Body size throughout the life-course and incident benign prostatic hyperplasia-related outcomes and nocturia.

BACKGROUND: Existing evidence suggests that there is an association between body size and prevalent Benign Prostatic Hyperplasia (BPH)-related outcomes and nocturia. However, there is limited evidence on the association between body size throughout the life-course and incident BPH-related outcomes. METHODS: Our study population consisted of men without histories of prostate cancer, BPH-related outcomes, or nocturia in the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (n = 4710). Associations for body size in early- (age 20), mid- (age 50) and late-life (age ≥ 55, mean age 60.7 years) and weight change with incident BPH-related outcomes (including self-reported nocturia and physician diagnosis of BPH, digital rectal examination-estimated prostate volume ≥ 30 cc, and prostate-specific antigen [PSA] concentration > 1.4 ng/mL) were examined using Poisson regression with robust variance estimation. RESULTS: Men who were obese in late-life were 25% more likely to report nocturia (Relative Risk (RR): 1.25, 95% Confidence Interval (CI): 1.11-1.40; p-trendfor continuous BMI < 0.0001) and men who were either overweight or obese in late-life were more likely to report a prostate volume ≥ 30 cc (RRoverweight: 1.13, 95% CI 1.07-1.21; RRobese: 1.10, 95% CI 1.02-1.19; p-trendfor continuous BMI = 0.017) as compared to normal weight men. Obesity at ages 20 and 50 was similarly associated with both nocturia and prostate volume ≥ 30 cc. Considering trajectories of body size, men who were normal weight at age 20 and became overweight or obese by later-life had increased risks of nocturia (RRnormal to overweight: 1.09, 95% CI 0.98-1.22; RRnormal to obese: 1.28, 95% CI 1.10-1.47) and a prostate volume ≥ 30 cc (RRnormal to overweight: 1.12, 95% CI 1.05-1.20). Too few men were obese early in life to examine the independent effect of early-life body size. Later-life body size modified the association between physical activity and nocturia. CONCLUSIONS: We found that later-life body size, independent of early-life body size, was associated with adverse BPH outcomes, suggesting that interventions to reduce body size even late in life can potentially reduce the burden of BPH-related outcomes and nocturia.

Aspirin but not ibuprofen use is associated with reduced risk of prostate cancer: a PLCO study.

BACKGROUND: Although most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear. METHODS: We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55-74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified. RESULTS: After adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with <1 and ≥ 1 pill of aspirin daily were 0.98 (95% confidence interval (CI), 0.90-1.07) and 0.92 (95% CI: 0.85-0.99), respectively, compared with never use (P for trend 0.04). The effect of taking at least one aspirin daily was more pronounced when restricting the analyses to men older than age 65 or men who had a history of cardiovascular-related diseases or arthritis (HR (95% CI); 0.87 (0.78-0.97), 0.89 (0.80-0.99), and 0.88 (0.78-1.00), respectively). The data did not support an association between ibuprofen use and prostate cancer risk. CONCLUSION: Daily aspirin use, but not ibuprofen use, was associated with lower risk of prostate cancer risk.

Cerebral hemodynamics and cognitive impairment: baseline data from the RECON trial.

