Cerebral-placental-uterine ratio as novel predictor of late fetal growth restriction: prospective cohort study.

OBJECTIVE: Fetal growth restriction (FGR) is a major risk factor for stillbirth and most commonly arises from uteroplacental insufficiency. Despite clinical examination and third-trimester fetal biometry, cases of FGR often remain undetected antenatally. Placental insufficiency is known to be associated with altered blood flow resistance in maternal, placental and fetal vessels. The aim of this study was to evaluate the performance of individual and combined Doppler blood flow resistance measurements in the prediction of term small-for-gestational age and FGR. METHODS: This was a prospective study of 347 nulliparous women with a singleton pregnancy at 36 weeks' gestation in which fetal growth and Doppler measurements were obtained. Pulsatility indices (PI) of the uterine arteries (UtA), umbilical artery (UA) and fetal vessels were analyzed, individually and in combination, for prediction of birth weight < 10th , < 5th and < 3rd centiles. Doppler values were converted into centiles or multiples of the median (MoM) for gestational age. The sensitivities, positive and negative predictive values and odds ratios (OR) of the Doppler parameters for these birth weights at ∼ 90% specificity were assessed. Additionally, the correlations between Doppler measurements and other measures of placental insufficiency, namely fetal growth velocity and neonatal body fat measures, were analyzed. RESULTS: The Doppler combination most strongly associated with placental insufficiency was a newly generated parameter, which we have named the cerebral-placental-uterine ratio (CPUR). CPUR is the cerebroplacental ratio (CPR) (middle cerebral artery PI/UA-PI) divided by mean UtA-PI. CPUR MoM detected FGR better than did mean UtA-PI MoM or CPR MoM alone. At ∼ 90% specificity, low CPUR MoM had sensitivities of 50% for birth weight < 10th centile, 68% for < 5th centile and 89% for < 3rd centile. The respective sensitivities of low CPR MoM were 26%, 37% and 44% and those of high UtA-PI MoM were 34%, 47% and 67%. Low CPUR MoM was associated with birth weight < 10th centile with an OR of 9.1, < 5th centile with an OR of 17.3 and < 3rd centile with an OR of 57.0 (P < 0.0001 for all). CPUR MoM was also correlated most strongly with fetal growth velocity and neonatal body fat measures, as compared with CPR MoM or UtA-PI MoM alone. CONCLUSIONS: In this cohort, a novel Doppler variable combination, the CPUR (CPR/UtA-PI), had the strongest association with indicators of placental insufficiency. CPUR detected more cases of FGR than did any other Doppler parameter measured. If these results are replicated independently, this new parameter may lead to better identification of fetuses at increased risk of stillbirth that may benefit from obstetric intervention. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database.

OBJECTIVES: To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout the UK. DESIGN: A descriptive study. SETTING: The study was carried out in the General Practice Research Database (GPRD), a primary care database representative of the UK population. MAIN OUTCOME MEASURES: Incidence and prevalence of MS per 100 000 population. Secular and geographical trends in incidence and prevalence of MS. RESULTS: The prevalence of MS recorded in GPRD increased by about 2.4% per year (95% CI 2.3% to 2.6%) reaching 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) by 2010. There was a consistent downward trend in incidence of MS reaching 11.52 per 100 000/year (95% CI 10.96 to 12.11) in women and 4.84 per 100 000/year (95% CI 4.54 to 5.16) in men by 2010. Peak incidence occurred between ages 40 and 50 years and maximum prevalence between ages 55 and 60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest incidence and prevalence rates in the UK. CONCLUSIONS: We estimate that 126 669 people were living with MS in the UK in 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed that year (9.64 per 100 000/year). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK.

Antiplatelet drug interactions.

