Biomedical subjects
Publications and source records attributed to E A Millar.
A case of adenocarcinoma in an ileal duplication cyst is presented. The pathological and radiological findings are described. A review of the literature on this rare condition is discussed.
The Sta-Peg procedure is most effective in the non-rigid foot in which reasonable muscle balance can be attained. Where such balance cannot be attained or where rigid deformity exists, this procedure will not solve the problem and should not be used. The authors want to emphasize that this study pertains to the use of Sta-Peg in the valgus foot caused by cerebral palsy. The procedure is rarely needed in the flexible flatfoot of a normal child.
STUDY OBJECTIVES: Endothelin (ET)-1 is a potent bronchoconstrictor, and asthmatics demonstrate bronchial hyperresponsiveness to ET-1 given by inhalation. Angiotensin II (Ang II) is increased in plasma in acute severe asthma, causes bronchoconstriction in asthmatics, and potentiates contractions induced by ET-1 in bovine bronchial smooth muscle in vitro, and contractions induced by methacholine both in vitro and in vivo. We wished to examine any potentiation of the bronchoconstrictor activity of inhaled ET-1 by infused Ang II at subbronchoconstrictor doses. DESIGN: Double-blind randomized placebo-controlled study. SETTING: Asthma research unit in university hospital. PATIENTS: Eight asthmatic subjects with baseline FEV1 88% predicted, bronchial hyperreactivity (geometric mean, concentration of methacholine producing 20% fall, methacholine PC20 2.5 mg/mL), and mean age 37.1 years. INTERVENTIONS: We examined the effect of subbronchoconstrictor doses of infused Ang II (1 ng/kg/min and 2 ng/kg/min) or placebo on bronchoconstrictor responses to inhaled ET-1 (dose range, 0.96 to 15.36 nmol). MEASUREMENTS: Oxygen saturation, noninvasive BP, and spirometric measurements were made throughout the study visits. Blood was sampled for plasma Ang II levels at baseline and before and after ET-1 inhalation. RESULTS: Ang II infusion did not produce bronchoconstriction per se at either dose prior to ET-1 challenge. Bronchial challenge with inhaled ET-1 produced dose-dependent bronchoconstriction, but there was no difference in bronchial responsiveness to ET-1 comparing infusion of placebo with Ang II at 1 ng/kg/min or 2 ng/kg/min (geometric mean, concentration of ET-1 producing 15% fall, 5.34 nmol, 4.95 nmol, and 4.96 nmol, respectively) (analysis of variance, p > 0.05). There was an increase in systolic and diastolic BP at the higher dose of Ang II compared to placebo (mean 136/86 vs 117/75 mm Hg, respectively). Plasma Ang II was elevated following infusion of both doses of Ang II compared to placebo. CONCLUSIONS: In contrast to the potentiating effect on methacholine-induced bronchoconstriction, Ang II at subbronchoconstrictor doses does not potentiate ET-1-induced bronchoconstriction in asthma.
Fibre-optic bronchoscopy is widely used to diagnose bronchial carcinoma. There is considerable variation in techniques for patient sedation, methods of obtaining samples and histopathological yield. We wished to examine variations in practice in different centres throughout Scotland and derive realistic audit standards for best clinical practice from these results. Diagnostic bronchoscopies from five centres were included. Patient details, grade of individual performing the test, endobronchial abnormalities, specimens taken and the histocytological yield were recorded. A patient satisfaction questionnaire was completed. One thousand eight hundred and two bronchoscopies were performed to look for bronchial carcinoma. Sedation and anaesthesia techniques varied considerably between centres. There were marked differences in patient satisfaction between centres. Nearly twice as many females as males would prefer not to have bronchoscopy repeated. Six hundred and fifty-eight carcinomas were confirmed by histocytology. Yield was unaffected by the grade of doctor performing bronchoscopy. Improving yield may be achieved by increasing the number of sampling techniques employed and changing the order in which specimens are taken (biopsies first and washings last). Eighty-seven percent of endoscopically visible tumours were confirmed histocytologically. There was a considerable variation in histological spectra between centres that may relate to differences in pathological interpretation rather than actual differences in case mix. Suggested audit standards are discussed. This study demonstrates the variety of techniques and also the levels of histocytological yield and patient satisfaction that can be achieved. Provisional standards of practice for this procedure have been agreed with a view to auditing performance against these. It is hoped that centres will adopt the methods that are shown to achieve the highest standards.
