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1.  A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency 
Background
The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T−B− severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes.
Objective
We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations.
Methods
We have developed a flow cytometry–based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1−/− pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology.
Results
Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity.
Conclusions
Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process.
doi:10.1016/j.jaci.2013.10.007
PMCID: PMC4005599  PMID: 24290284
Recombination-activating gene 1; V(D)J recombination; severe combined immune deficiency; Omenn syndrome; autoimmunity; genotype-phenotype correlation; immune repertoire
2.  Transplantation Outcomes for Severe Combined Immunodeficiency, 2000–2009 
The New England journal of medicine  2014;371(5):434-446.
BACKGROUND
The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth.
METHODS
We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009).
RESULTS
Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell–depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pre-transplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival.
CONCLUSIONS
Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.)
doi:10.1056/NEJMoa1401177
PMCID: PMC4183064  PMID: 25075835
3.  The effects of dwarfing genes on seedling root growth of wheat 
Journal of Experimental Botany  2009;60(9):2565-2573.
Most modern wheat cultivars contain major dwarfing genes, but their effects on root growth are unclear. Near-isogenic lines (NILs) containing Rht-B1b, Rht-D1b, Rht-B1c, Rht8c, Rht-D1c, and Rht12 were used to characterize the effects of semi-dwarfing and dwarfing alleles on root growth of ‘Mercia’ and ‘Maris Widgeon’ wheat cultivars. Wheat seedlings were grown in gel chambers, soil-filled columns, and in the field. Roots were extracted and length and dry mass measured. No significant differences in root length were found between semi-dwarfing lines and the control lines in any experiment, nor was there a significant difference between the root lengths of the two cultivars grown in the field. Total root length of the dwarf lines (Rht-B1c, Rht-D1c, and Rht12) was significantly different from that of the control although the effect was dependent on the experimental methodology; in gel chambers root length of dwarfing lines was increased by ∼40% while in both soil media it was decreased (by 24–33%). Root dry mass was 22–30% of the total dry mass in the soil-filled column and field experiments. Root length increased proportionally with grain mass, which varied between NILs, so grain mass was a covariate for the analysis of variance. Although total root length was altered by dwarf lines, root architecture (average root diameter, lateral root:total root ratio) was not affected by reduced height alleles. A direct effect of dwarfing alleles on root growth during seedling establishment, rather than a secondary partitioning effect, was suggested by the present experiments.
doi:10.1093/jxb/erp107
PMCID: PMC2692010  PMID: 19439763
Rht1; Rht2; Rht3; Rht8; Rht10; Rht12; Triticum aestivum
4.  Bilateral juxtapapillary choroidal neovascularisation associated with interferon alfa treatment of a metastatic cutaneous melanoma 
doi:10.1136/bjo.2005.084681
PMCID: PMC1857019  PMID: 16547342
interferon alfa; juxtapapillary choroidal neovascularisation; interferon's ocular adverse events
5.  Population implications of lipid lowering for prevention of coronary heart disease: data from the 1995 Scottish health survey 
Heart  2001;86(3):289-295.
OBJECTIVE—To determine the proportion of the population, firstly, with cholesterol ⩾ 5.0 mmol/l and, secondly, with any cholesterol concentration, who might benefit from statin treatment for the following: secondary prevention of coronary heart disease (CHD); primary prevention at CHD risk 30%, 20%, 15%, and 6% over 10 years; and primary prevention at projected CHD risk 20% over 10 years (CHD risk at age 60 years if actual age < 60 years).
SUBJECTS—Random stratified sample of 3963 subjects aged 35-64 years from the Scottish health survey 1995.
