Evaluating S100B as a serum biomarker for central neurosarcoidosis.

BACKGROUND: S100B is a calcium-binding protein found primarily in glial cells. In the setting of neuronal injury and disruption of the blood brain barrier, S100B can leak into the cerebrospinal fluid and systemic circulation. OBJECTIVES: To determine if serum S100B distinguishes patients with central neurosarcoidosis (NS) from patients with extra-neurologic sarcoidosis (ENS) and healthy controls, and if S100B levels correlate with MRI measures of disease burden. METHODS: Patients were enrolled from the Cleveland Clinic Sarcoidosis Center. Patients with traumatic brain injury, central nervous system (CNS) infections, CNS malignancy, neurodegenerative disorders, schizophrenia, bipolar disorder, or melanoma were excluded. S100B levels were compared between patients with NS, ENS, and healthy controls, and between NS patients with varying degrees of post-contrast enhancement on MRI. RESULTS: Median (interquartile range) S100B levels were 101 pg/mL (92, 136) for 11 NS patients, 89 pg/mL (73, 107) for 11 ENS patients, and 60 pg/mL (39, 74) for 26 healthy controls. There was a significant difference between NS and control groups (p = 0.01). The difference between NS and ENS groups did not rise to the level of statistical significance (p = 0.178). S100B levels were significantly different between NS patients with varying degrees of enhancement on MRI (p = 0.04). CONCLUSIONS: S100B deserves additional study as a biomarker for CNS injury in NS. It may be useful as a longitudinal measure of disease activity.

Endpoints for clinical trials of sarcoidosis.

Over the past few years an increasing number of prospective controlled sarcoidosis treatment trials have been completed. Unfortunately, these studies utilize different endpoints making comparisons between studies difficult. At the recent World Association of Sarcoidosis and other Granulomatous disease (WASOG) meeting, a session was dedicated to the evaluation of clinical endpoints for various disease manifestations. These included pulmonary, pulmonary hypertension, fatigue, cutaneous, and a classification of clinical disease phenotypes. Based on the available literature and our current understanding of the disease, recommendations for clinical evaluation were proposed for each disease category. For example, it was recommended that pulmonary studies should include changes in the forced vital capacity. Additionally, it was recommended that all trials should incorporate measurement of quality of life.

Metabolism-perfusion imaging to predict disease activity in cardiac sarcoidosis.

FDG-PET is a sensitive but not specific test for myocardial sarcoidosis and its ability to define prognosis remains unclear. Combination with perfusion scanning may improve accuracy by differentiating scar from inflammation. We conducted this retrospective chart review to ascertain the utility of a rubidium -FDG PET scan for assessment of disease activity in patients with cardiac sarcoidosis. The presence of any perfusion-metabolism mismatch or a mismatch of > 6% of the myocardium on the scan were compared with the clinical course. Among 18 subjects, mismatched segments were present in 11 scans, whereas 7 demonstrated mismatch > 6%. There was a suggestion of association between PET scan and active disease using the threshold of any mismatch (p=0.09), with sensitivity of 80% and specificity of 62.5%. The threshold of >6% mismatch improved the specificity to 100% with 70% sensitivity, and the association between PET findings and clinically active disease was highly significant (p=0.0002). Eight patients had follow-up Rb-FDG PET scans, all of which were concordant with the clinical course. The positive predictive value of Rb-FDG PET scan showing >6% mismatch for detecting clinically active cardiac sarcoidosis was 100%. However, the finding of any mismatch still portends a high chance of clinical activity. Further studies to define the utility of Rb-FDG PET scan for management of cardiac sarcoidosis are warranted.

Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis.

Leflunomide has been reported as an alternative therapy in sarcoidosis. However, the published data are limited. We performed a retrospective chart review of the tolerance and effects of leflunomide therapy in patients with sarcoidosis. 76 patients were included. The most common reasons for initiation were progression of disease or failure of other immunomodulator therapy. Side-effects attributable to leflunomide were noted in 34% of subjects, prompting discontinuation in 17%. The lungs were a target of therapy in 33 (44%) and extrapulmonary organs were a target in 45 (59%). The mean ± sd change in forced vital capacity in the 6 months prior to leflunomide was -0.1 ± 0.3 L, and it was +0.09 ± 0.3 L in the following 6 months (p=0.01). For extrapulmonary target organ response, 51% had a good response and 32% a partial response. The median corticosteroid dose at initiation was 10 mg (interquartile range 5-20) mg at baseline, and 0 (0-10) mg at the 6-month follow-up (p<0.001). Leflunomide is a viable alternative agent for pulmonary and extrapulmonary sarcoidosis. Leflunomide appears to facilitate reduction of steroid dose and can be considered as monotherapy or as add-on therapy in cases of progressive disease.