STUDY OBJECTIVE: We have previously described activation of the renin-angiotensin system (RAS) in acute severe asthma and have also reported activation of the RAS in normal subjects by single doses of nebulized beta 2-agonists. In the present study, we have examined the effect of single and multiple doses of nebulized albuterol on the activity of the RAS in mild asthma. DESIGN: Eight patients with mild asthma were studied. The effect of single and multiple doses of nebulized albuterol (5 mg) on the activity of the RAS was compared with that of placebo using a randomized, double-blind crossover study design. Nebulized drugs were administered at time 0 and 30 min. MEASUREMENTS: Plasma renin, angiotensin II (Ang II), and serum potassium levels were measured at baseline following a short rest, and thereafter at intervals up to 150 min. RESULTS: Renin levels increased after both the single (S) and double (D) nebulized doses of albuterol and were significantly greater than placebo at 30 min after S, and at 45 and 120 min after D. Plasma Ang II level also increased after S and D and was significantly greater than placebo at 30 and 45 min after S, and at 30 min and all timepoints thereafter following D. In addition, the effect of D was significantly greater than S at 45 min. CONCLUSIONS: These results confirm that there is activation of the RAS in asthmatic subjects by single doses of nebulized beta 2-agonists and that repeated dosing with nebulized albuterol has further, additive effects on plasma Ang II levels. It therefore seems likely that these agents are contributing to activation of the RAS in acute asthma, although the exact clinical significance of these transient changes in plasma Ang II levels in asthma is at present unclear.
Explore the source record for details and available documents.
BACKGROUND: The hormone atrial natriuretic peptide (ANP) causes bronchodilation and partially protects against direct and indirect bronchial challenges. Both in vitro and in vivo studies have found that the protective effect of ANP against bronchoconstriction is enhanced by inhibition of the enzyme neutral endopeptidase (NEP). It was hypothesised that pretreatment with thiorphan, an NEP inhibitor, might enhance the bronchodilator response to inhaled ANP. METHODS: In a randomised double blind placebo controlled crossover study, six asthmatic patients (one woman) of mean (SD) age 47.3 (3.8) years and forced expiratory volume in one second (FEV1) 1.91 (0.42) 1, 55 (3.8)% predicted, were studied. All were shown at screening to have at least a 25% improvement in FEV1 to inhaled salbutamol. On five study visits the patients received either thiorphan 1 mg (in 2 ml) followed by ANP 5 mg or placebo (saline), or placebo (saline) followed by ANP (5 mg), placebo or salbutamol 5 mg. Spirometric parameters were measured after each inhalation and thereafter for the next two hours. RESULTS: ANP alone caused a bronchodilator response up to 15 minutes when compared with placebo or thiorphan alone with a mean (SE) change in FEV1 of 16.8 (8.1)% and 16.1 (6.8)% at 10 and 15 minutes from baseline, respectively. Prior inhalation of thiorphan prolonged the duration of the bronchodilator effect of ANP up to 60 minutes with a mean (SE) change in FEV1 of 23.1 (3.4)% at 60 minutes. There was no difference in the maximum degree of bronchodilation following the administration of ANP alone compared with the combination of thiorphan and ANP. The degree and duration of the bronchodilator response produced by ANP, or the combination of the NEP inhibitor and ANP, were less than that produced by salbutamol. CONCLUSIONS: These results confirm that, at least in part, the bronchodilator response to inhaled ANP is modulated by NEP. Analogues of ANP which are stable to NEP may have greater bronchodilator activity than ANP in the treatment of asthma.