RESULTS—For secondary prevention 7.8% (95% confidence interval (CI) 6.9% to 8.6%) of the population with cholesterol ⩾ 5.0 mmol/l would benefit from statins. For primary prevention, the prevalence of people at CHD risk 30%, 20%, 15%, and 6% over 10 years is 1.5% (95% CI 1.2% to 1.9%), 5.4% (95% CI 4.7% to 6.1%), 9.7% (95% CI 8.8% to 10.6%), and 32.9% (95% CI 31.5% to 34.4%), respectively. At projected CHD risk 20% over 10 years, 12.4% (95% CI 11.4% to 13.5%) would be treated with statins. Removing the 5.0 mmol/l cholesterol threshold makes little difference to population prevalence at high CHD risk.
CONCLUSIONS—Statin treatment would be required for 7.8% of the population for secondary prevention. For primary prevention, among other factors, guidelines should take into account the number of patients needing treatment at different levels of CHD risk when choosing the CHD risk to target. The analysis supports a policy of targeting treatment at CHD risk 30% over 10 years as a minimum, as recommended in current British guidelines, with a move to treating at CHD risk 15% over 10 years as resources permit.


Keywords: statins; coronary risk; secondary prevention; primary prevention
doi:10.1136/heart.86.3.289
PMCID: PMC1729888  PMID: 11514481
6.  Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials 
Heart  2001;85(3):265-271.
OBJECTIVE—To determine the cardiovascular and coronary risk thresholds at which aspirin for primary prevention of coronary heart disease is safe and worthwhile.
DESIGN—Meta-analysis of four randomised controlled trials of aspirin for primary prevention. The benefit and harm from aspirin treatment were examined to determine: (1) the cardiovascular and coronary risk threshold at which benefit in prevention of myocardial infarction exceeds harm from significant bleeding; and (2) the absolute benefit expressed as number needed to treat (NNT) for aspirin net of cerebral haemorrhage and other bleeding complications at different levels of coronary risk.
MAIN OUTCOME MEASURES—Benefit from aspirin, expressed as reduction in cardiovascular events, myocardial infarctions, strokes, and total mortality; harm caused by aspirin in relation to significant bleeds and major haemorrhages.
RESULTS—Aspirin for primary prevention significantly reduced all cardiovascular events by 15% (95% confidence interval (CI) 6% to 22%) and myocardial infarctions by 30% (95% CI 21% to 38%), and non-significantly reduced all deaths by 6% (95% CI −4% to 15%). Aspirin non-significantly increased strokes by 6% (95% CI −24% to 9%) and significantly increased bleeding complications by 69% (95% CI 38% to 107%). The risk of major bleeding balanced the reduction in cardiovascular events when cardiovascular event risk was 0.22%/year. The upper 95% CI for this estimate suggests that harm from aspirin is unlikely to outweigh benefit provided the cardiovascular event risk is 0.8%/year, equivalent to a coronary risk of 0.6%/year. At coronary event risk 1.5%/year, the five year NNT was 44 to prevent a myocardial infarction, and 77 to prevent a myocardial infarction net of any important bleeding complication. At coronary event risk 1%/year the NNT was 67 to prevent a myocardial infarction, and 182 to prevent a myocardial infarction net of important bleeding.
CONCLUSIONS—Aspirin treatment for primary prevention is safe and worthwhile at coronary event risk ⩾ 1.5%/year; safe but of limited value at coronary risk 1%/year; and unsafe at coronary event risk 0.5%/year. Advice on aspirin for primary prevention requires formal accurate estimation of absolute coronary event risk.


Keywords: aspirin; coronary heart disease; primary prevention; meta-analysis
doi:10.1136/heart.85.3.265
PMCID: PMC1729640  PMID: 11179262
7.  The Use of Blunt-tipped 12-mm Trocars Without Fascial Closure in Laparoscopic Live Donor Nephrectomy 
Objectives:
Blunt-tipped trocar placement may eliminate the need for fascial closure in transperitoneal laparoscopic live donor nephrectomies (LDN). The process of 12-mm blunt-tipped trocar insertion through the abdominal wall involves fascial and muscle spreading, not incision. Coaptation of the tissue layers occurs during withdrawal of the trocar, preventing volume gaps that can be prone to herniation.