Detecting cardiac involvement in sarcoidosis: a call for prospective studies of newer imaging techniques.

Diagnosis of cardiac involvement in sarcoidosis is challenging and usually relies on a combination of clinical findings and imaging abnormalities. The case of a 53-yr-old female is described who presented with ventricular tachycardia and suspected angiosarcoma involving the right atrium and superior vena cava. A combination of magnetic resonance imaging and (18)F-2-fluoro-2-deoxyglucose-positron emission tomography were essential to the diagnosis of cardiac sarcoidosis. Reversibility of the disease was predicted more clearly by (18)F-2-fluoro-2-deoxyglucose-positron emission tomography than by magnetic resonance imaging, and clinical activity was predicted by persistent hypermetabolism on serial (18)F-2-fluoro-2-deoxyglucose-positron emission tomography.

Hepatitis E virus antibody prevalence among persons who work with swine.

Prevalence of antibody and risk factors to hepatitis E virus (HEV) infection were determined in a cross-sectional study of 2 group-matched populations: swine farmers (n=264) and persons without occupational exposure to swine (n=255) in Moldova, a country without reported cases of hepatitis E. The prevalence of HEV infection was higher among swine farmers than among the comparison group (51.1% vs. 24.7%; prevalence ratio, 2.07; 95% confidence interval [CI], 1.62-2.64). In multivariate analysis, HEV infection was associated with an occupational history of cleaning barns or assisting sows at birth (odds ratio [OR], 2.46; 95% CI, 1.52-4.01), years of occupational exposure (OR, 1.04 per year; 95% CI, 1.01-1.07), and a history of drinking raw milk (OR, 1.61; 95% CI, 1.08-2.40). HEV infection was not associated with civilian travel abroad or having piped water in the household. The increased prevalence of HEV infection among persons with occupational exposure to swine suggests animal-to-human transmission of this infection.

Surgical site infection (SSI) rates in the United States, 1992-1998: the National Nosocomial Infections Surveillance System basic SSI risk index.

By use of the National Nosocomial Infections Surveillance (NNIS) System's surgical patient surveillance component protocol, the NNIS basic risk index was examined to predict the risk of a surgical site infection (SSI). The NNIS basic SSI risk index is composed of the following criteria: American Society of Anesthesiologists score of 3, 4, or 5; wound class; and duration of surgery. The effect when a laparoscope was used was also determined. Overall, for 34 of the 44 NNIS procedure categories, SSI rates increased significantly (P< .05) with the number of risk factors present. With regard to cholecystectomy and colon surgery, the SSI rate was significantly lower when the procedure was done laparoscopically within each risk index category. With regard to appendectomy and gastric surgery, use of a laparoscope affected SSI rates only when no other risk factors were present. The NNIS basic SSI index is useful for risk adjustment for a wide variety of procedures. For 4 operations, the use of a laparoscope lowered SSI risk, requiring modification of the NNIS basic SSI risk index.

A prevalence study of hepatitis A virus infection in a migrant community: Is hepatitis A vaccine indicated?

BACKGROUND: The Advisory Committee on Immunization Practices recommends routine hepatitis A vaccination of children living in communities with high rates of hepatitis A. Rates among children living in migrant farm worker families are unknown. METHODS: Participants recruited from the 1243 migrant children aged 2 to 18 years in Okeechobee County, Florida, were administered a questionnaire. A blood sample was taken for testing for antibodies to hepatitis A virus (anti-HAV), and hepatitis A vaccine was administered. RESULTS: Of 244 (20%) participating children, 125 (51%) were anti-HAV-positive. Seropositivity increased with age from 34% (2- to 5-year-olds) to 81% (>/=14-year-olds) (P <.0001). In multivariate analysis, age (odds ratio [OR] = 1.2/year; 95% CI = 1.1 to 1.3), having a Mexican-born father (OR = 12.2; 95% CI = 2.2 to 227.9), and age on moving to the United States (OR = 1.3/year; 95% CI = 1.0 to 1.6) were independently associated with anti-HAV positivity. Among US-born children aged 2 to 5 years who had never left the United States, 33% were anti-HAV-positive. CONCLUSIONS: Anti-HAV prevalence among migrant children in Okeechobee County, including the youngest US-born children, is high, indicating ongoing transmission of HAV. Children in this and other US migrant communities may benefit from hepatitis A vaccination.