1. We have previously described activation of the renin-angiotensin system in asthma, and also by high-dose nebulized beta 2-agonists. In this study we sought to determine the mechanism responsible. 2. The influence of the angiotensin-converting enzyme inhibitor, lisinopril, on the response of the renin-angiotensin system and serum potassium to nebulized salbutamol was investigated in a randomized, double-blind, crossover study in eight healthy volunteers using a factorial block design. On study days, subjects received lisinopril 20 mg orally or identical placebo tablets followed 3 h later by nebulized salbutamol or placebo inhalation; plasma renin, angiotensin II, serum angiotensin-converting enzyme and potassium were measured at intervals for 120 min after inhalation. 3. Following salbutamol, plasma renin and angiotensin II concentrations were increased significantly compared with placebo [mean (SEM) plasma renin of 61.7 (15.6) mu-units/ml and angiotensin II of 17.7 (5.4) pg/mol 15 min after salbutamol, P < 0.05 versus placebo]. Baseline plasma renin concentrations were increased [160.1 (20.6) mu-units/ml] and baseline plasma angiotensin II concentrations were reduced [1.4 (0.1) pg/ml] by lisinopril, P < 0.05 versus placebo in each case. Inhibition of angiotensin-converting enzyme completely inhibited this salbutamol-induced rise in plasma angiotensin II [mean (SEM) plasma angiotensin II of 1.5 (0.4) pg/ml 15 min after salbutamol, P < 0.05 versus placebo] but had no effect on the changes in plasma renin concentrations after the beta 2-agonist [mean (SEM) plasma renin of 198.4 (18.9) mu-units/ml 15 min after salbutamol].(ABSTRACT TRUNCATED AT 250 WORDS)
1. We have reported that the renin-angiotensin system is activated in acute asthma, and also by high-dose nebulized beta 2-agonists. The contribution of other possible stimuli such as hypoxia is unknown. The present study examined the effect of hypoxia alone and also combined with beta 2-agonists on the activity of the renin-angiotensin system. 2. In a double-blind crossover study, eight healthy subjects were randomized to inhale a hypoxic (FiO2 = 12%) or normoxic mixture for a period of 30 min, with either nebulized salbutamol (5 mg) or placebo administered into the circuit after 10 min. Plasma renin, angiotensin II and serum angiotensin-converting enzyme were measured at baseline and at intervals up to 2 h. Pulse rate and oxygen saturation were monitored continuously throughout the study. 3. After hypoxia alone, there was no change in the levels of plasma renin or angiotensin II. When salbutamol was added to the hypoxic mixture, there was a significant rise in plasma renin and angiotensin II [mean (SEM) maximal increase in angiotensin II of 5.6 (2.9) pg/ml and renin of 15.5 (6.3) mu-units/ml at 60 min, P < 0.05 compared with normoxia]. When salbutamol was administered in the normoxic mixture, plasma renin and angiotensin II also increased but this effect was similar to the effect of salbutamol in the hypoxic mixture. Serum angiotensin-converting enzyme levels were unaffected by hypoxia or salbutamol. 4. We conclude from these results that there is activation of the renin-angiotensin system in healthy subjects by salbutamol, but not hypoxia. (ABSTRACT TRUNCATED AT 250 WORDS)
Explore the source record for details and available documents.