Methods:
We retrospectively assessed the safety and efficacy of fascial nonclosure after 12-mm blunt-tipped port insertion in 70 transperitoneal LDNs performed between October 1998 and March 2001. Five ports (two 12-mm blunt-tipped and three 5-mm blunt-tipped) were used in all cases. The 12-mm trocars were inserted at the lateral border of the rectus muscle, approximately 8 cm below the costal margin and also along the anterior axillary line approximately 8 cm below the costal margin. Fascial non-closure was performed in all 70 patients. Postoperative data were analyzed regarding complications and long-term outcomes.
Results:
Three major and 7 minor complications occurred in this series. No patient developed clinically detectable trocar-site hernias or other complications related to blunt-trocar placement.
Conclusions:
Our data shows that fascial nonclosure after transperitoneal 12-mm blunt-tipped trocar insertion is safe. Visualization of the tissue layers during port placement facilitated the insertion process. Further application of this method in a larger number of patients is needed to confirm its clinical applicability.
PMCID: PMC3015504  PMID: 14974663
Laparoscopy; Renal transplantation; Hernia
8.  Parental attitudes regarding interviews about injuries to their children 
Injury Prevention  2000;6(4):311.
doi:10.1136/ip.6.4.311
PMCID: PMC1730663  PMID: 11144637
9.  Holmium Laser Enucleation of the Prostate (HoLEP): A Technical Update 
Introduction
Holmium laser enucleation of the prostate (HoLEP) combined with mechanical morcellation represents the latest refinement of holmium:YAG surgical treatment for benign prostatic hyperplasia (BPH). Utilizing this technique, even the largest of glands can be effectively treated with minimal morbidity. The learning curve remains an obstacle, preventing more widespread adoption of this procedure. This paper provides an outline of the HoLEP technique as is currently used at two centers in hopes of easing the initial learning curve.
Technical considerations
Detailed descriptions of the major steps of the HoLEP procedure are provided with attention to critical steps such as identification of the surgical capsule, median and lateral lobe enucleation, and morcellation of enucleated tissue.
Conclusions
HoLEP is a promising alternative for the surgical treatment of BPH which allows complete removal of intact lobes of the prostate. Obstruction is relieved immediately with superior hemostasis, no risk of TUR syndrome, and a minimal hospital stay.
doi:10.1186/1477-7819-1-6
PMCID: PMC165416  PMID: 12818001
Benign prostatic hyperplasia; Holmium; Lasers
10.  Cost effectiveness of statins 
Heart  2000;83(6):713.
doi:10.1136/heart.83.6.713a
PMCID: PMC1760882  PMID: 10885942
11.  Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle 
Journal of Clinical Investigation  2003;111(5):607-616.
Our purpose here is to test the hypothesis that Randall’s plaques, calcium phosphate deposits in kidneys of patients with calcium renal stones, arise in unique anatomical regions of the kidney, their formation conditioned by specific stone-forming pathophysiologies. To test this hypothesis, we performed intraoperative biopsies of plaques in kidneys of idiopathic-calcium-stone formers and patients with stones due to obesity-related bypass procedures and obtained papillary specimens from non–stone formers after nephrectomy. Plaque originates in the basement membranes of the thin loops of Henle and spreads from there through the interstitium to beneath the urothelium. Patients who have undergone bypass surgery do not produce such plaque but instead form intratubular hydroxyapatite crystals in collecting ducts. Non–stone formers also do not form plaque. Plaque is specific to certain kinds of stone-forming patients and is initiated specifically in thin-limb basement membranes by mechanisms that remain to be elucidated.
doi:10.1172/JCI200317038
PMCID: PMC151900  PMID: 12618515
12.  Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment 
Heart  1999;82(3):325-332.
OBJECTIVES—To estimate the cost effectiveness of statin treatment in preventing coronary heart disease (CHD) and to examine the effect of the CHD risk level targeted and the cost of statins on the cost effectiveness of treatment.
