Isolated, Nonsyndromic Mucocutaneous Plexiform Neurofibromas: A Systematic Review of the Clinicopathologic Features.

ABSTRACT: Plexiform neurofibromas are benign neural tumors observed in association with neurofibromatosis. Isolated lesions exist. We conducted a systematic review of the published literature indexed in the PubMed/Medline database using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirty-five studies describing isolated plexiform neurofibromas were included detailing 41 tumors. Isolated lesions occur in all age groups, in both sexes and in all races. Cutaneous and mucosal lesions were reported. Asymptomatic, slowly enlarging masses were the most common clinical presentation, but lesions could be painful. Trauma-associated lesions were uncommon, but reported. Histopathologic features were similar to syndromic counterparts, but well-circumscribed/encapsulated lesions, rare association with diffuse neurofibroma, lack of reported malignant degeneration, and rare named-nerve origin were observed. Excision was curative in many cases, but recurrence could occur. Plexiform neurofibromas occur without neurofibromatosis in a subset of patients with isolated tumors.

Sinus Tachycardia: a Multidisciplinary Expert Focused Review.

Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current medical condition that precipitates an increase in the sinus rate, but ST at rest without physiological triggers may also represent a spectrum of normal. In other cases, ST may not have an easily explainable cause but may represent serious underlying pathology and can be associated with intolerable symptoms. The classification of ST, consideration of possible etiologies, as well as the decisions of when and how to intervene can be difficult. ST can be classified as secondary to a specific, usually treatable, medical condition (eg, pulmonary embolism, anemia, infection, or hyperthyroidism) or be related to several incompletely defined conditions (eg, inappropriate ST, postural tachycardia syndrome, mast cell disorder, or post-COVID syndrome). While cardiologists and cardiac electrophysiologists often evaluate patients with symptoms associated with persistent or paroxysmal ST, an optimal approach remains uncertain. Due to the many possible conditions associated with ST, and an overlap in medical specialists who see these patients, the inclusion of experts in different fields is essential for a more comprehensive understanding. This article is unique in that it was composed by international experts in Neurology, Psychology, Autonomic Medicine, Allergy and Immunology, Exercise Physiology, Pulmonology and Critical Care Medicine, Endocrinology, Cardiology, and Cardiac Electrophysiology in the hope that it will facilitate a more complete understanding and thereby result in the better care of patients with ST.

Orthostatic Hypotension: Management of a Complex, But Common, Medical Problem.

Orthostatic hypotension (OH), a common, often overlooked, disorder with many causes, is associated with debilitating symptoms, falls, syncope, cognitive impairment, and risk of death. Chronic OH, a cardinal sign of autonomic dysfunction, increases with advancing age and is commonly associated with neurodegenerative and autoimmune diseases, diabetes, hypertension, heart failure, and kidney failure. Management typically involves a multidisciplinary, patient-centered, approach to arrive at an appropriate underlying diagnosis that is causing OH, treating accompanying conditions, and providing individually tailored pharmacological and nonpharmacological treatment. We propose a novel streamlined pathophysiological classification of OH; review the relationship between the cardiovascular disease continuum and OH; discuss OH-mediated end-organ damage; provide diagnostic and therapeutic algorithms to guide clinical decision making and patient care; identify current gaps in knowledge and try to define future research directions. Using a case-based learning approach, specific clinical scenarios are presented highlighting various presentations of OH to provide a practical guide to evaluate and manage patients who have OH.

Women's Knowledge of Bladder Health: What We Have Learned in the Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium.

Purpose of Review: The goal of this manuscript is to review the current literature on bladder health education, summarize Prevention of Lower Urinary Tract Symptoms (PLUS) [50] findings on environmental factors that influence knowledge and beliefs about toileting and bladder function, and describe how PLUS work will contribute to improved understanding of women's bladder-related knowledge and inform prevention intervention strategies. Recent Findings: Analysis of focus group transcripts revealed the various ways women view, experience, and describe bladder function. In the absence of formal bladder health educational platforms, women appear to develop knowledge of normal and abnormal bladder function from a variety of social processes including environmental cues and interpersonal sources. Importantly, focus group participants expressed frustration with the absence of structured bladder education to inform knowledge and practices. Summary: There is a lack of bladder health educational programming in the USA, and it is unknown to what degree women's knowledge, attitudes, and beliefs influence their risk of developing lower urinary tract symptoms (LUTS). The PLUS Consortium RISE FOR HEALTH study will estimate the prevalence of bladder health in adult women and assess risk and protective factors. A Knowledge, Attitudes, and Beliefs (KAB) questionnaire will be administered to determine KAB around bladder function, toileting, and bladder-related behaviors, and examine the relationship of KAB to bladder health and LUTS. The data generated from PLUS studies will identify opportunities for educational strategies to improve bladder health promotion and well-being across the life course.