Both laboratory studies in healthy volunteers and clinical studies have suggested adverse interactions between antiplatelet drugs and other commonly used medications. Interactions described include those between aspirin and ibuprofen, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and the thienopyridine, clopidogrel, and drugs inhibiting CYP2C19, notably the proton pump inhibitors (PPI) omeprazole and esomeprazole. Other interactions between thienopyridines and CYP3A4/5 have also been reported for statins and calcium channel blockers. The ibuprofen/aspirin interaction is thought to be caused by ibuprofen blocking the access of aspirin to platelet cyclo-oxygenase. The thienopyridine interactions are caused by inhibition of microsomal enzymes that metabolize these pro-drugs to their active metabolites. We review the evidence for these interactions, assess their clinical importance and suggest strategies of how to deal with them in clinical practice. We conclude that ibuprofen is likely to interact with aspirin and reduce its anti-platelet action particularly in those patients who take ibuprofen chronically. This interaction is of greater relevance to those patients at high cardiovascular risk. A sensible strategy is to advise users of aspirin to avoid chronic ibuprofen or to ingest aspirin at least 2 h prior to ibuprofen. Clearly the use of NSAIDs that do not interact in this way is preferred. For the clopidogrel CYP2C19 and CYP3A4/5 interactions, there is good evidence that these interactions occur. However, there is less good evidence to support the clinical importance of these interactions. Again, a reasonable strategy is to avoid the chronic use of drugs that inhibit CYP2C19, notably PPIs, in subjects taking clopidogrel and use high dose H2 antagonists instead. Finally, anti-platelet agents probably interact with other drugs that affect platelet function such as selective serotonin reuptake inhibitors, and clinicians should probably judge patients taking such combination therapies as at high risk for bleeding.

The effects of lumiracoxib 100 mg once daily vs. ibuprofen 600 mg three times daily on the blood pressure profiles of hypertensive osteoarthritis patients taking different classes of antihypertensive agents.

AIMS: To examine whether the blood pressure (BP) profiles of lumiracoxib and high-dose ibuprofen differed in patients treated with different classes of antihypertensive medications. METHODS: A 4-week, multicentre, randomised, double-blind study has compared the effects of lumiracoxib 100 mg once daily (od) (n = 394) and ibuprofen 600 mg three times daily (tid) (n = 393) on ambulatory BP in osteoarthritis (OA) patients with controlled hypertension. Here, we present subgroup analyses for patients receiving different antihypertensive classes. The primary outcome was a comparison of the change in 24-h mean systolic ambulatory BP (MSABP) from baseline to week 4. Patients receiving angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) represented the largest subgroups receiving antihypertensive monotherapy. RESULTS: For patients receiving an ARB monotherapy, the least squares mean (LSM) 24-h MSABP at week 4 fell with lumiracoxib 100 mg od and increased with ibuprofen 600 mg tid, creating an estimated treatment difference of 8.1 mmHg in favour of lumiracoxib (p < 0.001). For patients receiving an ACEI and a beta-blocker monotherapy, the estimated treatment difference was 8.2 mmHg (p < 0.001) and 5.8 mmHg (p = 0.002) in favour of lumiracoxib respectively. These treatment differences were greater than observed in the overall population (5.0 mmHg in favour of lumiracoxib). In patients receiving diuretics or calcium channel blockers, treatment differences in MSABP were smaller and not statistically significant, although they remained in favour of lumiracoxib. CONCLUSION: Lumiracoxib 100 mg od resulted in less destabilisation of BP than high-dose ibuprofen 600 mg tid, and this effect was the greatest in subgroups treated with drugs blocking the renin-angiotensin system.

Influenza but not pneumococcal vaccination protects against all-cause mortality in patients with COPD.

BACKGROUND: Influenza and pneumococcal vaccination are recommended in patients with chronic obstructive pulmonary disease (COPD). A recent study from Tayside found a reduced risk of all-cause mortality with vaccination in patients with COPD. The Health Improvement Network (THIN) database was used to test this hypothesis in a different data source. METHODS: The THIN database was searched for patients with COPD. Vaccination status against Pneumococcus and the annual influenza vaccination status were determined. Mortality rates were calculated in the periods December to March and April to November. Relative risks for the effect of vaccination on all-cause mortality were estimated by Poisson regression, adjusting for age, sex, year and serious co-morbidities. RESULTS: 177,120 patients with COPD (mean age 65 years) were identified, with a mean follow-up of 6.8 years between 1988 and 2006. Vaccination rates against influenza rose from <30% before 1995 to >70% in 2005 in patients aged 60 years or more. The cumulative vaccination rate against pneumonia rose from almost zero to 70% in patients aged 70 years or more over the same period. For all-cause mortality the adjusted relative risks associated with influenza vaccination were 0.59 (95% CI 0.57 to 0.61) during the influenza season and 0.97 (95% CI 0.94 to 1.00) outside the season in patients not vaccinated against pneumonia, and 0.30 (95% CI 0.28 to 0.32) and 0.98 (95% CI 0.96 to 1.11), respectively, in patients vaccinated against pneumonia. The relative risk associated with pneumococcal vaccination was >1 at all times of the year. CONCLUSIONS: Influenza but not pneumococcal vaccination was associated with a reduced risk of all-cause mortality in COPD.