DESIGN—Cohort life table method using data from outcome trials.
MAIN OUTCOME MEASURES—The cost per life year gained for lifelong statin treatment at annual CHD event risks of 4.5% (secondary prevention) and 3.0%, 2.0%, and 1.5% (all primary prevention), with the cost of statins varied from £100 to £800 per year.
RESULTS—The costs per life year gained according to annual CHD event risk were: for 4.5%, £5100; 3.0%, £8200; 2.0%, £10 700; and 1.5%, £12 500. Reducing the cost of statins increases cost effectiveness, and narrows the difference in cost effectiveness across the range of CHD event risks.
CONCLUSIONS—At current prices statin treatment for secondary prevention, and for primary prevention at a CHD event risk 3.0% per year, is as cost effective as many treatments in wide use. Primary prevention at lower CHD event risks (< 3.0% per year) is less cost effective and unlikely to be affordable at current prices and levels of health service funding. As the cost of statins falls, primary prevention at lower risk levels becomes more cost effective. However, the large volume of treatment needed will remain a major problem.


Keywords: coronary artery disease; cost effectiveness; statins; primary prevention; secondary prevention
PMCID: PMC1729169  PMID: 10455083
13.  Injury surveillance in an accident and emergency department: a year in the life of CHIRPP 
Archives of Disease in Childhood  1999;80(6):533-536.
BACKGROUND—The design of childhood injury prevention programmes is hindered by a dearth of valid and reliable information on injury frequency, cause, and outcome. A number of local injury surveillance systems have been developed to address this issue. One example is CHIRPP (Canadian Hospitals Injury Reporting and Prevention Program), which has been imported into the accident and emergency department at the Royal Hospital for Sick Children, Glasgow. This paper examines a year of CHIRPP data.
METHODS—A CHIRPP questionnaire was completed for 7940 children presenting in 1996 to the accident and emergency department with an injury or poisoning. The first part of the questionnaire was completed by the parent or accompanying adult, the second part by the clinician. These data were computerised and analysed using SPSSPC for Windows.
RESULTS—Injuries commonly occurred in the child's own home, particularly in children aged 0-4 years. These children commonly presented with bruising, ingestions, and foreign bodies. With increasing age, higher proportions of children presented with injuries occurring outside the home. These were most commonly fractures, sprains, strains, and inflammation/oedema. Seasonal variations were evident, with presentations peaking in the summer.
CONCLUSIONS—There are several limitations to the current CHIRPP system in Glasgow: it is not population based, only injuries presented to the accident and emergency department are included, and injury severity is not recorded. Nevertheless, CHIRPP is a valuable source of information on patterns of childhood injury. It offers local professionals a comprehensive dataset that may be used to develop, implement, and evaluate child injury prevention activities.


PMCID: PMC1717950  PMID: 10332002
14.  Is the Framingham risk function valid for northern European populations? A comparison of methods for estimating absolute coronary risk in high risk men 
Heart  1999;81(1):40-46.
Objective—To examine the validity of estimates of coronary heart disease (CHD) risk by the Framingham risk function, for European populations.
Design—Comparison of CHD risk estimates for individuals derived from the Framingham, prospective cardiovascular Münster (PROCAM), Dundee, and British regional heart (BRHS) risk functions.
Setting—Sheffield Hypertension Clinic. 
 Patients—206 consecutive hypertensive men aged 35-75 years without preexisting vascular disease. 
Results—There was close agreement among the Framingham, PROCAM, and Dundee risk functions for average CHD risk. For individuals the best correlation was between Framingham and PROCAM, both of which use high density lipoprotein (HDL) cholesterol. When Framingham was used to target a CHD event rate > 3% per year, it identified men with mean CHD risk by PROCAM of 4.6% per year and all had CHD event risks > 1.5% per year. Men at lower risk by Framingham had a mean CHD risk by PROCAM of 1.5% per year, with 16% having a CHD event risk > 3.0% per year. BRHS risk function estimates of CHD risk were fourfold lower than those for the other three risk functions, but with moderate correlations, suggesting an important systematic error.