Management of Orthostatic Hypotension in the Hospitalized Patient: A Narrative Review.

Orthostatic hypotension is a frequent cause of falls and syncope, impairing quality of life. It is an independent risk factor of mortality and a common cause of hospitalizations, which exponentially increases in the geriatric population. We present a management plan based on a systematic literature review and understanding of the underlying pathophysiology and relevant clinical pharmacology. Initial treatment measures include removing offending medications and avoiding large meals. Clinical assessment of the patients' residual sympathetic tone can aid in the selection of initial therapy between norepinephrine "enhancers" or "replacers." Role of splanchnic venous pooling is overlooked, and applying abdominal binders to improve venous return may be effective. The treatment goal is not normalizing upright blood pressure but increasing it above the cerebral autoregulation threshold required to improve symptoms. Hypertension is the most common associated comorbidity, and confining patients to bed while using pressor agents only increases supine blood pressure, leading to worsening pressure diuresis and orthostatic hypotension. Avoiding bedrest deconditioning and using pressors as part of an orthostatic rehab program are crucial in reducing hospital stay.

Evaluation of a Clinical Pharmacist Specialist Transition of Care Pathway to Manage Heart Failure Readmissions During a Provider Shortage.

BACKGROUND: Evidence supports scheduling early follow-up after heart failure (HF) hospitalization with a provider capable of managing hypervolemia. Often this service is provided by cardiologists or specialty nurse practitioners. Continuity or "familiar" providers may be better positioned to identify decompensating HF in patients who have advanced HF and/or multiple complicating medical problems. The objective of this study was to evaluate whether a clinical pharmacy specialist (CPS) service, covering the role of a "familiar" provider in an advanced HF specialty clinic (AHFC) during a staffing shortage, may prevent readmission metrics from worsening. METHODS: We evaluated the entire, eligible concurrent cohorts, representing 175 AHFC-CPS and 273 control patient-admissions, respectively. Study- and disease-specific predictors for readmission were assessed. A matched cohort of 202 patient-admissions (101 AHFC-CPS:101 NO-CPS) were evaluated. RESULTS: Subjects were predominantly white, elderly males. While overall "clinic [performance] profiling" outcomes for readmissions (p = 0.43) and mortality (p = 0.66) did not statistically differ between the AHFC-CPS and NO-CPS groups, an imbalance in severity of illness persisted. A survival curve and analysis were constructed, and the hazard ratio for all-cause mortality was 0.69 (p = 0.033). CONCLUSIONS: This retrospective project supports the premise that AHFC-CPS intervention may be a suitable alternative to maintain the volume status for AHFC patients during a staffing short-fall. More work needs to be done to determine intervention effect size, predictors for readmission, specifically in advanced cardiovascular disease, and to evaluate CPS opportunities in the provision of independent HF care, particularly for patients with advanced HF.

Apple cider vinegar administration on carcass characteristics and meat quality of broiler chickens.

This study evaluated the effect of apple cider vinegar (ACV) on the carcass characteristics and meat quality of broiler chickens. A total of 300 broilers (Arbor Acre) were randomized to six treatments replicated 5 times (50 birds/treatment and 10 birds/replicate) from 2 days old till the sixth week of age in a 2 by 3 factorial layout consisting of dosages (5.0 mL/L and 10.0 mL/L ACV) and administration frequency (antibiotics following standard schedule, twice/week ACV and thrice/week ACV). At the sixth week, sixty birds (10 birds/treatment) were selected for carcass yield, cut part yield, organ weight, meat technological properties, lipid profiles, and malondialdehyde (MDA) level evaluation. Data obtained were subjected to two-way ANOVA followed by Tukey's test at a P < 0.05 significant level. Birds administered 5.0 mL/L ACV thrice weekly presented a significantly (P < 0.05) higher plucked, eviscerated, dressed, thigh and breast weight compared with the other treatments. The spleen of birds in the control group was significantly (P < 0.05) heavier than those administered ACV. The meat from the 5.0 mL/L ACV group had significantly higher (P < 0.05) water absorptive power and lower refrigeration loss, as depicted in the main effect table. Meat cholesterol, phospholipids, and MDA levels did not differ across the treatments except triglyceride, which was significantly (P < 0.05) lower in the 5.0 mL/L ACV thrice-weekly group. This study concludes that ACV administration could improve carcass yield and meat quality indices. Thus, its use as an alternative to conventional antibiotics for broiler chickens might be beneficial.