OBJECTIVE: To determine whether unihemispheral hemodynamic failure is independently associated with cognitive impairment among participants in the National Institute of Neurological Disorders and Stroke-sponsored, multicenter, randomized clinical trial, Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON). METHODS: Forty-three patients were randomized into RECON after recent symptomatic carotid artery occlusion and asymmetrically increased oxygen extraction fraction (OEF) by PET (OEF ratio >1.13), indicating stage II hemodynamic failure on the side of occlusion. The PET-positive patients were compared with 28 RECON-enrolled patients who met all clinical and radiographic inclusion/exclusion criteria but had no OEF asymmetry. A multivariable regression compared patients with PET OEF >1.13 or ≤1.13, stratifying by TIA vs. stroke as the qualifying event. The dependent variable was a composite neurocognitive score derived from averaging age-normalized z scores on a test battery that included global and internal carotid artery (ICA) side-relevant hemisphere-specific tests. RESULTS: There were no differences in demographic, clinical, or radiologic characteristics between the PET-positive and PET-negative patients except for PET OEF asymmetry. The unadjusted average neurocognitive z score was -1.45 for the PET-positive and -1.25 for the PET-negative patients, indicating cognitive impairment in both groups but no difference between them (p = 0.641). After adjustment for age, education, side of occlusion, depression, and previous stroke, there was a significant difference between PET-positive and PET-negative patients among those with TIA as a qualifying event (average z score = -1.41 vs. -0.76, p = 0.040). Older age and right ICA side were also significant in this model. CONCLUSION: Hemodynamic failure is independently associated with cognitive impairment in patients with carotid occlusion. This finding establishes the physiologic parameter upon which the extracranial-intracranial bypass will be tested.

Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839) is the predisposition to develop smooth muscle tumours of the skin and uterus and/or renal cancer and is associated with mutations in the fumarate hydratase gene (FH). Here we characterise the clinical and genetic features of 21 new families and present the first report of two African-American families with HLRCC. METHODS: Using direct sequencing analysis we identified FH germline mutations in 100% (21/21) of new families with HLRCC. RESULTS: We identified 14 germline FH mutations (10 missense, one insertion, two nonsense, and one splice site) located along the entire length of the coding region. Nine of these were novel, with six missense (L89S, R117G, R190C, A342D, S376P, Q396P), one nonsense (S102X), one insertion (111insA), and one splice site (138+1G>C) mutation. Four unrelated families had the R58X mutation and five unrelated families the R190H mutation. Of families with HLRCC, 62% (13/21) had renal cancer and 76% (16/21) cutaneous leiomyomas. Of women FH mutation carriers from 16 families, 100% (22/22) had uterine fibroids. Our study shows that expression of cutaneous manifestations in HLRCC ranges from absent to mild to severe cutaneous leiomyomas. FH mutations were associated with a spectrum of renal tumours. No genotype-phenotype correlations were identified. CONCLUSIONS: In combination with our previous report, we identify 31 different germline FH mutations in 56 families with HLRCC (20 missense, eight frameshifts, two nonsense, and one splice site). Our FH mutation detection rate is 93% (52/56) in families suspected of HLRCC.

Comparison of PET oxygen extraction fraction methods for the prediction of stroke risk.

UNLABELLED: PET measurement of increased oxygen extraction fraction (OEF) identifies patients at high risk for subsequent stroke. OEF methodology remains controversial. In this study we compare the sensitivity and specificity of absolute OEF measurements with ipsilateral-to-contralateral ratios of absolute OEF and count-based OEF estimates. METHODS: Multivariate analyses of OEF methods were performed using data from patients with symptomatic carotid artery occlusion (n = 68). Outcome and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: All 3 methods were predictive of stroke risk in univariate analysis. Only the count-based method remained significant in multivariate analysis. The area under the ROC curve was greatest for the count-based ratio: 0.815 versus 0.769 (absolute) and 0.737 (ratios of absolute). CONCLUSION: All 3 methods are predictive of stroke risk in patients with unilateral carotid artery occlusion. ROC curve analysis is useful for selecting optimal thresholds for maximal sensitivity and specificity.

Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage.