Exercise blood pressure and endothelial dysfunction in hypertension.

BACKGROUND: Hypertensive patients with persistent endothelial dysfunction have adverse cardiovascular prognosis. However, current methods aimed to assess endothelial dysfunction in those patients who possess clinical applicability. We hypothesised that such individuals could potentially be identified by an exaggerated systolic blood pressure (BP) response to a submaximal exercise. METHODS: We studied 22 male patients with essential hypertension who were categorised into two age-matched groups depending on their exercise systolic BP (ExSBP) rise during the 3-min exercise step test; the exaggerated ExSBP group [hyper-responders (> or = 40 mmHg)] and the low ExSBP responder group [hypo-responders (< or = 20 mmHg)]. Eleven healthy volunteers matched for age were used as control. Clinic and daytime ambulatory BP were assessed after 14 days of anti-hypertensive treatment withdrawal, which were not significantly different between groups. Vascular reactivity in response to intra-arterial infusions of acetylcholine, N(G)-monomethyl-l-arginine (l-NMMA) and sodium nitroprusside was assessed using forearm venous occlusion plethysmography. RESULTS: The hyper-responder group had significantly less forearm vasodilatation to acetylcholine compared with the hypo-responder group [percentage change in the forearm blood flow 125 (17) vs. 260 (28), mean (SEM); p < 0.001]. Similarly, the vasoconstrictive response to l-NMMA was significantly impaired in the hyper-responder group in comparison to the hypo-responder group [-30 (2) vs. -45 (4); p < 0.05]. In contrast, the vascular response to sodium nitroprusside was not different between groups suggesting preserved endothelial-independent vasodilatation. CONCLUSIONS: Despite similar ambulatory and office BP, the exaggerated ExSBP group had significantly worse endothelial function compared with the low ExSBP responder group. This simple and non-invasive test may be useful in routine clinical practice to aid risk stratification in hypertensive patients.

Association between allopurinol and mortality in heart failure patients: a long-term follow-up study.

AIMS: The aim of the study was to explore the long-term effect of allopurinol on mortality and cardiovascular hospitalisations in heart failure (HF) patients. METHODS: This is a population-based cohort study using a record-linkage database in Tayside, Scotland. A total of 4785 HF patients (4260 non-users, 267 incident users and 258 prevalent users) were studied between 1993 and 2002. RESULTS: Compared with non-users, low-dose users in the incident group had a significant increased risk of all-cause mortality, cardiovascular mortality and cardiovascular recurrence (adjusted HR, 1.60, 95%CI 1.26-2.03; 1.70, 1.29-2.23 and 1.44, 1.01-2.07). For the prevalent users, the adjusted HR were 1.27, 0.98-1.64; 1.43, 1.07-1.90 and 1.27, 0.91-1.76 respectively. There was no increased risk of outcome for high-dose users when compared with non-users (adjusted HR, 1.18, 0.84-1.66; 1.14, 0.76-1.71 and 1.36, 0.88-2.10 for the incident users, and 0.86, 0.64-1.15; 0.90, 0.64-1.26; and 1.27, 0.93-1.74 for the prevalent users respectively). High-dose allopurinol was associated with reduced risk of all-course mortality for prevalent users when compared with low-dose (adjusted HR 0.65, 95%CI 0.42-0.99). CONCLUSIONS: The prevalent high-dose allopurinol use had a lower risk of mortality than the prevalent low-dose use suggesting that allopurinol may be of benefit in HF patients.

Increasing prevalence and incidence of thyroid disease in Tayside, Scotland: the Thyroid Epidemiology Audit and Research Study (TEARS).