Local Passive Heat for the Treatment of Hypertension in Autonomic Failure.

Background Supine hypertension affects a majority of patients with autonomic failure; it is associated with end-organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP-lowering effect in patients with autonomic failure and could be used to treat their supine hypertension. Methods and Results In Protocol 1 (n=22), the acute effects of local heat (40-42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by -19±4 mm Hg (versus 3±4 with sham, P<0.001) owing to decreases in stroke volume (-18±5% versus -4±4%, P=0.013 ) and cardiac output (-15±5% versus -2±4%, P=0.013). In Protocol 2 (proof-of-concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water-perfused heating pad placed under the torso from 10 pm to 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change -28±6 versus -2±6 mm Hg, P<0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume (r=0.57, P=0.072) and an improvement in the morning upright systolic BP (r=-0.76, P=0.007). Conclusions Local heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long-term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.

Bioaccumulation of heavy metals, lipid profiles, and antioxidant status of snails (Achatina achatina) around cement factory vicinities.

Some snails (Achatina spp) can be used as a biosensor of heavy metal poisoning. This study thus estimated some heavy metal levels, antioxidant markers, and lipid profiles of snails handpicked around cement factory vicinities in Ogun State, Nigeria. Snails and soil samples were collected from Oke, Ewekoro, Papalanto, and Mowodani Imeko-Afon (control site). Lead (Pb), cadmium (Cd), and arsenic (As) levels were estimated in the soil, snail foot, hemolymph, and shell using Atomic Absorption Spectrophotometry. Triacylglycerol (TAG), phospholipids (PHOL), cholesterol (CHOL), malondialdehyde (MDA), and reduced glutathione (GSH) levels, as well as glutathione-S-transferase (GST), lactate dehydrogenase (LDH), and arylesterase (AR) activities in the hemolymph, were estimated spectrophotometrically. The snails collected from the Oke site had the highest foot Pb (274.66 ± 13.50 mg/g tissue), CHOL, TAG, PHOL levels, and GST activity when compared with other sites. Snails collected from Papa had the highest Cd levels (1.79 ± 0.74 mg/kg), As (1206 ± 18.87 mg/g tissue) in the foot, and LDH activity, while Ewekoro snails had highest MDA levels and AR activities but the lowest GSH levels. Additionally, there were negative correlations between the heavy metal levels and the activities of GST and AR as well as GSH levels, while positively correlating with LDH activity and MDA level. Workers and the general public around cement factories are at a greater risk of heavy metal-induced pathologies. More so, consumption of snails around these sites may be deleterious to health.

Management of neurogenic orthostatic hypotension in the heart failure patient.

Neurogenic orthostatic hypotension (nOH) is a common comorbidity in patients with neurodegenerative diseases. It is associated with an increased risk of falls, incident cardiovascular disease, and all-cause mortality. There are over 5 million individuals in the U.S. with heart failure (HF) with an associated 50% mortality rate at 5 years. The prevalence of nOH and HF increase with age and, as the population continues to age, will be increasingly common comorbid conditions. Thus, the effective management of these conditions has important implications for public health. The management of orthostatic hypotension in the context of congestive heart failure is challenging due to the fact that the fundamental principles of management of these disease states are in opposition to each other. In this review, we will discuss the principles of management of nOH and HF and outline strategies for the effective treatment of these comorbid conditions.

Linear body measurements and productivity of subtropical Holstein-Friesian dairy calves.

