Biomedical subjects
Publications and source records attributed to K Sankaran.
Three radiologically and bacteriologically confirmed pulmonary tuberculosis patients had eosinophilic pneumonia, as demonstrated by BAL. In two patients, pulmonary eosinophilia was present only at the site of the lesion and the third had eosinophilia in both peripheral blood and lung. There was complete elimination of the eosinophilic inflammatory process in two patients who had successfully completed antituberculosis treatment.
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Fifty patients with tropical eosinophilia were studied clinically and physiologically, before and after a standard 3-week course of diethylcarbamazine. Before treatment the main physiological abnormality was a reduction in the carbon monoxide transfer factor. One month after the start of treatment most patients had shown a marked symptomatic improvement, but peripheral blood eosinophilia persisted in 52%, radiographic abnormalities in 44%, cough in 22% and chest signs in 8%. Significant improvement was noted in almost all aspects of lung function including blood gases, but the mean values for forced expiratory volume in one second, forced vital capacity, transfer factor and transfer coefficient continued to be significantly lower than predicted values. This study demonstrates the incomplete reversal of clinical, haematological, radiological and physiological changes in tropical eosinophilia one month after starting a 3-week course of diethylcarbamazine.
Bronchoalveolar lavage studies in 33 patients with acute untreated tropical eosinophilia have demonstrated intense eosinophilic alveolitis. Following treatment with a standard 3-week course of diethylcarbamazine, there was a significant fall in lung eosinophils (p less than 0.001). However, a mild alveolitis characterised by hypercellular lavage fluid due to a significant increase in absolute alveolar macrophages (p less than 0.001) and due to an increase in both the absolute number (p less than 0.01) and percentage of eosinophils (p = 0.02) was persisting at 1 month despite treatment. Long-term follow-up is essential to know the fate of alveolitis.
Forty-one patients with untreated tropical pulmonary eosinophilia (TPE) were studied to determine whether there was any relationship between lower respiratory tract inflammation and either changes in lung function or abnormalities in chest roentgenograms. Total number of inflammatory cells in bronchoalveolar lavage (BAL) fluid, consisting of alveolar macrophages, lymphocytes, eosinophils and neutrophils had significant negative correlations with transfer factor (TLCO) (r = 0.519, p less than 0.001), transfer coefficient (KCO) (r = 0.312, p less than 0.05) and total lung capacity (TLC) (r = 0.352, p less than 0.05). The absolute count of eosinophils in BAL fluid had a significant negative correlation with TLCO (r = 0.430, p less than 0.01) and KCO (r = 0.300, p = 0.05), but not with forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) or TLC. However, the absolute count of alveolar macrophages had a significant negative correlation with FVC (r = 0.343, p less than 0.05), FEV1 (r = 0.341, p less than 0.05) and TLC (r = 0.305, p less than 0.05), but not with TLCO or KCO. The total number of lymphocytes had a negative correlation with TLC (r = 0.315, p less than 0.05). There was no correlation between the types of cells recovered in BAL fluid and changes in chest radiographs as assessed by the ILO classification for occupational lung diseases. These data suggest that there may be a dissociation of pulmonary pathophysiological changes produced by different inflammatory cells in the lower respiratory tract. Macrophages and lymphocytes may produce more harm to the lung, as evidenced by significant negative correlations of these cells with lung volumes.