OBJECTIVE: We aimed to describe the changing incidence of thyroid disease in a population-based study in Tayside, Scotland (population 390 000) between 1994 and 2001. DESIGN: A retrospective, data-linkage, population-based study measuring the incidence and prevalence of thyroid disease. PATIENTS: All patients with newly diagnosed, treated and stable thyroid disease in Tayside were identified by electronic linkage of six datasets, including all regional biochemistry data, hospital admissions, deaths and a thyroid follow-up register. RESULTS: The overall prevalence of thyroid dysfunction has increased from 2.3% to 3.8% (1994-2001). The prevalence of ever having had hyperthyroidism increased from 0.86% to 1.26% in females and 0.17% to 0.24% in males (P < 0.0001 for both). The standardized incidence of hyperthyroidism increased from 0.68 to 0.87 per 1000 females/year, representing a 6.3% annual increase (P < 0.0001). The prevalence of primary hypothyroidism increased from 3.12% to 5.14% in females and 0.51% to 0.88% in males (P < 0.0001 for both). The standardized incidence of primary hypothyroidism did not change and varied between 3.90 and 4.89 per 1000 females/year over the 8 years. Incidence of hypothyroidism in males increased from 0.65 to 1.01 per 1000 males/year (P = 0.0017). Mean age at diagnosis of primary hypothyroidism declined in females from 1994 to 2001. CONCLUSIONS: The prevalence of primary hypothyroidism and previous hyperthyroidism has increased in Tayside, Scotland. This is partly due to an increasing incidence of disease, increased ascertainment and earlier diagnosis of disease. This will result in an increased workload for endocrinologists and general practitioners.

Treatment patterns of hypertension and dyslipidaemia in hypertensive patients at higher and lower risk of cardiovascular disease in primary care in the United Kingdom.

Few studies have investigated the presence of dyslipidaemia in hypertensive individuals. In addition, few data exist on the concurrent treatment of both conditions for the prevention of cardiovascular disease (CVD). This retrospective cohort study examined treatment patterns for hypertension and dyslipidaemia among hypertensive patients in UK primary care. We defined a population of patients aged > or =40 years from the UK General Practice Research Database. Hypertensive individuals with > or =3 additional cardiovascular risk factors (ARFs) were compared with a cohort comprising hypertensive patients with < or =2 ARFs. We analysed the prevalence of risk factors and the prevalence and incidence of treatment for hypertension, dyslipidaemia and for both conditions between January 1997 and December 2001. A total of 117 840 hypertensive patients were identified (23 655 with > or =3 ARFs, 94 185 with < or =2 ARFs) in 1997; in 2001, the number diagnosed as hypertensive was 133 683 (40 248 > or =3 ARFs, 93 435 < or =2 ARFs). The prevalence of antihypertensive treatment in the hypertensive patients with > or =3 ARFs increased during the study. In 2001, approximately one-third of hypertensive patients with > or =3 ARFs were not receiving antihypertensives. Among those patients who received such treatment, the majority received > or =2 separate agents in accordance with current guidelines. Treatment for concurrent hypertension and dyslipidaemia was initiated in <8% of patients with hypertension and > or =3 ARFs in each year. These findings demonstrate the under-recognition/undertreatment of cardiovascular risk factors in UK primary care among patients at risk of CVD.

Mortality and vascular outcomes in patients treated for thyroid dysfunction.

