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OBJECTIVE: Patients with arthritis frequently are at increased risk for future cardiovascular (CV) events. We investigated the performance of the cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) for predicting CV events in patients with arthritis taking chronic nonsteroidal antiinflammatory drugs (NSAID). METHODS: We evaluated 2-year CV outcomes in a prospective, nested biomarker study among patients (N = 6273) with rheumatoid arthritis and osteoarthritis treated with NSAID in the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-term) trial. Patients were stratified by quartiles of baseline NT-proBNP and established cutpoints of NT-proBNP and hsCRP. RESULTS: NT-proBNP demonstrated a strong graded relationship with CV outcomes, including CV death (p for trend < 0.0001), myocardial infarction (MI) (p for trend = 0.02), heart failure (HF) (p for trend < 0.0001), and a composite of thrombotic events (CV death, MI, stroke) or HF (p for trend < 0.0001). Baseline levels of hsCRP were not associated with CV events (CV death/MI/stroke/HF; p for trend = 0.65). NT-proBNP remained strongly predictive of CV events after adjustment for age, sex, diabetes, hypertension, hyperlipidemia, smoking, type of arthritis, body mass index, creatinine clearance, history of CV disease, and hsCRP (CV death/MI/stroke/HF: Q4 vs Q1 hazard ratio 3.53, 95% CI 1.89–6.58). Patients with a NT-proBNP level below 100 pg/ml had a 0.94% rate of thrombotic events or heart failure at 2 years. CONCLUSION: NT-proBNP is a simple and robust noninvasive indicator of CV risk in patients with arthritis. Risk stratification based on NT-proBNP may facilitate identification of patients with arthritis who are at low CV risk during chronic NSAID treatment.

Otamixaban is an intravenous direct factor Xa inhibitor. We aimed to assess its efficacy and safety in non-ST-elevation acute coronary syndromes and to identify the optimum dose range for further assessment in a phase 3 study.

The purpose of this study was to examine the patterns of change in microdialysate concentrations of glucose, lactate, pyruvate, and glutamate in the brain during periods of hypoxia/ischemia identified by monitoring brain tissue pO2 (PbtO2). Of particular interest was a better understanding of what additional information could be obtained by the microdialysis parameters that was not available from the PbtO2. Fifty-seven patients admitted with severe traumatic brain injury who had placement of both a brain tissue pO2 (PbtO2) and microdialysis probe were studied. The microdialysis probe was perfused with Ringer's solution at 0.3 μL/min and dialysate was collected at 1-h intervals. The concentration of glucose, pyruvate, lactate, and glutamate were measured in each dialysate sample. Changes in the microdialysis parameters were examined during episodes where the PbtO2 decreased to below 10 mm Hg. Ten episodes of tissue hypoxia/ischemia identified by a decrease in PbtO2 below 10 mm Hg were observed during the period of monitoring. The concentration of the dialysate glucose closely followed the PbtO2. The dialysate pyruvate concentration was more variable and in some patients transiently increased as the PbtO2 dropped below 10 mm Hg. The dialysate concentration of lactate was significantly increased as the PbtO2 decreased to less than 10 mm Hg. Dialysate glutamate was significantly elevated only when PbtO2 decreased to very low levels. Although changes in the PbtO2 provided the earliest sign of hypoxia/ischemia, the microdialysis assays provided additional information about the consequences that the reduced tissue pO2 has on brain metabolism, which may be helpful in managing these critically ill patients.

Background:It is controversial whether a low cerebral blood flow (CBF) simply reflects the severity of injury or whether ischemia contributes to the brain’s injury. It is also not clear whether posttraumatic cerebral hypoperfusion results from intracranial hypertension or from pathologic changes of the cerebral vasculature. The answers to these questions have important implications for whether and how to treat a low CBF.

Traumatic brain injury causes a reduction in cerebral blood flow, which may cause additional damage to the brain. The purpose of this study was to examine the role of nitric oxide produced by endothelial nitric oxide synthase (eNOS) in these vascular effects of trauma. To accomplish this, cerebral hemodynamics were monitored in mice deficient in eNOS and wild-type control mice that underwent lateral controlled cortical impact injury followed by administration of either L-arginine, 300 mg/kg, or saline at 5 min after the impact injury. The eNOS deficient mice had a greater reduction in laser Doppler flow (LDF) in the contused brain tissue at the impact site after injury, despite maintaining a higher blood pressure. L-Arginine administration increased LDF post-injury only in the wild-type mice. L-Arginine administration also resulted in a reduction in contusion volume, from 2.4 ± 1.5 to 1.1 ± 1.2 mm3 in wild-type mice. Contusion volume in the eNOS deficient mice was not significantly altered by L-arginine administration. These differences in cerebral hemodynamics between the eNOS-deficient and the wild-type mice suggest an important role for nitric oxide produced by eNOS in the preservation of cerebral blood flow in contused brain following traumatic injury, and in the improvement in cerebral blood flow with L-arginine administration.