Although the metabolism and pharmacokinetics of chloral hydrate (CH) have been studied in healthy adults, no comprehensive studies have been done in neonates and young infants. Major physiological differences between these groups could greatly affect drug disposition. In this study the patient population (22 patients) was divided into three groups according to postconceptual age: group 1 = preterm infants (31-37 weeks), group 2 = fullterm infants (38-42 weeks) and group 3 = toddler-child patients (57-708 weeks). After receiving one 50 mg/kg oral dose of CH, the parent drug and its metabolites were determined by gas chromatography utilizing an electron capture detector. CH, contrary to what has been reported in the adult, was detectable for several hours after oral administration to patients in all three groups. A highly significant negative correlation was observed amongst the three groups for the half-life (t1/2) and area-under-the-curve for 0 to infinity values for trichloroethanol (TCE), the active metabolite responsible for the sedation effect. The t1/2 value for TCE in group 3 (9.67 h) was similar to that reported for the adult population, but in the less mature subjects it was approximately three (group 2: 27.8 h) to four times (group 1: 39.8 h) greater. Trichloroacetic acid had a remarkably long residence time in the study population after a single dose of CH. The concentration of this metabolite failed to decline even 6 days after dose. These issues should be carefully considered when CH administration is contemplated for clinical use in neonates, infants and children.
A simple, rapid and sensitive electron-capture gas chromatographic method has been developed for the simultaneous determination of chloral hydrate, trichloroethanol and trichloroacetic acid in biological fluids. The described method is applicable to single-dose pharmacokinetic studies of chloral hydrate in the adult. The method also meets the important requirement of using very small sample volumes and is sufficiently sensitive and reliable for disposition studies in the neonate.
Intact secretory granules isolated from bovine adrenal medulla express tyrosine hydroxylase (TH) activity. Granule-associated TH sediments on continuous sucrose gradients with dopamine beta-hydroxylase, a marker for granule membranes, indicating that TH is associated with chromaffin granules. Membranes prepared from lysed granules retain TH, whereas granule contents are free of the enzyme. TH immunoreactivity was detected in granule membranes by immunoblot analysis using a polyclonal antiserum against TH. TH immunoreactivity cannot be removed from membranes by washes in high ionic strength buffers and is only partially removed from membranes by treatment with either urea or Na2CO3. TH can be removed from granule membranes by the detergents Nonidet P-40, Triton X-100, and 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. Treatment of membranes with a phosphatidylinositol-specific phospholipase C did not remove TH, ruling out the possibility of a glycosyl phosphatidyl anchor. Fractionation of granule membranes by temperature-induced phase separation in Triton X-114 revealed that TH is recovered in phases in which integral (detergent phase) and hydrophobic (phospholipid phase) membrane proteins are typically found. By contrast, TH from adrenal cytosol fractionated exclusively into the aqueous phase along with other soluble proteins. Digestion of granules with various protease enzymes revealed that TH is resistant to degradation, suggesting that the enzyme is embedded within membranes. TH becomes phosphorylated when intact granules are exposed to the catalytic subunit of the cAMP-dependent protein kinase, indicating that at least the N-terminal region of TH is exposed on the cytoplasmic surface of granules. These results establish that a fraction of TH is an integral component of bovine granule membranes. The association of TH with granule membranes may play a role in coordinating TH activity and catecholamine release.
Forced vital capacity, forced expiratory volume in one second, functional residual capacity, residual volume, total lung capacity, and single breath diffusing capacity measurements (effective alveolar volume, carbon monoxide transfer factor, and transfer coefficient) were measured in 247 young healthy adults (130 male, 117 female) aged 15-40 years living in Madras. Subjects were of Dravidian stock, living at sea level with rice as their staple diet. Regression equations were derived for men and women for predicting normal pulmonary function for young adults in South India. The values were similar to those reported for subjects from Western India and lower than those reported for North Indians and caucasians.