CONTEXT: There are limited studies describing mortality and morbidity in patients treated for hyperthyroidism, and no data exist for people with treated hypothyroidism. OBJECTIVE: The objective of the study was to describe all-cause mortality and vascular mortality and morbidity in patients after treatment for hyperthyroidism and hypothyroidism. DESIGN: This was a population-based cohort study from 1994 to 2001. SETTING: The study was conducted in Tayside, Scotland. PATIENTS: All patients were treated for thyroid dysfunction. INTERVENTION(S): Event rates among patients with thyroid dysfunction were compared with rates in the general population. We measured standardized mortality ratio and standardized incidence ratio (SIR). MAIN OUTCOME MEASURE(S): The primary outcome was all-cause mortality. The secondary outcome was serious vascular event, the composite end point of nonfatal myocardial infarction, nonfatal stroke, or vascular death. RESULTS: There were 15,889 primary hypothyroid and 3,888 hyperthyroid patients. There were 3,116,719 patient-years of follow-up in 524,152 subjects in the general population. No increase was found in all-cause mortality or serious vascular events in patients with treated hypothyroidism or hyperthyroidism. Nonfatal ischemic heart disease [SIR 1.23, 95% confidence interval (CI) 1.10-1.36] and dysrhythmias (SIR 1.32, 95% CI 1.11-1.57) were increased in treated hypothyroidism when adjusted for age, sex, diabetic status, and previous vascular disease. In treated stabilized hyperthyroidism, only the risk of dysrhythmias was increased (SIR 2.71, 95% CI 1.63-4.24). Risk of heart failure or cerebrovascular disease was not increased in either patient group. CONCLUSIONS: We found no increase in all-cause mortality in subjects with treated thyroid disease. However, there was increased risk of cardiovascular morbidity in patients with treated primary hypothyroidism and dysrhythmias in treated hyperthyroidism.

Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study.

BACKGROUND: Vascular endothelial dysfunction may predict future atherosclerosis. Hence, an antihypertensive agent that reverses endothelial dysfunction and lowers blood pressure might improve the prognosis of patients with hypertension. We hypothesized that nebivolol, a vasodilating beta-blocker, could improve endothelial dysfunction. We tested this hypothesis by comparing the effects of nebivolol and atenolol on endothelial function. METHODS AND RESULTS: Twelve hypertensive patients with a mean ambulatory blood pressure of 154+/-7/97+/-10 mm Hg were randomized after a 2-week placebo run-in period (baseline) in a double-blind, crossover fashion to 8-week treatment periods with either 5 mg of nebivolol with 2.5 mg of bendrofluazide or 50 mg of atenolol with 2.5 mg of bendrofluazide. Forearm venous occlusion plethysmography and intra-arterial infusions of acetylcholine and N(G)-monomethyl-L-arginine (L-NMMA) were used to assess stimulated and basal endothelium-dependent nitric oxide release, respectively. Sodium nitroprusside was used as an endothelium-independent control. Nebivolol/bendrofluazide and atenolol/bendrofluazide each lowered the clinic blood pressure to the same extent (132+/-7/82+/-6 and 132+/-9/83+/-8 mm Hg, respectively; P<0.001 from baseline). The vasodilatory response to acetylcholine was significantly increased with nebivolol/bendrofluazide (maximum percentage change in forearm blood flow [mean+/-SEM], 435+/-27%, P<0.001) but not with atenolol/bendrofluazide. Similarly, the endothelium-dependent vasoconstrictive response to L-NMMA was significantly improved only with nebivolol treatment (percentage change in forearm blood flow, -54+/-5%; P<0.001). The response to sodium nitroprusside was not different between treatments, suggesting that the endothelium-independent pathway was unaffected. CONCLUSIONS: Nebivolol/bendrofluazide increased both stimulated and basal endothelial nitric oxide release, whereas for the same degree of blood pressure control, atenolol/bendrofluazide had no effect on nitric oxide bioactivity. Thus, nebivolol may offer additional vascular protection in treating hypertension.

Impact of type 1 and type 2 diabetes on patterns and costs of drug prescribing: a population-based study.

OBJECTIVE: Utilization and costs of prescription drugs were investigated in diabetic and nondiabetic patients. RESEARCH DESIGN AND METHODS: The study was carried out in Tayside, Scotland, U.K. A validated population-based diabetes register was used to identify patients with type 1 and type 2 diabetes, and a database of all prescriptions dispensed in the community was used to investigate drug utilization in 1995. RESULTS: In a population of 406,526, there were 974 (0.2%) with type 1 diabetes and 6,869 (1.7%) with type 2 diabetes. The mean dispensed prescribing rates for all drugs (excluding antidiabetic medication) were higher across all age-groups for diabetic patients. After adjusting for age, patients with type 1 diabetes were 2.07 times (95% CI 2.03-2.11) more likely and patients with type 2 diabetes were 1.70 times (1.69-1.71) more likely to be dispensed a drug item than people without diabetes. This likelihood was increased in every drug category, even those not directly related to diabetes, and the proportion and cost of drug items dispensed to diabetic patients was therefore higher than expected given the prevalence of diabetes. Upon projecting these results to the U.K. population, it was discovered that nearly 8% of the U.K. drug budget (Pound Sterling 350 million) is accounted for by patients with diabetes (90% of that by patients with type 2 diabetes). CONCLUSIONS: This study highlights the increased usage and cost of prescription drugs in diabetes, with type 2 diabetes constituting a particular burden. It was discovered that 1.4% of drug usage in the entire population can be accounted for by the increased prescribing rate of diabetic patients compared with that of nondiabetic patients.