OBJECTIVE: The study aimed to describe growth parameters and to quantify the association between linear body measurements as predictors of liveweight (LW) of Holstein-Friesian (HF), and HF crossbred dairy calves in Queensland. A secondary objective was to quantify the effect of disease events on LW change. STUDY DESIGN: Longitudinal study. METHODS: Fortnightly LW, hip height (HH), hip width (HW) and heart girth (HG) measurements were recorded from 16 male and 28 female HF calves from birth until weaning. The association between linear body measurement and the effect of a disease event on LW change were explored using linear mixed-effects modelling with random intercepts and random slopes. RESULTS: HG was the best body measure used individually as a predictor of calf LW (R2 = 82%; P < 0.001), while the combined use of HG, HW and HH was the most accurate predictor of calf LW between birth and weaning (R2 = 90%; P < 0.001). HW, average feed intake and total feed intake were significantly affected by disease events (P < 0.05). On average, total average LW loss associated with a single pneumonia event was estimated at 14.6 kg (95% CI = 10.5 to 18.7 kg; P < 0.05). CONCLUSIONS: Calves of this study performed at a level consistent with the previously published reports. Growth performance was significantly compromised by pneumonia. HW was found to be the least predictive individual measure, and the combined use of HH, HW and HG had the most accurate prediction of calf liveweight from birth to weaning.

Blood Pressure Management in Afferent Baroreflex Failure: JACC Review Topic of the Week.

Afferent baroreflex failure is most often due to damage of the carotid sinus nerve because of neck surgery or radiation. The clinical picture is characterized by extreme blood pressure lability with severe hypertensive crises, hypotensive episodes, and orthostatic hypotension, making it the most difficult form of hypertension to manage. There is little evidence-based data to guide treatment. Recommendations rely on understanding the underlying pathophysiology, relevant clinical pharmacology, and anecdotal experience. The goal of treatment should be improving quality of life rather than normalization of blood pressure, which is rarely achievable. Long-acting central sympatholytic drugs are the mainstay of treatment, used at the lowest doses that prevent the largest hypertensive surges. Short-acting clonidine should be avoided because of rebound hypertension, but can be added to control residual hypertensive episodes, often triggered by mental stress or exertion. Hypotensive episodes can be managed with countermeasures and short-acting pressor agents if necessary.

Initiation of droxidopa during hospital admission for management of refractory neurogenic orthostatic hypotension in severely ill patients.

Orthostatic hypotension (OH) is a common cause of hospitalization, particularly in the elderly. Hospitalized patients with OH are often severely ill, with complex medical comorbidities and high rates of disability. Droxidopa is a norepinephrine precursor approved for the treatment of neurogenic OH (nOH) associated with autonomic failure that is commonly used in the outpatient setting, but there are currently no data regarding the safety and efficacy of droxidopa initiation in medically complex patients. We performed a retrospective review of patients started on droxidopa for refractory nOH while hospitalized at Vanderbilt University Medical Center between October 2014 and May 2017. Primary outcome measures were safety, change in physician global impression of illness severity from admission to discharge, and persistence on medication after 180-day follow-up. A total of 20 patients were identified through chart review. Patients were medically complex with high rates of cardiovascular comorbidities and a diverse array of underlying autonomic diagnoses. Rapid titration of droxidopa was safe and well tolerated in this cohort, with no cardiovascular events or new onset arrhythmias. Supine hypertension requiring treatment occurred in four patients. One death occurred during hospital admission due to organ failure associated with end-stage amyloidosis. Treating physicians noted improvements in presyncopal symptoms in 80% of patients. After 6 months, 13 patients (65%) continued on droxidopa therapy. In a retrospective cohort of hospitalized, severely ill patients with refractory nOH, supervised rapid titration of droxidopa was safe and effective. Treatment persistence was high, suggesting that symptomatic benefit extended beyond acute intervention.

Reinforcer quality matters: A test of the Mathematical Principles of Reinforcement with domestic hens (Gallus gallus domesticus).

This study evaluated the ability of Killeen's (1994) Mathematical Principles of Reinforcement to account for the effects of changes in reinforcer quality on hens' rates of responding on fixed-ratio schedules. Hens were trained to peck a key on a fixed-ratio schedule of reinforcement and then experienced an ascending series of ratio values in two separate conditions. In different conditions, the food reinforcer was either wheat or puffed wheat. Response rates initially increased with increases in ratio requirement before eventually decreasing at larger ratios. Quantitative fits of the model accounted for the data well. The fits revealed that different foods were systematically associated with changes in the specific activation parameter, a, and these were consistent with previous reports of preference for those food items.

New furoquinoline alkaloid and flavanone glycoside derivatives from the leaves of Oricia suaveolens and Oricia renieri (Rutaceae).