Conclusion—There is close agreement between the Framingham, PROCAM, and Dundee risk functions as regards average CHD risk, and moderate agreement for estimates within individuals. Taking PROCAM as the external standard, the Framingham function separates high and low CHD risk groups and is acceptably accurate for northern European populations, at least in men. 

 Keywords: ischaemic heart disease;  prevention;  risk factors
PMCID: PMC1728900  PMID: 10220543
15.  The effect of dietary amino acid composition on egg production in blue tits 
Most studies on the interaction between food supply and reproduction in animals have assumed that energy is likely to be the factor limiting egg number and/or size. In this paper, we investigate whether dietary protein proximately constrains egg production in birds. We provisioned breeding blue tits with two food supplements that differed only in the concentration of five essential amino acids. Birds receiving a supplementary diet containing an amino acid balance close to that required for egg protein formation laid significantly larger clutches (18% greater) than control birds, whereas birds receiving an otherwise identical supplementary diet but without a favourable amino acid balance did not increase egg production. To our knowledge, this is the first demonstration that dietary amino acid composition may limit egg production in free-living birds.
doi:10.1098/rspb.1998.0448
PMCID: PMC1689217
16.  Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients 
Aims
To investigate whether an interaction between diltiazem and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin may enhance the cholesterol-lowering response to simvastatin in diltiazem-treated patients.
Methods
One hundred and thirty-five patients attending the Sheffield hypertension clinic who started consecutively on simvastatin for primary or secondary prevention of coronary heart disease (CHD) during the 2 years June, 1996—May 1998 were surveyed. From the clinic records we extracted and recorded absolute and percentage cholesterol responses to the starting dose of simvastatin and coprescription of diltiazem.
Results
The cholesterol reduction for the 19 patients on diltiazem was 33.3% compared with 24.7% in the remaining 116 patients (median difference 8.6%, 95% CI 1.1–12.2%, P < 0.02). The interindividual variability of cholesterol response to simvastatin was greater for patients not taking diltiazem than for those patients taking diltiazem. The ratio of the variances in response for the nondiltiazem group relative to the diltiazem group was 1.34 at 10 mg simvastatin daily (not significant, 95% CI 0.16–4.11), and 3.42 at 20 mg daily (P < 0.01, 95% CI 1.26–7.18). Concurrent diltiazem therapy (P < 0.04), age (P = 0.001) and starting dose of simvastatin (P = 0.002) were found to be significant independent predictors of percentage cholesterol response.
Conclusions
Patients who take both simvastatin and diltiazem may need lower doses of simvastatin to achieve the recommended reduction in cholesterol. The pharmacokinetic and pharmacodynamic aspects of this interaction need further study to confirm an enhanced effect on cholesterol reduction, and exclude an increased risk of adverse events.
doi:10.1046/j.1365-2125.1999.00066.x
PMCID: PMC2014381  PMID: 10583033
cholesterol reduction; CYP3A4; diltiazem; interaction; simvastatin
18.  Use of statins 
BMJ : British Medical Journal  1998;317(7156):473.
PMCID: PMC1113724  PMID: 9703541
20.  Acute renal failure with ACE inhibition in aortic coarctation. 
Postgraduate Medical Journal  1994;70(830):927-929.
A 43 year old man with inoperable aortic coarctation and severe hypertension requiring near maximal anti-hypertensive treatment was admitted in severe heart failure. After 2 weeks of treatment the heart failure and blood pressure were incompletely controlled and angiotensin converting enzyme (ACE) inhibitor was started. Serum creatinine was normal before starting the ACE inhibitor and on discharge from hospital. The patient was re-admitted a week later with gross fluid retention and in renal failure. In the absence of alternative causes, a diagnosis of ACE inhibitor-induced renal failure was made and treatment was stopped. The patient required haemodialysis for 2 days and within 1 week the renal function had reverted to normal and has remained so for 1 year. We propose that the renal haemodynamics in severe aortic coarctation are similar to those in bilateral severe renal artery stenosis and advise caution in the use of ACE inhibitors for adults with aortic coarctation.
