened over the 10-month observation period. 1,25-(OH)2D3 improved hyperparathyroid bone disease in most patients, as reflected by a reduction in osteoclast and osteoblast numbers, but had no demonstrable effect on mild osteomalacia. 24,25-(OH)2D3 had no significant effect on plasma biochemistry or bone histology, and the effect of combined treatment on histology was similar to that of 1,25-(OH)2D3 alone. Stainable bone aluminum increased slightly in patients given 1,25-(OH)2D3, but aluminum did not affect the response to treatment. We conclude that 1,25-(OH)2D3 is a useful agent in the treatment of renal bone disease, but no therapeutic role is apparent for 24,25-(OH)2D3.

The pathogenesis of renal osteodystrophy: role of vitamin D, aluminium, parathyroid hormone, calcium and phosphorus.

Biochemical data and bone histology from 44 haemodialysis patients was compared using an histologic technique capable of evaluating separately the individual components of osteodystrophy. Hyperparathyroid bone disease was diagnosed by an elevated osteoclast count, and in advanced disease there was also fibrosis and woven bone. Osteomalacia, defined as an impairment in the rate of bone mineralisation, was present in two distinct forms: osteomalacia type I, characterised by wide osteoid seams, and osteomalacia type II, characterised by extensive thin, inactive osteoid. The histologic diagnoses were hyperparathyroid bone disease (15), osteomalacia type I (3), osteomalacia type II (6), hyperparathyroid bone disease and osteomalacia type I (12), hyperparathyroid bone disease and osteomalacia type II (6), normal (2). Aluminium was evident histochemically in 17 biopsies. Vitamin D metabolite levels were low in most patients and did not correlate with any biochemical or histological parameter. Parathyroid hormone levels were highly correlated with histological features of hyperparathyroid bone disease, and also correlated with plasma calcium, suggesting a degree of autonomy of parathyroid hormone secretion. Urea and creatinine were higher in the hyperparathyroid bone disease than the osteomalacia groups suggesting that poor dialysis contributes to the former. Statistical analysis showed that osteomalacia type I was associated with relatively low plasma calcium and phosphorus levels; osteomalacia type II was associated with increased bone aluminium and with the uraemic process itself, as reflected in the plasma creatinine level. This study shows relationships between renal osteodystrophy and plasma calcium and phosphorus levels, but no relationship with vitamin D metabolites. Aluminium appears to impair mineralisation even at relatively low levels of accumulation. However there are other unidentified factors associated with the uraemic process, contributing to all three components of renal osteodystrophy.