Fractionation of the methanol extract of the leaves of Oricia renieri and Oricia suaveolens (Rutaceae) led to the isolation of 13 compounds including the hitherto unknown furoquinoline alkaloid named 6,7-methylenedioxy-5-hydroxy-8-methoxy-dictamnine (1) and a flavanone glycoside named 5-hydroxy-4'-methoxy-7-O-[α-L-rhamnopyranosyl(1‴→5″)-ß-D-apiofuranosyl]-flavanoside (2), together with 11 known compounds (3-13). The structures of the compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral data and comparison. All compounds isolated were examined for their activity against human carcinoma cell lines. The alkaloids 1, 5, 12, 13 and the phenolic 2, 8, 11 tested compounds exhibited non-selective moderate cytotoxic activity with IC50 8.7-15.9 µM whereas compounds 3, 4, 6, 7, 9 and 10 showed low activity.

A Phase I, Single Ascending Dose Study of Cimaglermin Alfa (Neuregulin 1ß3) in Patients With Systolic Dysfunction and Heart Failure.

A first-in-human, phase 1, double blind, placebo-controlled, single ascending dose study examined the safety, tolerability, and exploratory efficacy of intravenous infusion of a recombinant growth factor, cimaglermin alfa, in patients with heart failure and left ventricular systolic dysfunction (LVSD). In these patients on optimal guideline-directed medical therapy, cimaglermin treatment was generally tolerated except for transient nausea and headache and a dose-limiting toxicity was noted at the highest planned dose. There was a dose-dependent improvement in left ventricular ejection fraction lasting 90 days following infusion. Thus, cimaglermin is a potential therapy to enhance cardiac function in LVSD and warrants further investigation.

Recognition deficits in mice carrying mutations of genes encoding BLOC-1 subunits pallidin or dysbindin.

Numerous studies have implicated DTNBP1, the gene encoding dystrobrevin-binding protein or dysbindin, as a candidate risk gene for schizophrenia, though this relationship remains somewhat controversial. Variation in dysbindin, and its location on chromosome 6p, has been associated with cognitive processes, including those relying on a complex system of glutamatergic and dopaminergic interactions. Dysbindin is one of the seven protein subunits that comprise the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin protein levels are lower in mice with null mutations in pallidin, another gene in the BLOC-1, and pallidin levels are lower in mice with null mutations in the dysbindin gene, suggesting that multiple subunit proteins must be present to form a functional oligomeric complex. Furthermore, pallidin and dysbindin have similar distribution patterns in a mouse and human brain. Here, we investigated whether the apparent correspondence of pallid and dysbindin at the level of gene expression is also found at the level of behavior. Hypothesizing a mutation leading to underexpression of either of these proteins should show similar phenotypic effects, we studied recognition memory in both strains using the novel object recognition task (NORT) and social novelty recognition task (SNRT). We found that mice with a null mutation in either gene are impaired on SNRT and NORT when compared with wild-type controls. These results support the conclusion that deficits consistent with recognition memory impairment, a cognitive function that is impaired in schizophrenia, result from either pallidin or dysbindin mutations, possibly through degradation of BLOC-1 expression and/or function.

The Impact of Inpatient Versus Outpatient Initiation on Early Warfarin Dosing.

BACKGROUND AND OBJECTIVES: Dosing algorithms for warfarin incorporate clinical and genetic factors but may not account for the numerous comorbidities affecting patients who start warfarin while hospitalized. We aimed to determine whether these algorithms perform differently when warfarin is initiated for inpatients compared with outpatients. PATIENTS AND METHODS: We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial who were randomized to either pharmacogenetically or clinically guided warfarin dosing algorithms. Clinicians and participants were blinded to dose during the first 28 days. We compared groups, based on location at the time of the first warfarin dose request, in relation to the following outcomes: percentage of time in the therapeutic international normalized ratio (INR) range (PTTR) during the first 4 weeks, time to first therapeutic INR, time to maintenance dose, and the difference between predicted and observed maintenance doses. RESULTS: A total of 527 participants started warfarin as inpatients and 488 as outpatients. There was no difference in PTTR based on location: 43.2 % for inpatient versus 47.4 % for outpatient initiation [mean adjusted difference -2.2 %; 95 % confidence interval (CI) -5.9 to 1.6]. Similarly, there were no differences in time to first therapeutic INR [hazard ratio (HR) 1.06; 95 % CI 0.91-1.24] or to maintenance dose (HR 0.96; 95 % CI 0.81-1.14). There was no evidence of interaction between study intervention (pharmacogenetically vs. clinically guided therapy) and location of initiation for these main outcomes. The difference between predicted and observed maintenance doses was similar for both locations. CONCLUSION: The warfarin dosing algorithms performed similarly for subjects who initiated warfarin as inpatients and outpatients, regardless of whether dosing was pharmacogenetically or clinically guided.