PMCID: PMC2398015  PMID: 7870644
21.  Cytochromes P450 mediating the N-demethylation of amitriptyline  
Aims Using human liver microsomes and heterologously expressed human enzymes, we have investigated the involvement of CYPs 1A2, 2C9, 2C19, 2D6 and 3A4 in the N-demethylation of amitriptyline (AMI), with a view to defining likely influences on its clinical pharmacokinetics.
Methods The kinetics of formation of nortriptyline (NT) from AMI were measured over the substrate concentration range 1–500 μm, using liver microsomes from four extensive metabolisers (EM) and one poor metaboliser (PM) with respect to CYP2D6 activity.
Results The data were best described by a two-site model comprising a Michaelis-Menten function for a high affinity site and a Hill function for a low affinity site. The activity at the low affinity site was eliminated by triacetyloleandomycin and ketoconazole, selective inhibitors of CYP3A4, such that the kinetics were then described by a two-site model comprising two Michaelis-Menten functions. A further decrease in activity was associated with the addition of the CYP2C9 inhibitor sulphaphenazole such that the residual kinetics were best described by a single Michaelis-Menten function. The addition of quinidine, a selective inhibitor of CYP2D6, along with triacetyloleandomycin and sulphaphenazole produced an additional decrease in the rate of NT formation in all but the PM liver, but did not completely eliminate the reaction. The remaining activity was best described by a single Michaelis-Menten function. Inhibitors of CYP1A2 (furafylline) and CYP2C19 (mephenytoin) did not impair NT formation. Microsomes from yeast cells expressing CYP2D6 and from human lymphoblastoid cells expressing CYP3A4 or CYP2C9-Arg N-demethylated AMI, but those from cells expressing CYPs 1A2 and 2C19 did not.
Conclusions We conclude that CYPs 3A4, 2C9 and 2D6 together with an unidentified enzyme, but not CYPs 1A2 and 2C19, mediate the N-demethylation of AMI. Thus, the clinical pharmacokinetics of AMI would be expected to depend upon the net activities of all of these enzymes. However, the quantitative importance of each isoform is difficult to predict without knowledge of the exposure of the enzymes in vivo to AMI.
doi:10.1046/j.1365-2125.1997.05382.x
PMCID: PMC2042727  PMID: 9131945
cytochrome P450; CYP2D6; amitriptyline; N-dealkylation
22.  Resolution of ACE inhibitor cough: changes in subjective cough and responses to inhaled capsaicin, intradermal bradykinin and substance-P. 
1. In eight hypertensive patients with ACE inhibitor-induced cough the resolution of the cough was examined in a prospective observational study over 4 weeks duration. Resolution of cough was measured by visual analogue scales and questionnaire at baseline and days 3, 7, 14 and 28. In addition changes in cough sensitivity to inhaled capsaicin, and skin responses to bradykinin and substance-P were measured at the same time points. 2. All patients recorded significant subjective improvement in cough questionnaire scores for severity and night time waking, and by visual analogue scales for severity and frequency of cough (all P < 0.0005 for trend from day 0-28). Significant changes in subjective measures were recorded by 3 to 7 days for most measures, but further reductions were observed up to day 28 (all P < 0.01 day 28 vs day 0). 3. The sensitivity to inhaled capsaicin fell over the 28 days of study after stopping enalapril. The potency of capsaicin relative to day 0 was reduced to 0.25 (95% CI 0.07-0.87) by day 14, and to 0.20 (95% CI 0.06-0.67) by 28 days. 4. After stopping enalapril there was a highly significant reduction in wheal area produced by intradermal bradykinin, with the majority of the effect seen by day 3 (P < 0.0005). The wheal area to intradermal substance-P also declined with time after stopping enalapril, but significant changes were not observed until 14 days (P < 0.01). 5. Multiple regression analysis of the rates of decline for the subjective and objective measures of cough showed significant associations between the response to inhaled capsaicin and the VAS scores for severity of cough (P = 0.005) and frequency of cough (P = 0.011). Capsaicin response was not related significantly to the severity of cough measured by self-administered questionnaire. 6. There was a significant association between bradykinin response and VAS scores for frequency of cough (P < 0.04) and severity of cough (P < 0.05), but not with cough by questionnaire or the capsaicin response. The response to substance-P did not relate significantly to any of the measures of cough. 7. Cough caused by enalapril improved markedly by 14 days but took up to 28 days to resolve. It was associated with increased sensitivity to inhaled capsaicin which decreased over 28 days, and which paralleled changes in subjective cough scores.