A zone of hypoperfusion surrounding acute intracerebral hemorrhage (ICH) has been interpreted as regional ischemia. To determine if ischemia is present in the periclot area, the authors measured cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and oxygen extraction fraction (OEF) with positron emission tomography (PET) in 19 patients 5 to 22 hours after hemorrhage onset. Periclot CBF, CMRO2, and OEF were determined in a 1-cm-wide area around the clot. In the 16 patients without midline shift, periclot data were compared with mirror contralateral regions. All PET images were masked to exclude noncerebral structures, and all PET measurements were corrected for partial volume effect due to clot and ventricles. Both periclot CBF and CMRO2 were significantly reduced compared with contralateral values (CBF: 20.9 +/- 7.6 vs. 37.0 +/- 13.9 mL 100 g(-1) min(-1), P = 0.0004; CMRO2: 1.4 +/- 0.5 vs. 2.9 +/- 0.9 mL 100 g(-1) min(-1), P = 0.00001). Periclot OEF was less than both hemispheric OEF (0.42 +/- 0.15 vs. 0.47 +/- 0.13, P = 0.05; n = 19) and contralateral regional OEF (0.44 +/- 0.16 vs. 0.51 +/- 0.13, P = 0.05; n = 16). In conclusion, CMRO2 was reduced to a greater degree than CBF in the periclot region in acute ICH, resulting in reduced OEF rather than the increased OEF that occurs in ischemia. Thus, the authors found no evidence for ischemia in the periclot zone of hypoperfusion in acute ICH patients studied 5 to 22 hours after hemorrhage onset.

Autoregulation of cerebral blood flow surrounding acute (6 to 22 hours) intracerebral hemorrhage.

BACKGROUND: Arterial hypertension is common in the first 24 hours after acute intracerebral hemorrhage (ICH). Although increased blood pressure usually declines to baseline values within several days, the appropriate treatment during the acute period has remained controversial. Arguments against treatment of hypertension in patients with acute ICH are based primarily on the concern that reducing arterial blood pressure will reduce cerebral blood flow (CBF). The authors undertook this study to provide further information on the changes in whole-brain and periclot regional CBF that occur with pharmacologic reductions in mean arterial pressure (MAP) in patients with acute ICH. METHODS: Fourteen patients with acute supratentorial ICH 1 to 45 mL in size were studied 6 to 22 hours after onset. CBF was measured with PET and (15)O-water. After completion of the first CBF measurement, patients were randomized to receive either nicardipine or labetalol to reduce MAP by 15%, and the CBF study was repeated. RESULTS: MAP was lowered by -16.7 +/- 5.4% from 143 +/- 10 to 119 +/- 11 mm Hg. There was no significant change in either global CBF or periclot CBF. Calculation of the 95% CI demonstrated that there is less than a 5% chance that global or periclot CBF fell by more than -2.7 mL x 100 g(-1) x min(-1). CONCLUSION: In patients with small- to medium-sized acute ICH, autoregulation of CBF was preserved with arterial blood pressure reductions in the range studied.

Severe hemodynamic impairment and border zone--region infarction.

PURPOSE: To investigate the relationship between the patterns of cerebral infarction that have been associated with hemodynamic impairment and the presence of severe chronic hemodynamic compromise (increased oxygen extraction fraction) in a large prospectively enrolled group of patients with carotid artery occlusion. MATERIALS AND METHODS: At enrollment in a prospective study of cerebral hemodynamics, 110 patients with carotid occlusion underwent (a) positron emission tomography for the measurement of cerebral oxygen extraction fraction and (b) computed tomographic (CT) or magnetic resonance (MR) examinations of the brain. Infarcts were categorized retrospectively by vascular territory, location, and pattern. The association of these findings with hemodynamic impairment (increased oxygen extraction fraction) was investigated. RESULTS: No border zone-region infarctions were found in 35 asymptomatic patients. In 75 symptomatic patients, cortical border zone-region infarction was found in seven of 36 patients with increased oxygen extraction fraction, and in two of 39 with normal oxygen extraction fraction (P =.08, difference not significant). The pattern of multiple white matter lesions arranged parallel to the lateral ventricle was observed only in symptomatic patients with increased oxygen extraction fraction (eight of 36 patients; P =.002; sensitivity, 22%; specificity, 100%). This finding was more frequent with MR imaging (seven of 14 patients) than with CT (one of 22 patients). CONCLUSION: Multiple white matter infarctions, arranged parallel to the lateral ventricle, are associated with severe hemodynamic impairment. This pattern of infarction is likely due to a hemodynamic mechanism.