Pulmonary membrane diffusing capacity (Dm) and pulmonary capillary blood volume (Vc) measurements were carried out in 21 patients with untreated tropical eosinophilia and 21 healthy controls matched for age, sex, height, and smoking habit. The mean single breath transfer factor (Dco) and the mean membrane diffusing capacity were significantly lower (p less than 0.001) in patients with tropical eosinophilia compared with control subjects. However, the mean capillary blood volume was not significantly different (p greater than 0.2). The positive correlations between Dm and transfer factor (r = 0.825), between Dm and effective alveolar volume (VA) (r = 0.721), and between Dco and VA (r = 0.774) were also highly significant (p less than 0.001) in study patients prior to treatment. These data suggest that reduction in single breath transfer factor in untreated tropical eosinophilia may be due to a reduction in membrane diffusing capacity, which in turn may be due to a reduction in area of membrane available for diffusion, as evidenced by the significantly reduced VA (p less than 0.001) in these patients. Since pulmonary capillary blood volume was normal, the pulmonary perfusion was within normal limits. Following three weeks of treatment with diethylcarbamazine citrate, although there was a significant rise in single breath transfer factor (p less than 0.001) and membrane diffusing capacity (p less than 0.05), both Dco (p less than 0.01) and Dm (p less than 0.01) continued to be significantly lower than those of control subjects. However, pulmonary capillary blood volume did not show any change (p greater than 0.2).
We examined the records of 14 patients aged 7 months to 10 1/4 years who were treated for bacterial tracheitis from May 1982 to December 1987; the management protocol for 13 of the patients included the use of nasotracheal intubation. The infection was caused by Staphylococcus aureus in seven, Haemophilus influenzae in three, Branhamella catarrhalis in one and Streptococcus pneumoniae in one. Both H. influenzae and B. catarrhalis were isolated in another patient, and no organism was found in the remaining patient. In addition to the bacteria, viruses were cultured from the tracheal secretions of two patients. The mean duration of intubation was 7.6 days and of hospital stay 9.2 days. Twelve of the cases occurred during the cold months of the year (October to March). Of the three deaths only one occurred in the pediatric intensive care unit and was due to severe bronchospasm and an air leak that caused bilateral pneumothorax and pneumomediastinum. In one patient subglottic stenosis developed that necessitated tracheostomy. Healing began 5 to 9 days after the onset of symptoms, as demonstrated with the use of repeated fibreoptic bronchoscopy. We found that the airway could be safely managed with the use of a nasotracheal tube. Bronchoscopy helped to confirm the diagnosis, to remove adherent secretions and to monitor the course of the disease. The ventilation tube can be removed after the patient's temperature returns to normal, if there is an air leak around the tube, if the quantity and viscosity of the secretions decrease and if healing is observed at bronchoscopy.
The ability of Shigella spp. to bind Congo red from agar medium is generally correlated with their virulence properties. We used a metabolically active culture of Shigella flexneri 2a to determine the effect of Congo red on its membrane protein profiles. Virulent S. flexneri grown in the presence of Congo red at 37 degrees C showed increased levels of three proteins with Mrs of 43,000, 58,000, and 63,000 (43K, 58K, and 63K proteins) in the Sarkosyl-soluble membrane fractions. The observed phenomenon was temperature dependent. At 30 or 42 degrees C the protein levels remained unaffected by the presence of Congo red. Similar regulation of the levels of the 43K, 58K, and 63K membrane proteins was also observed with Shigella dysenteriae 1 and enteroinvasive Escherichia coli, but not with enteropathogenic E. coli. The cellular uptake of Congo red seemed to be essential, but not sufficient, for regulation. All three proteins reacted with human convalescent-phase sera in immunoblots of S. flexneri 2a Sarkosyl-soluble membrane fractions. Using the 43K-specific antiserum as the primary antibody, by indirect immunofluorescence studies, we detected an increase in the level of the 43K protein in S. flexneri which had invaded epithelial cells. These observations strongly indicate that the 43K, 58K, and 63K proteins are virulence associated. We propose that the observed regulatory effect of Congo red on membrane proteins of S. flexneri is mediated through induction. Since the same regulatory effect was also observed during the invasion of epithelial cells by S. flexneri, it is suggested that Congo red mimics some host tissue factor in vitro.