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate signficant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.

The relation between outcome and duration of adverse physiological events was studied, using suggested critical physiological values. Subjects were 184 patients with severe traumatic brain injury who received continuous monitoring of intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP), and jugular venous oxygen satuation. Longer durations of adverse physiological events were significantly related to Glasgow Outcome Scale (GOS) scores and Disability Rating Scale (DRS) scores for all variables at all timepoints postinjury. When analyses excluded patients who died, the relation between adverse physiological events and GOS was non-significant; however, duration of ICP, MAP, and CPP still accounted for a significant portion of the variance in DRS scalres. The relative sensitivity of the GOS and DRS is discussed.

To investigate the frequency and pattern of bilineal transmission in families of patients with Tourette syndrome (TS) compared with normal control subjects.

Near-infrared spectroscopy (NIRS) is a noninvasive technique for assessing cerebral hemodynamic variables and oxidative status in the neonatal intensive care setting. It can be performed for extended periods of time at the bedside without interfering with routine patient care. MRS appears to have the ability to not only assess relative changes in oxygenated and deoxygenated hemoglobin, total hemoglobin, and cytochrome aa3, but it can also produce estimates of cerebral blood volume and cerebral blood flow. Research data document significant changes in these hemodynamic variables with patient activity and clinical interventions in both premature and term infants. MRS may evolve into an important diagnostic and prognostic tool for neonatal neurologic outcome.

Introduction:Large population studies of adult patients suggest an incidence of cytomegalovirus (CMV) retinitis as high as 19% to 20% as a late complication of adult HIV infection. We conducted this prospective study of a large cohort of HIV-infected children to determine the incidence of CMV retinitis in HIV-infected children. Methods:From January 1984 to August 1997, 173 HIV-infected children were followed up for an average of 55.3 months (13-164 months). The patients were seen in the Department of Pediatrics at least once every 6 months. Ophthalmologic examinations were initiated when a patient's CD4 count dropped below 50 or sooner if required for ophthalmologic or other indications. Ophthalmologic examination was then repeated every 6 months. Results:A total of 116 (67%) of 173 patients underwent ophthalmologic examination. Four (3.4%) of 116 patients had CMV retinitis at a mean time of 17.3 months (8-38 months) after their CD4 counts dropped below 20. None of the 4 patients with CMV retinitis had subjective visual complaints despite advanced retinitis. Three patients had bilateral and 1 patient had unilateral CMV retinitis. Conclusions:CMV retinitis occurred infrequently in HIV-infected pediatric patients and was diagnosed only in patients with a CD4 count below 20. Routine ophthalmologic screening examinations may not be necessary in pediatric patients until the CD4 count is below 20. Because children may not complain of decreased vision, at-risk children should undergo frequent ophthalmologic examination. (J AAPOS 1999;3:245-9)

Introduction:We undertook this study to compare the clinical outcomes in patients treated for threshold retinopathy of prematurity (ROP) with transpupillary diode laser photocoagulation versus transscleral cryotherapy. Methods:A retrospective chart review was performed of patients treated for threshold ROP at our institution between 1988 and 1997. Cryotherapy was used to treat patients before 1992, and diode laser was used thereafter. One hundred fifteen eyes of 63 patients underwent cryotherapy, and 130 eyes of 70 patients underwent laser treatment. Because strong concordance exists between fellow eyes treated for ROP, statistical analysis was done for right eye outcomes only. Demographics, short-term complications, and treatment parameters were compared on the entire cohort of patients. Structural outcomes were compared between a group of 79 cryotreated eyes (39 OD, 40 OS) and a group of 113 laser-treated eyes (56 OD, 57 OS). Mean cycloplegic refraction was compared between a group of 38 cryotreated eyes (18 OD, 20 OS) and a group of 90 laser-treated eyes (46 OD, 44 OS). Visual acuity for preverbal and nonverbal children was estimated and converted to a Snellen visual acuity equivalent. Geometric mean visual acuity was then compared between a group of 44 cryotreated eyes (22 OD, 22 OS) and a group of 92 laser-treated eyes (47 OD, 45 OS). Patients were included in each outcome analysis if adequate documentation was present in the patient record. Results:Demographics and short-term complications were not significantly different between the 2 groups. In the statistical group, 22 of 39 right eyes (56.4%) in the cryotherapy group versus 49 of 56 right eyes (87.5%) in the laser group had resolution of ROP after treatment (P= .0008). Mean spherical equivalent cycloplegic refraction at 12 months of age and over the follow-up period was not significantly different between the cryotherapy and laser groups. Estimated geometric mean visual acuity in the cryotherapy group was 20/103 and in the laser group was 20/49 at 12 months of age (P= .0099). Conclusions:Diode laser photocoagulation was associated with a better long-term structural outcome and visual acuity compared with cryotherapy for the treatment of threshold ROP. Refractive error was not significantly different between the 2 groups over an equivalent follow-up period. (J AAPOS 1999;4:234-40)