Risks of stroke and current indications for cerebral revascularization in patients with carotid occlusion.

Preventing further stroke in patients with complete carotid artery occlusion remains a difficult challenge because there is no therapy proven effective for this prevention. These patients comprise approximately 15% of patients with carotid artery territory transient ischemic attacks or infarction. Patients with symptomatic carotid artery occlusion have an overall risk of subsequent stroke of 7% per year and a risk of stroke ipsilateral to the occluded carotid artery of 5.9% per year. The presence of severe hemodynamic failure demonstrated by increased oxygen extraction fraction (OEF) of the brain, in a cerebral hemisphere distal to a symptomatic occluded carotid artery, is an independent predictor of subsequent ischemic stroke with a risk comparable to that seen in medically treated patients with symptomatic severe carotid artery stenosis.

Preview of a new trial of extracranial-to-intracranial arterial anastomosis: the carotid occlusion surgery study.

In 1985, the International Study of Extracranial-to-Intracranial Arterial Anastomosis demonstrated no benefit from extracranial-to-intracranial arterial bypass operations in treatment of patients with extensive cerebrovascular disease including those with occlusions of the internal carotid artery. Interest in the potential use of extracranial-to-intracranial arterial bypass operations, however, has been rekindled by evidence that some patients with occlusion of the internal carotid artery have a poor collateral circulation and a high risk for recurrent ischemic events. Other patients with adequate perfusion after occlusion have a low likelihood for recurrent stroke. Restricting surgical treatment to only those patients judged to have a high risk for recurrent stroke might improve the usefulness of the bypass operation. A new clinical trial is proposed, testing the potential usefulness of extracranial-to-intracranial arterial bypass operations for treatment of carefully selected patients with occlusion of the internal carotid artery. Several issues that are being addressed in this new trial are described in this article.

Paramedics can apply and read Mantoux tuberculosis tests.

Selected paramedics (26) received 2 h of training in the application and interpretation of Mantoux skin tests by a specially trained registered nurse. Instruction included a lecture, a video tape, and practice skin test administration on "induration arms." All students successfully completed written and skills tests. During a follow-up period, registered nurses directly observed skin test application and interpretation by the paramedics when applying the skin test to other departmental fire fighters and compared these to set criteria. Interpretation of skin test results included appropriate referral for positive results. Paramedics administered 319 skin tests during subsequent follow-up and 305/319 (96%) were monitored by a registered nurse. All administration criteria were performed as indicated 100% of the time except for the criterion requiring a 5-10 mm wheal. The application was appropriately repeated in each case. In one application, a paramedic began to use the same needle and syringe to draw up additional solution, but was immediately corrected. Among 227 cases of test interpretation by paramedics, paramedics were monitored by a registered nurse in 169 interpretations (74%). All monitoring criteria were performed as indicated 100% of the time. Nurses concurred with each monitored measurement. Induration results were 0 mm, 216 tests; 1-9 mm, 9 tests; > or =10 mm, 2 tests. Appropriate follow-up was provided to the two individuals with > or =10 mm induration. The results indicate that paramedics can successfully apply and accurately interpret Mantoux skin tests on public safety employees, although the number of positive tests was low, reducing the reliability of the findings.

Calibration of an extreme-ultraviolet transmission grating spectrometer with synchrotron radiation.

The responsivity of an extreme-ultraviolet transmission grating spectrometer with silicon photodiode detectors was measured with synchrotron radiation. The spectrometer was designed to record the absolute radiation flux in a wavelength bandpass centered at 30 nm. The transmission grating had a period of 200 nm and relatively high efficiencies in the +1 and the -1 diffraction orders that were dispersed on either side of the zero-order beam. Three photodiodes were positioned to measure the signals in the zero order and in the +1 and -1 orders. The photodiodes had aluminum overcoatings that passed the desired wavelength bandpass centered at 30 nm and attenuated higher-order radiation and wavelengths longer than approximately 80 nm. The spectrometer's responsivity, the ratio of the photodiode current to the incident radiation power, was determined as a function of the incident wavelength and the angle of the spectrometer with respect to the incident radiation beam. The spectrometer's responsivity was consistent with the product of the photodiode responsivity and the grating efficiency, both of which were separately measured while removed from the spectrometer.