PMCID: PMC1365187  PMID: 8703645
23.  Effect of dose adjustment on enalapril-induced cough and the response to inhaled capsaicin. 
1. In nine hypertensive patients with enalapril-induced cough the effect of altering the dose of enalapril on subjective cough and the cough response to inhaled capsaicin was examined in a random single-blind balanced cross-over study. They received three doses of enalapril, each for 3 weeks; the dose at entry (mean 10 mg daily); double this dose (mean 20 mg daily); and half this dose (mean 5 mg daily). 2. The cough response to inhaled capsaicin was also measured in two control groups: hypertensive patients on long-term enalapril treatment with no cough (n = 18), and hypertensive patients taking nifedipine (n = 17). 3. In patients with enalapril-induced cough there were significant dose-responses for enalapril as regards severity of cough (P < 0.05) and night time waking by cough (P < 0.05), but not for frequency of cough. Although the cough was less severe (P < 0.02) and caused less night time waking (P < 0.03) on the lowest dose of enalapril (mean 5 mg daily) it did not disappear completely in any patient. 4. The sensitivity to inhaled capsaicin did not differ significantly on the three doses of enalapril. The relative potency of capsaicin on enalapril 20 mg compared with enalapril 5 mg was 1.0 (95% CI 0.4-2.2). The wide confidence limits indicate that an important dose-dependent shift in capsaicin sensitivity is not excluded. 5. The sensitivity to inhaled capsaicin differed significantly between patients with enalapril-induced cough and both control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1365003  PMID: 7619668
24.  Relation between changes in blood pressure and serum ACE activity after a single dose of enalapril and ACE genotype in healthy subjects. 
1. The effects of a single oral dose of enalapril 10 mg on serum ACE activity and blood pressure in relation to the ACE genotype were studied in 27 healthy men, n = 9 each of genotype DD, ID and II, in a parallel group study design. 2. Before treatment serum ACE activity differed significantly between the genotypes, with serum ACE activity 56% higher in DD than II subjects, and the genotype explaining 40% of between-subject variance in serum ACE activity. 3. After oral enalapril 10 mg the absolute fall in serum ACE activity was significantly larger in DD than II subjects at 2, 4, and 6 h (by 9.0 (95% CI 0.7-17.2), 10.7 (3.8-17.6), and 9.7 (2.8-16.6) nmol ml-1 min-1 respectively), but not at 24 h (fall in II > DD by 1.1 (-8.9 to 6.7) nmol ml-1 min-1). 4. Serum ACE activity remained significantly related to the ACE genotype at each time-point after enalapril, with the genotype explaining 22-46% of between-subject variance in serum ACE. 5. Falls in mean arterial pressure in response to enalapril were not significantly related to the ACE genotype, with the average fall over 6 h in DD > II genotype by 0.7 mm Hg (95% CI -5.5 to 4.1). 6. Blood pressure responses to enalapril did not correlate significantly with the initial serum ACE, or the absolute or percent reductions in serum ACE activity after enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1364949  PMID: 7742150

Results 1-25 (129)