ACE inhibitor use is associated with hospitalization for severe hypoglycemia in patients with diabetes. DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside, Scotland. Medicines Monitoring Unit.

OBJECTIVE: To evaluate the association between the use of ACE inhibitors and hospital admission for severe hypoglycemia and to explore the effects of potential confounding variables on this relationship. RESEARCH DESIGN AND METHODS: The association between the use of ACE inhibitors and the incidence of hypoglycemia is controversial. A recent study reported that 14% of all hospital admissions for hypoglycemia might be attributable to ACE inhibitors. We performed a nested case-control study, using a cohort of 6,649 diabetic patients taking insulin or oral antidiabetic drugs, on the Diabetes Audit and Research in Tayside, Scotland (DARTS) database. From 1 January 1993 to 30 April 1994, we identified 64 patients who had been admitted to Tayside hospitals with hypoglycemia and selected 440 control patients from the same cohort. RESULTS: Hypoglycemia was associated with the use of ACE inhibitors (odds ratio [OR] 3.2, 95% CI 1.2-8.3, P = 0.023), whereas use of beta-blockers and calcium antagonists was not associated with an increased risk of hospitalization for hypoglycemia with ORs of 0.9 (95% CI 0.3-3.3) and 1.7 (95% CI 0.2-2.1), respectively. There were significant differences between case and control patients in type of diabetes treatment, diabetes duration, place of routine diabetes care, and congestive cardiac failure. These differences did not confound the relationship between ACE inhibitors and hypoglycemia (adjusted OR 4.3, 95% CI 1.2-16.0). CONCLUSIONS: The results show that the association between ACE inhibitor therapy and hospital admission for severe hypoglycemia is not explained by these confounding factors. Although ACE inhibitors have distinct advantages over other antihypertensive drugs in diabetes, the risk of hypoglycemia should be considered.

Diabetes and lower-limb amputations in the community. A retrospective cohort study. DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside Scotland/Medicines Monitoring Unit.

OBJECTIVE: There are few U.K. data on the incidence rates of amputation in diabetic subjects compared with the nondiabetic population. RESEARCH DESIGN AND METHODS: We performed a historical cohort study of first lower-extremity amputations based in Tayside, Scotland (population 364,880) from 1 January 1993 to 31 December 1994. The Diabetes Audit and Research in Tayside Scotland (DARTS) database was used to identify a prevalence cohort of 7,079 diabetic patients on 1 January 1993. We estimated age-specific and standardized incidence rates of lower-limb amputations in the diabetic and nondiabetic cohorts. Results were compared with a previous study that evaluated lower-extremity amputations in diabetic patients in Tayside in 1980-1982. RESULTS: There were 221 subjects who underwent a total of 258 nontraumatic amputations. Of the 221 subjects, 60 (27%) patients were diabetic (93% NIDDM), and 63% were first amputations. The median duration of diabetes was 6 years (range: newly diagnosed to 41 years). Nonhealing ulceration (31%) and gangrene (29%) were the two main indications for amputation in the diabetic subjects. Of the 161 nondiabetic subjects, 140 (80%) underwent first amputations. The adjusted incidences in the diabetic and nondiabetic groups were 248 and 20 per 100,000 person-years, respectively. Tayside patients with diabetes thus had a 12.3-fold risk of an amputation compared with nondiabetic residents (95% CI 8.6-17.5). The estimated proportion of diabetic patients in the population rose from 0.81% in 1980-1982 to 1.94% in 1993-1994, whereas the absolute rate of amputation in diabetic subjects was unchanged from that in 1980-1982. CONCLUSIONS: These population-based U.K. amputation data are similar to amputation rates in the U.S. Amputation rates appear to have decreased significantly since 1980-1982. The impact of diabetes education and prevention programs that target the processes leading to amputation can now be evaluated.