Cost-effectiveness analysis of therapy for symptomatic carotid occlusion: PET screening before selective extracranial-to-intracranial bypass versus medical treatment.

UNLABELLED: The St. Louis Carotid Occlusion Study (STLCOS) demonstrated that increased cerebral oxygen extraction fraction (OEF) detected by PET scanning predicted stroke in patients with symptomatic carotid occlusion. Consequently, a trial of extracranial-to-intracranial (EC/IC) arterial bypass for these patients was proposed. The purpose of this study was to examine the cost-effectiveness of using PET in identifying candidates for EC/IC bypass. METHODS: A Markov model was created to estimate the cost-effectiveness of PET screening and treating a cohort of 45 symptomatic patients with carotid occlusion. The primary outcome was incremental cost for PET screening and EC/IC bypass (if OEF was elevated) per incremental quality-adjusted life year (QALY) saved. Rates of stroke and death with surgical and medical treatment were obtained from EC/IC Bypass Trial and STLCOS data. Costs were estimated from the literature. Sensitivity analyses were performed for all assumed variables, including the PET OEF threshold used to select patients for surgery. RESULTS: In the base case, PET screening of the cohort followed by EC/IC bypass on 36 of the 45 patients yielded 23.2 additional QALYs at a cost of $20,000 per QALY, compared with medical therapy alone. A more specific PET threshold, which identified 18 surgical candidates, gained 22.6 QALYs at less cost than medical therapy alone. The results were sensitive to the perioperative stroke rate and the stroke risk reduction conferred by EC/IC bypass surgery. CONCLUSION: If postoperative stroke rates are similar to stroke rates observed in the EC/IC Bypass Trial, EC/IC bypass will be cost-effective in patients with symptomatic carotid occlusion who have increased OEF. A clinical trial of medical therapy versus PET followed by EC/IC bypass (if OEF is elevated) is warranted.

Absence of selective deep white matter ischemia in chronic carotid disease: a positron emission tomographic study of regional oxygen extraction.

BACKGROUND AND PURPOSE: Deep white matter may be the location of an internal arterial border zone. The purpose of this study was to determine whether the deep white matter was subject to a greater degree of ischemia than was the cortex among patients with chronic carotid occlusion. METHODS: Thirty-six patients with carotid occlusion and structurally normal deep white matter were studied with positron emission tomography. Measurements of oxygen extraction fraction were made in superficial (cortical and subcortical) regions in the middle cerebral artery territory and in deep white matter (internal border zone) regions. The presence of selective ischemia of the deep white matter was assessed by the ratio of deep white matter:superficial oxygen extraction fraction. Ipsilateral hemispheric ratios among patients were assessed as a group as compared with contralateral hemispheric ratios and as compared with normal hemispheric ratios from 15 control volunteers. RESULTS: Mean deep white matter to superficial oxygen extraction fraction ratios (+/-95% confidence limits) were 0.99 (+/-0.07), 1.01 (+/-0.06), and 1.02 (+/-0.08) for ipsilateral, contralateral, and normal hemispheres, respectively. No statistically significant difference was found between ipsilateral and contralateral (P = .691) or normal hemispheres (P = .68), nor was any statistically significant difference found when the analysis was limited to patients with increased superficial oxygen extraction fraction (n = 9). Individual deep white matter:superficial ratios were within the normal range for all patients. CONCLUSION: Normal deep white matter among patients with carotid occlusion is not subject to a greater degree of ischemia than is the overlying cortex. It is unlikely that deep white matter infarctions observed among patients with carotid occlusion are owing to chronic selective hemodynamic compromise occurring at an internal arterial border zone.