The reduced ability of inhaled compared with intravenous atrial natriuretic peptide (ANP) to modify bronchial reactivity and tone may be due to degradation of the peptide by neutral endopeptidase (NEP) within the airways. To test this hypothesis, we have examined the effect of thiorphan, an NEP inhibitor, on the protection afforded by inhaled ANP against histamine-induced bronchoconstriction in 10 mildly asthmatic patients. Pretreatment with ANP alone attenuated the bronchoconstrictor response to histamine with a mean (SEM) maximum percent fall in FEV1 after histamine of 15.9 (2.9) (p < 0.05) compared with 24 (2.9) after placebo and 24 (4) after pretreatment with thiorphan alone. Prior inhalation of thiorphan greatly enhanced the ANP effect: the mean maximum percent fall after this combination was 5.1 (2.3) (p < 0.01, compared with ANP alone). Our results suggest that airway NEP is important in modulating the effect of inhaled ANP. It may be possible to exploit the guanylyl cyclase pathway, by which ANP acts, in the treatment of asthma by the administration of ANP analogues stable to neutral endopeptidase.
Angiotensin II levels are elevated in patients with acute severe asthma. In addition, intravenous angiotensin II causes bronchoconstriction in mild asthmatic patients. In the present study, we examined the effects of this hormone on bronchi in vitro and its interaction with the cholinergic agonist methacholine both in vivo and in vitro. Contractions of rings of human bronchi were measured isometrically. Concentration-response curves were obtained to angiotensin II and to methacholine in the presence and absence of angiotensin II. In addition, seven asthmatic patients with mild bronchial hyperreactivity to methacholine received placebo, angiotensin II, 1 or 2 ng.kg-1.min, by infusion, followed by methacholine challenge. Forced expiratory volume in one second (FEV1) values were measured at baseline, at the end of the infusion and during methacholine challenge. Angiotensin II alone in vitro evoked small contractions of human bronchi ( < 0.25 g wt). Pre-incubation with low concentrations of angiotensin II significantly enhanced contractions to methacholine. In mild asthmatic patients, angiotensin II alone evoked no change in baseline FEV1 values at the levels studied. Compared to placebo, angiotensin II 2 ng.kg-1.min, but not 1 ng.kg-1.min, evoked a significant increase in bronchial reactivity to methacholine. Angiotensin II in subthreshold concentrations enhances methacholine-evoked bronchoconstrictions both in human in vitro and in mild asthmatic patients in vivo. Our findings suggest a novel role for angiotensin II as a putative mediator in asthma.
Aarskog-Scott syndrome was tentatively mapped to Xq13 on the basis of an X:8 translocation by Bawle et al. [Am J Med Genet 17:595-602, 1984]. A review of the cytogenetics and the use of molecular markers in that family have resulted in revision of the breakpoints of the translocation to Xp 11.2 and 8q11.21 [Glover et al., Hum Mol Genet 2:1717-1718, 1993]. Two families, including one of the two initial families with Aarskog-Scott syndrome [Scott, BD:OAS VII (6): 240-246, 1971], have participated in our study to evaluate the localization of the gene for Aarskog-Scott syndrome to the pericentromeric region of the X chromosome. Using a series of DNA probes, we have been able to confirm linkage to the X chromosome, with multipoint analysis indicating the most likely localization of the gene to be on the proximal short arm.
BACKGROUND: The activity of the renin-angiotensin system in asthma has not been studied previously and the effect of angiotensin II (AII) on bronchomotor tone in vivo is unknown. METHODS: Plasma levels of renin and AII levels were measured in 20 patients with acute severe asthma, nine with mild asthma, 10 with severe chronic asthma, and 16 normal volunteers. The effect of AII, given as an intravenous infusion, on bronchomotor tone was also investigated in eight mild asthmatic patients. RESULTS: In acute severe asthma plasma levels of renin [median (interquartile range)] were elevated on days 1, 2, and 5 after admission [48.7 (24-79), 44.2 (15-75), and 45.5 (21-70) microU/ml, respectively]. Plasma AII levels were significantly elevated at day 5 [56 (12-109) pg/ml]. In the second study a bronchoconstrictor response to intravenous AII was seen with a mean (SE) maximal fall in FEV1 of 0.34 (0.13) litres or 12.4 (3.3)% from baseline following the high dose infusion of AII (8 ng/kg/min) with a corresponding plasma AII concentration of 121.3 pg/ml. CONCLUSIONS: The renin-angiotensin system is activated in acute asthma and AII causes bronchoconstriction in vivo in man. These observations suggest that in some patients AII may contribute to bronchoconstriction during acute severe asthma.