The thyroid epidemiology, audit, and research study: thyroid dysfunction in the general population.

The objective of this study was to define the level of treated thyroid dysfunction in a complete and representative population base in an area of sufficient dietary iodine intake. We used record-linkage technology to retrospectively identify subjects treated for hyperthyroidism or hypothyroidism in the general population of Tayside, Scotland from 1 January 1993 to 30 April 1997. Thyroid status was ascertained by record linkage of patient-level datasets containing details of treatments for hyperthyroidism and hypothyroidism. We identified 620 incident cases of hyperthyroidism, an incidence rate of 0.77/1000 x yr [95% confidence interval (CI), 0.70-0.84] in females and 0.14/1000 x yr (95% CI, 0.12-0.18) in males. There were 3,486 incident cases of diagnosed primary hypothyroidism, an incidence rate of 4.98/1000 x yr (95% CI, 4.81-5.17) in females and 0.88/1000 x yr (95% CI, 0.80-0.96) in males. For both hyperthyroidism and hypothyroidism, the incidence increased with age, and females were affected two to eight times more than males across the age range. The midyear point prevalence of all-cause hypothyroidism rose from 2.2% in 1993 to 3.0% in 1996. The level of thyroid dysfunction in Tayside, Scotland is higher than previously reported, and it increased from 1993 to 1996.

Irbesartan reduces QT dispersion in hypertensive individuals.

Angiotensin type 1 receptor antagonists have direct effects on the autonomic nervous system and myocardium. Because of this, we hypothesized that irbesartan would reduce QT dispersion to a greater degree than amlodipine, a highly selective vasodilator. To test this, we gathered electrocardiographic (ECG) data from a multinational, multicenter, randomized, double-blind parallel group study that compared the antihypertensive efficacy of irbesartan and amlodipine in elderly subjects with mild to moderate hypertension. Subjects were treated for 6 months with either drug. Hydrochlorothiazide and atenolol were added after 12 weeks if blood pressure (BP) remained uncontrolled. ECGs were obtained before randomization and at 6 months. A total of 188 subjects (118 with baseline ECGs) were randomized. We analyzed 104 subjects who had complete ECGs at baseline and after 6 months of treatment. Baseline characteristics between treatments were similar, apart from a slight imbalance in diastolic BP (irbesartan [n=53] versus amlodipine [n=51], 99.2 [SD 3. 6] versus 100.8 [3.8] mm Hg; P=0.03). There were no significant differences in BP normalization (diastolic BP <90 mm Hg) between treatments at 6 months (irbesartan versus amlodipine, 80% versus 88%; P=0.378). We found a significant reduction in QT indexes in the irbesartan group (QTc dispersion mean, -11.4 [34.5] milliseconds, P=0.02; QTc max, -12.8 [35.5] milliseconds, P=0.01), and QTc dispersion did not correlate with the change in BP. The reduction in QT indexes with amlodipine (QTc dispersion, -9.7 [35.4] milliseconds, P=0.06; QTc max, -8.6 [33.2] milliseconds, P=0.07) did not quite reach statistical significance, but there was a correlation between the change in QT indexes and changes in systolic BP. In conclusion, irbesartan improved QT dispersion, and this effect may be important in preventing sudden cardiac death in at-risk hypertensive subjects.

Selegiline and mortality in subjects with Parkinson's disease: a longitudinal community study.

OBJECTIVE: To estimate mortality by drug use in a cohort of patients with PD relative to age- and sex-matched comparators. METHODS: two longitudinal cohorts of patients with 7 and 11 years' duration of PD were constructed with matched comparators in Tayside, Scotland. Subjects were eligible for inclusion if they received a first prescription for an anti-Parkinson's drug from July 1989 to December 1995, with no PD drug prescription in the previous 6 months. Those who had previously taken a neuroleptic drug or were younger than 40 years of age were excluded. RESULTS: Overall, subjects with PD in relation to comparators had higher mortality with a rate ratio (RR) of 1.76 (95% CI 1.11, 2.81) in the 7-year cohort. There was significantly greater mortality in patients with PD who received levodopa monotherapy (RR = 2.45, 95% CI 1.42, 4.23) relative to the comparators, adjusting for previous cardiovascular drug use and diabetes. However, there was no significant difference in mortality in those with PD receiving combination therapy of selegiline with levodopa and other drugs in relation to the comparators (RR = 0.92, 95% CI 0.37, 2.31). CONCLUSIONS: Subjects with PD had twice the rate of mortality relative to age- and sex-matched comparators. However, those subjects who received selegiline at any time in combination with co-careldopa or co-beneldopa showed no significant difference in mortality compared with the comparators. Monotherapy with levodopa was associated with the highest mortality.