Benign prognosis of never-symptomatic carotid occlusion.

OBJECTIVE: To determine the prognosis of asymptomatic carotid artery occlusion. BACKGROUND: As opposed to symptomatic carotid occlusion, little information is available on the prognosis of asymptomatic carotid occlusion. METHOD: Thirty never-symptomatic and 81 symptomatic patients with carotid occlusion underwent baseline assessment of 15 risk factors together with PET measurements of oxygen extraction fraction (OEF). Every 6-month telephone contact recorded interval medical treatment and subsequent stroke occurrence during an average follow-up of 32 months. Patients, treating physicians, and an end point adjudicator were blinded to PET results. RESULTS: Ischemic stroke occurred in 1 of 30 of never-symptomatic patients (3.3%) and 15 of 81 of symptomatic patients (18.5%; p = 0.03). No strokes in the carotid territory distal to the occluded vessel occurred in the never-symptomatic patients. Multivariate analysis of baseline risk factors for all 111 patients revealed that age, plasma fibrinogen level, and PET findings of high OEF distal to the occluded carotid artery were the only independent predictors of subsequent stroke (p < 0.05). Previous ipsilateral hemispheric or retinal symptoms was not a significant predictive variable. The lower risk of stroke in never-symptomatic patients was associated with a lower incidence of high OEF (4 of 30) as opposed to symptomatic patients (39 of 81; p = 0.002), but there was no significant difference in age or fibrinogen level. CONCLUSIONS: Never-symptomatic carotid occlusion carries a very low risk of subsequent ischemic stroke. This benign prognosis is associated with a low incidence of cerebral hemodynamic compromise in these patients. These data support further the importance of hemodynamic factors in the pathogenesis of ischemic stroke in patients with carotid occlusion.

No reduction in cerebral metabolism as a result of early moderate hyperventilation following severe traumatic brain injury.

OBJECT: Hyperventilation has been used for many years in the management of patients with traumatic brain injury (TBI). Concern has been raised that hyperventilation could lead to cerebral ischemia; these concerns have been magnified by reports of reduced cerebral blood flow (CBF) early after severe TBI. The authors tested the hypothesis that moderate hyperventilation induced early after TBI would not produce a reduction in CBF severe enough to cause cerebral energy failure (CBF that is insufficient to meet metabolic needs). METHODS: Nine patients were studied a mean of 11.2+/-1.6 hours (range 8-14 hours) after TBI occurred. The patients' mean Glasgow Coma Scale score was 5.6+/-1.8 and their mean age 27+/-9 years; eight of the patients were male. Intracranial pressure (ICP), mean arterial blood pressure, and jugular venous oxygen content were monitored and cerebral perfusion pressure was maintained at a level higher than 70 mm Hg by using vasopressors when needed. Measurements of CBF, cerebral blood volume (CBV), cerebral metabolic rate for oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral venous oxygen content (CvO2) were made before and after 30 minutes of hyperventilation to a PaCO2 of 30+/-2 mm Hg. Ten age-matched healthy volunteers were used as normocapnic controls. Global CBF, CBV, and CvO2 did not differ between the two groups, but in the TBI patients CMRO2 and OEF were reduced (1.59+/-0.44 ml/100 g/minute [p < 0.01] and 0.31+/-0.06 [p < 0.0001], respectively). During hyperventilation, global CBF decreased to 25.5+/-8.7 ml/100 g/minute (p < 0.0009), CBV fell to 2.8+/-0.56 ml/100 g (p < 0.001), OEF rose to 0.45+/-0.13 (p < 0.02), and CvO2 fell to 8.3+/-3 vol% (p < 0.02); CMRO2 remained unchanged. CONCLUSIONS: The authors conclude that early, brief, moderate hyperventilation does not impair global cerebral metabolism in patients with severe TBI and, thus, is unlikely to cause further neurological injury. Additional studies are needed to assess focal changes, the effects of more severe hyperventilation, and the effects of hyperventilation in the setting of increased ICP.