Further delineation of a generalized bone dysplasia which we call spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type is presented. This dwarfing condition has several serious complications, with the most common cause of death being spinal cord damage secondary to atlantoaxial instability. It is a heritable condition with an autosomal recessive mode of transmission. Radiologic diagnostic criteria are developed on the basis of studies in 8 patients with the oldest being between 4 and 5 years old. The condition is clinically and radiographically apparent neonatally or in early infancy, and it is probable that all or almost all affected individuals will come to medical attention in the age range screened by this study.
Results from multiple tests including somatosensory evoked potentials, passive resistance to motion, upper extremity motor skills evaluation, neuromuscular examination, and parental interview were evaluated in 13 children with cerebral palsy (CP) who received chronic cerebellar stimulation (CCS) for reduction of spasticity and movement disorders during the past 14 years. The prospective study included immediate postoperative follow-up data as well as longer term results from the quantitative test series. Although CCS was effective in reducing hypertonicity in CP children during the immediate short-term, the diminishment waned significantly 3-5 years postoperatively.
The cases of nine children who survived the acute stage of meningococcal septicemia and secondary disseminated intravascular coagulation were reviewed. All of the children had major orthopaedic problems as a result of the acute disease. Detailed histological studies were performed on specimens of bone and cartilage, obtained when these patients had either acute amputation for gangrene or subsequent revision for a chondro-osseous deformity. In the specimens that were obtained from the children who had acute gangrene, the histological changes included small-vessel thrombi, osteonecrosis, subperiosteal new-bone formation, cortical disruption, cellular disorganization in the physis, and medullary inflammation. These findings were compatible with a combination of inflammation (acute osteomyelitis) and ischemia. In the specimens that were obtained during revision of the amputation, three years or more after the initial infectious or ischemic process, the clinically relevant findings involved the epiphyses and physes. The growth plates showed variable permanent ischemic damage. Bone bridges connecting the epiphysis and metaphysis were observed in various stages of formation, including several early bridges with involvement of only the physis and metaphysis. Endosteal and cortical bone, in contrast, showed complete recovery with no evidence of permanent ischemic damage. We concluded that children who survive meningococcal septicemia are at high risk for complex orthopaedic problems, both acute and chronic. The disseminated intravascular coagulation and focal infections of the acute phase are primarily responsible for the vascular injuries to the growing chondro-osseous tissues. Ischemic changes also selectively involve the physeal circulation, but may take several years to adversely affect longitudinal and transverse growth of bone.
Fifty-seven patients (seventy-one limbs) who had congenital longitudinal deficiency of the tibia (tibial hemimelia) were retrospectively categorized according to radiographic type (Types 1 through 4, as described by Jones et al.). At an average follow-up of nine years, fifty-six of fifty-seven patients walked independently. An ablative surgical procedure was performed on sixty-one of the seventy-one lower extremities. According to the classification of Jones et al., fifty-four limbs had a Type-1 (a or b) or Type-2 deficiency. In twenty-two of these extremities, disarticulation of the knee was performed; in twenty-five, a Syme amputation; and in one, a Chopart amputation. The ipsilateral foot was retained in six extremities that had a severe Type-1 or Type-2 deficiency. Medial transfer of the fibula (the Brown procedure) generally yielded less than satisfactory results; in ten of fourteen extremities, one or more additional operations were needed. Seventeen extremities were classified as having a Type-3 or Type-4 deficiency; Syme amputation was done in nine and Chopart amputation, in four. Despite satisfactory reconstruction of the ankle, a Syme amputation was necessary in most extremities that had a Type-4 deficiency because a major leg-length discrepancy was projected. In four limbs that had a Type-3 or Type-4 deficiency, the foot was retained.