Elevated blood pressure during the first two hours of ambulatory blood pressure monitoring: a study comparing consecutive twenty-four-hour monitoring periods.

OBJECTIVE AND DESIGN: Ambulatory blood pressure monitoring is being used increasingly in clinical practice and hypertension research. We have noted elevated blood pressure during the initial hours of monitoring. The objective of the present study was to examine the consistency, magnitude and duration of this elevation, and to determine whether this effect causes significant differences in the mean ambulatory blood pressure monitoring values comparing the first (day 1) and second (day 2) consecutive 24-h periods of monitoring. METHODS: Fifty patients who were hypertensive based on repeated clinic readings were studied prospectively. Each underwent continuous 48-h ambulatory blood pressure monitoring with a SpaceLabs 90207 monitor. The device recorded blood pressure at 15-min intervals during the daytime (0600-2159 h) and at 30-min intervals at night-time (2200-0559 h). From these readings hourly means were calculated. Repeated-measures analysis of variance was performed to compare the hourly means of days 1 and 2. RESULTS: Repeated-measures analysis of variance indicated that a significant difference existed for both systolic and diastolic blood pressure between day 1 and day 2. Paired Student's t-test revealed that this difference occurred during the first 2 h of monitoring. The daytime blood pressure was higher on day 1 as a result of the initial elevation of blood pressure at the onset of monitoring. The initial elevation of blood pressure was present both in white-coat hypertensives and in essential hypertensives. CONCLUSION: The first 2 h of ambulatory blood pressure monitoring are associated with elevated blood pressure both in white-coat hypertensives and in essential hypertensives. This has a minor effect on mean daytime and 24-h ambulatory blood pressures. We propose that improved ambulatory blood pressure monitoring recordings would be obtained in clinical practice, and more particularly in research applications, if 26-h ambulatory blood pressure monitoring was carried out, excluding the first 2 h from the summary analyses.

A review of the medical treatment of primary aldosteronism.

PURPOSE: Use of the aldosterone-to-renin ratio (ARR) has suggested that at least one in 10 hypertensive subjects have primary aldosteronism (PA). There is thus a timely need to review the literature for effective drug therapies and to speculate on other therapeutic options by taking into account recent advances in understanding of the PA disease pathophysiological process. DATA SOURCE: A MEDLINE and EMBASE search of all articles published from the start of the databases until July 1999 and reviews of the bibliographies of textbooks. STUDY SELECTION: Primary research articles on the medical treatment of PA with emphasis on diagnosis, treatment option, drug dosage, therapeutic response and adverse drug effect. DATA EXTRACTION: Study design and quality were assessed. Relevant data on diagnostic methodology, drug usage and response were analysed and compared. DATA SYNTHESIS: A select number of subjects with aldosterone-producing adenoma (APA) can be expected to respond well to surgical treatment For the majority of PA cases especially subjects with idiopathic hyperaldosteronism (IHA), long-term medical treatment is now safe and feasible although no randomized controlled trials have been carried out to date. The best therapeutic response is obtained by directly antagonizing aldosterone at the receptor level using medium to low dose spironolactone and this response can be predicted by a raised ARR. The response to other potassium-sparing diuretics and calcium channel blockers are modest. IHA responds better than angiotensin II-unresponsive APA to angiotensin converting enzyme inhibitors and this may also be true with angiotensin II receptor blockers. The discovery of the aldosterone synthase gene opens up the possibility for gene therapy. CONCLUSION: The diagnosis of PA allows appropriate management with resultant blood pressure control in many hypertensive subjects who otherwise have resistant hypertension despite multiple drug therapy.