In an attempt to prove whether beta-endorphin diurnal rhythm existed in neonates, 17 infants with a mean (+/- SD) gestational age of 31.7 +/- 4.8 weeks and a birth weight of 1,790 +/- 898 g were studied at a mean postnatal age of 3.3 +/- 0.5 days. Plasma samples were obtained from a pre-existing umbilical arterial line at 09.00 h, noon and 15.00 h. Mean plasma concentrations of beta-endorphin were 68.3 +/- 27.7, 54.5 +/- 13.7, and 45.1 +/- 10.8 pg/ml, respectively. Highly significant (p = 0.0002) variation of plasma beta-endorphin concentration was observed in these neonates suggesting the presence of a diurnal rhythm of beta-endorphin in neonates. It is important to specify the time of collection of blood samples for determination of opiates in neonates.
To determine whether a diurnal rhythm exists in neonates admitted to neonatal intensive care units where there is continuous artificial lighting and periodic nursing and medical care, plasma cortisol, adrenocorticotropin (ACTH), and beta-endorphin concentrations were measured in two groups of infants and in adult human volunteers. As expected, a diurnal rhythm was seen in adults. A diurnal rhythm was also found for cortisol and endorphin levels in neonates (3 to 4 days postnatally) with minimal stress and in infants who were clinically severely stressed. There was not a significant difference between the morning and afternoon concentrations of ACTH in these infants, but the afternoon concentrations were lower than the morning's, as would be expected. We found that a diurnal rhythm does exist in neonates within the first few days of postnatal life and that the continuous lighting and medical and nursing interventions do not interfere with this rhythm.
Bronchoalveolar lavage using flexible fibreoptic bronchoscope was carried out in 50 patients 1-2 1/2 yr after exposure to the 'toxic gas' at Bhopal. Thirty six patients in the analysis were categorised into 3 groups (viz., mild, moderate and severe), depending upon the severity of exposure. There was an increase in cellularity in the lower respiratory tract (alveolitis) of the severely exposed patients (in both smokers and non-smokers), compared to normals (P less than 0.05). The increase in cellularity in severely exposed non-smokers was due to abnormal accumulation of macrophages (P less than 0.01), and in severely exposed smokers, to macrophages (P less than 0.01) and neutrophils (P less than 0.05). Mild and moderately exposed patients did not show significant change in cellularity in lower respiratory tract, compared to normal individuals (P greater than 0.2). There was a trend towards increasing cellularity, as the severity increased (P less than 0.0001) and higher numbers of total cells were seen in severely exposed smokers, suggesting that smoking is a risk factor. It appears, therefore, that subjects severely exposed to the toxic gas at Bhopal may have a subclinical alveolitis characterised by accumulation and possibly activation of macrophages in the lower respiratory tract. Smokers, who were exposed to the gas had in addition, accumulation of neutrophils.
Chloral hydrate has been used clinically for over 100 years. There is significant paucity of information regarding chloral hydrate metabolism in neonates and infants. Chloral hydrate and its various metabolites were quantitated in 12 neonates and 2 infants at prescribed time intervals. The analysis of the data indicates accumulation of trichloroacetic acid and trichloroethanol in tissue of compromised infants. There is indirect evidence of competition for hepatic glucuronidation for bilirubin with trichloroethanol in ill preterm infants. Multiple dosing of chloral hydrate in preterm infants should be used with caution and frequent monitoring of serum bilirubin concentrations is indicated in such cases. The mechanism of chloral hydrate metabolism is discussed in detail.
A two-year-old child dying of pulmonary hypertension and cor pulmonale secondary to bronchopulmonary dysplasia, was demonstrated to have reactive pulmonary hypertension in response to 100% oxygen and isoproterenol infusion. In an attempt to find an oral medication to maintain pulmonary vasodilatation, experimental trials were done using hydralazine, salbutamol, nifedipine and diltiazem. Cardiac index, pulmonary and systemic vascular resistances and intrapulmonary shunts were monitored during the trials. Hydralazine, salbutamol and nifedipine were ineffective. Diltiazem 2.0 mg given every 6 h resulted in a profound and sustained decrease in pulmonary pressures and resistance, and a reversal of the cor pulmonale.