Phenobarbital sodium (PhS) has been used in anticonvulsant concentrations in premature newborns in attempts to prevent peri- and intraventricular hemorrhages (PIVH). Its effectiveness in preventing PIVH in clinical situations is still uncertain; however, PhS has reduced PIVH after hypertension in newborn beagles, and it has lowered cerebral blood flow (CBF) during hypertension in newborn beagles and piglets. We hypothesized that PhS might reduce CBF during systemic hypotension. Twelve control and 12 PhS-treated piglets (1 to 2 d old) were used for microsphere determinations of CBF during 1) steady state; 2) 30 min after PhS (treatment group) or saline infusion (controls); and 3 and 4) during two levels of graded hypotension. Mean arterial blood pressure (MABP) was 61 ± 13 (SD) mm Hg (controls) and 57 ± 13 (SD) mm Hg (PhS) during steady state. Thirty min after the PhS or saline infusion, MABP and CBF remained unchanged in both groups. CBF during hypotension at MABP of 41 ±5 (SD) mm Hg was significantly higher in controls than was CBF at MABP of 39 ± 6 (SD) mm Hg in the PhS-treated group (p = 0.044); CBF in the two groups during the second hypotensive phase was not significantly different. However, LOWESS regression suggested that the CBF from the controls dropped as the arterial pressure decreased to less than 37 mm Hg, whereas PhS treatment lowered CBF during hemorrhagic hypotension compared with controls at blood pressures greater than 37 mm Hg but did not lower CBF further at lower systemic blood pressures. This suggests that PhS would not, by itself, cause ischemia at blood pressures near the lower limit of autoregulation.

ABSTRACT: Phenobarbital sodium (PhS) has been used in anticonvulsant concentrations in premature newborns in attempts to prevent peri- and intraventricular hemorrhages (PIVH). Its effectiveness in preventing PIVH in clinical situations is still uncertain; however, PhS has reduced PIVH after hypertension in newborn beagles, and it has lowered cerebral blood flow (CBF) during hypertension in newborn beagles and piglets. We hypothesized that PhS might reduce CBF during systemic hypotension. Twelve control and 12 PhS-treated piglets (1 to 2 d old) were used for microsphere determinations of CBF during 1) steady state; 2) 30 min after PhS (treatment group) or saline infusion (controls); and 3 and 4) during two levels of graded hypotension. Mean arterial blood pressure (MABP) was 61 ± 13 (SD) mm Hg (controls) and 57 ± 13 (SD) mm Hg (PhS) during steady state. Thirty min after the PhS or saline infusion, MABP and CBF remained unchanged in both groups. CBF during hypotension at MABP of 41 ±5 (SD) mm Hg was significantly higher in controls than was CBF at MABP of 39 ± 6 (SD) mm Hg in the PhS-treated group (p = 0.044); CBF in the two groups during the second hypotensive phase was not significantly different. However, LOWESS regression suggested that the CBF from the controls dropped as the arterial pressure decreased to less than 37 mm Hg, whereas PhS treatment lowered CBF during hemorrhagic hypotension compared with controls at blood pressures greater than 37 mm Hg but did not lower CBF further at lower systemic blood pressures. This suggests that PhS would not, by itself, cause ischemia at blood pressures near the lower limit of autoregulation.

Purpose: The study design, research questions, and baseline data are presented from a multicenter longitudinal epidemiologic investigation of the impact of human immunodeficiency virus (HIV) infection on three areas of functioning in children and adolescents with hemophilia: physical growth and sexual maturation, immune function, and neurological and neuropsychological functioning.

Acute respiratory distress syndrome is commonly encountered in head-injured patients. Positive end expiratory pressure (PEEP) is useful in improving oxygenation. However, PEEP, by increasing intrathoracic pressure, decreases venous return, mean arterial pressure, and cardiac output and increases jugular vein pressure. There is conflicting evidence in the literature as to the potential effect of PEEP on intracranial pressure (ICP). The present study was undertaken to examine the effect of PEEP on ICP and intracranial compliance. Twelve male rabbits weighing 3.5–4.5 kg were used. The following parameters were monitored: arterial blood pressure, ICP (intraparenchymal Caminodevice), PaCO2, and PaO2. A space-occupying lesion was produced by inflation of a double lumen pediatric Swan-Ganz catheter placed over the right parietal dura. The amount of fluid required to reach the point of exponential increase of ICP was recorded at PEEP of 0 and 10 cm H2O. The mean volume needed to reach the deflection point of ICP was significantly lower when PEEP was 10 cm H2O compared to the value when PEEP was 0 cm H2O (685 ± 48 vs. 883.3 ± 46 μl, respectively; p < 0.01). The results of the present study indicated that PEEP of 10 cm H2O decreases intracranial compensatory reserves for maintaining ICP at normal levels in the presence of an expanding intracranial mass.