Decisional stage distribution for colorectal cancer screening among diverse, low-income study participants.

Colorectal cancer (CRC) screening uptake among minorities and those with lower incomes is suboptimal. Behavioral interventions specifically tailored to these populations can increase screening rates and save lives. The Precaution Adoption Process Model (PAPM) allows assignment of a decisional stage for adoption of a behavior such as CRC screening. Here, we characterize the PAPM decisional stage distribution among 470 low income, racially and ethnically diverse study participants at intake into a behavioral intervention study designed to increase CRC screening uptake. We staged participants for stool blood test (SBT) and colonoscopy separately and used the highest stage for the two tests as the 'overall' stage for CRC screening. For SBT, sex, language (English versus Spanish) and doctor recommendation were significantly related to PAPM stage for CRC screening. For colonoscopy, language, education level, doctor recommendation and self-efficacy were related to stage. For overall CRC screening stage, all the variables associated with either SBT or colonoscopy, with the exception of language were significant. This study suggests attending to these key variables in designing interventions to promote CRC screening, particularly with respect to medically underserved populations.

Circadian variability of fibrinolytic markers and endothelial function in patients with obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is strongly associated with cardiovascular disease, including stroke and acute coronary syndromes. Plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue-type plasminogen activator (t-PA), has a pronounced circadian rhythm and is elevated in both OSA and cardiovascular disease and may be an important link between the two conditions. Endothelial dysfunction is one of the underlying pathophysiological mechanisms of cardiovascular disease, and may be altered in OSA. Our primary aim was to compare circadian variability of PAI-1 and t-PA in patients with OSA and normal controls by determining the amplitude (peak level) and mesor (rhythm adjusted mean) of PAI-1 and t-PA in serial blood samples over a 24-h period. The secondary aim was to measure markers of endothelial function (brachial and radial artery flow) in patients with OSA compared with normal controls. SETTING: Cross-sectional cohort study. PATIENTS OR PARTICIPANTS: Subjects age 18 y or older, with a body mass index of 25-45 kg/m(2), with or without evidence of untreated OSA. INTERVENTIONS: Plasma samples were collected every 2 h, in OSA patients and matched controls, over a 24-h period. PAI-1 and t-PA antigen and activity were measured. The presence or absence of OSA (apnea-hypopnea index of 5 or greater) was confirmed by overnight polysomnography. Endothelial function was measured via brachial artery flow mediated vasodilatation and computerized arterial pulse waveform analysis. MEASUREMENTS AND RESULTS: The rhythm-adjusted mean levels of PAI-1 antigen levels in the OSA group (21.8 ng/mL, 95% confidence level [CI], 18 to 25.7) were significantly higher as compared to the non-OSA group (16 ng/mL, 95% CI, 12.2 to 19.8; P = 0.03). The rhythm-adjusted mean levels of PAI-1 activity levels in the OSA group (23.9 IU/mL, 95% CI, 21.4 to 26.5) were also significantly higher than in the non-OSA group (17.2 IU/ mL, 95% CI, 14.6 to 19.9; P < 0.001).There were strong correlations between amplitude of PAI-1 activity and severity of OSA as measured by AHI (P = 0.02), and minimum oxygen levels during sleep (P = 0.04). Endothelial function parameters did not differ significantly between the two groups. CONCLUSION: The presence of obstructive sleep apnea adversely affects circadian fibrinolytic balance with higher mean plasminogen activator inhibitor-1 activity and antigen, and significantly lower mean tissue-type plasminogen activator activity compared with controls. This perturbation may be an important mechanism for increased cardiovascular events in patients with obstructive sleep apnea. Intermittent hypoxia and changes in circadian clock gene activity in obstructive sleep apnea may be responsible for these findings and warrant further study. Favorable changes in fibrinolytic balance may underlie the reduction in cardiovascular events observed with the treatment of obstructive sleep apnea.