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.
We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009).
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.
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.)
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.
Rht1; Rht2; Rht3; Rht8; Rht10; Rht12; Triticum aestivum
interferon alfa; juxtapapillary choroidal neovascularisation; interferon's ocular adverse events
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
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
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.
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.
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.
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.
Laparoscopy; Renal transplantation; Hernia
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.
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.
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.
Benign prostatic hyperplasia; Holmium; Lasers
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.
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
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.
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.
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.
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
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
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.
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.
The association between haemospermia and hypertension was examined in a case-control study comparing 5 hypertensive patients with haemospermia to 20 age-matched hypertensive men. Patients with haemospermia had much higher blood pressures than hypertensive controls (200/131 mmHg vs 147/90 mmHg; P less than 0.0005/P less than 0.0001), higher left ventricular voltage on ECG (P less than 0.02), and higher concentrations of serum creatinine, proteinuria and renovascular disease (all P = 0.06 vs controls). Haemospermia is associated with severe uncontrolled hypertension. It is not, however, associated with hypertension per se, as the prevalence of hypertension in published series of patients with haemospermia is no higher than that expected in the general population. Men presenting with haemospermia should have their blood pressure measured carefully as they may require antihypertensive treatment urgently.
OBJECTIVE--To audit avoidable deaths from stroke and hypertensive disease. DESIGN--Details of care before death were obtained from general practitioners and other doctors, anonymised, and assessed by two experts against agreed minimum standards of good practice for detecting and managing hypertension. SETTING--Health authority with population of 250,000. SUBJECTS--All patients under 75 years who died of stroke, hypertensive disease, or hypertension related causes during November 1990 to October 1991. MAIN OUTCOME MEASURES--Presence of important avoidable factors and departures from minimum standards of good practice. RESULTS--Adequate information was obtained for 88% (123/139) of eligible cases. Agreement between the assessors was mostly satisfactory. 29% (36/123, 95% confidence interval 21% to 37%) of all cases and 44% (36/81, 34% to 55%) of those with definite hypertension had avoidable factors that may have contributed to death. These were most commonly failures of follow up and continuing smoking. Assessment against standards of minimum good practice showed that care was inadequate but not necessarily deemed to have contributed to death, in a large proportion of patients with definite hypertension. Common shortcomings were inadequate follow up, clinical investigation, and recording of smoking and other relevant risk behaviours. CONCLUSIONS--This method of audit can identify shortcomings in care of patients dying of hypertension related disease.