The gene for slow Wallerian degeneration (Wld(s)) is also protective against vincristine neuropathy.

Neurological diseases are frequently associated with axonal degeneration, which leads to dysfunction though separation of neurons from their targets. The mechanisms of axonal degeneration are largely unknown and in many cases are independent of those occurring within cell bodies in neurodegenerative disorders. The Wld(s) mouse mutant demonstrates the unique phenotype of resistance to axonal degeneration after axotomy (slow Wallerian degeneration), making it a powerful tool for studying mechanisms of axonal degeneration. We asked whether the Wld(s) mutation also provides resistance to axonal degeneration in a slowly progressing neuropathy. Using cultured dorsal root ganglion neurons we compared the course of axonal degeneration in response to exposure to the neurotoxin vincristine and found that Wld(s) neurites were relatively resistant to vincristine neuropathy. These findings suggest common pathophysiologic mechanisms between axotomy-induced Wallerian degeneration and toxic neuropathy. The implications are wide-ranging and are relevant to the pathophysiology of axonal degeneration seen in a wide spectrum of neurological diseases ranging from stroke and head trauma to spinal cord injury and peripheral neuropathy.

The WldS protein protects against axonal degeneration: a model of gene therapy for peripheral neuropathy.

The WldS mouse is a spontaneous mutant that is characterized by the phenotype of delayed degeneration of transected nerves (slow Wallerian degeneration). Molecular genetic analysis identified a mutation in this animal that codes for a unique protein expressed in brain tissue of WldS mice. We asked whether the WldS phenotype, in addition to delaying axonal degeneration after axotomy, might provide neuroprotection against toxic neuropathy. In dorsal root ganglia (DRG) cultures, neurites from WldS transiently exposed to vincristine not only resisted axonal degeneration but resumed growth after withdrawal of the toxin. Neurites from wild type mice died rapidly and did not recover. To prove that the identified mutation and its protein product are responsible for the WldS phenotype, we used an adenoviral gene transfer system to deliver the WldS to rat DRG neurons. Rat neurons expressing the WldS protein were resistant to vincristine-induced axonal degeneration, confirming the functional significance of the identified gene mutation. These data provide evidence that the WldS protein can be neuroprotective against vincristine neuropathy, and possibly other disorders characterized by axonal degeneration. In addition, delivery of this gene to wild type cells can transfer the WldS phenotype, providing the possibility of "gene therapy" for peripheral neuropathy.

Evaluation of the effectiveness of targeted lookback for HCV infection in the United States-interim results.

BACKGROUND: As part of a nationwide program to identify persons at increased risk for HCV infection, persons who received blood from donors who later tested positive for anti-HCV are being directly notified. STUDY DESIGN AND METHODS: In December 1999, all 198 blood collection establishments (BCEs) and 5442 hospital transfusion services (TSs) in the United States were surveyed by mailed questionnaire to evaluate their progress in carrying out this notification. RESULTS: Eighty-one percent of the BCEs and 64 percent of the TSs responded. After correcting for nonresponse, an estimated 98,484 components at potential risk for transmitting HCV, according to previous testing of multiantigen-screened donors, were identified nationwide, of which 85 percent had been transfused to recipients. Lookback for these recipients was completed for 80 percent, of whom 69 percent had died. Of those living, 78 percent were successfully notified. An estimated 49.5 percent of those notified were tested; 18.9 percent of those tested were anti-HCV positive, and 32 percent of that group knew they were positive before notification. On the basis of an 85.5 percent reported completion rate for component notifications back through 1988, an estimated 1520 persons will have been newly identified as anti-HCV-positive when lookback related to multiantigen screening of donors is completed. CONCLUSION: Targeted lookback related to previous multiantigen screening of donors will identify <1 percent of the estimated 300,000 HCV-positive persons in the United States who may have acquired their infection via blood transfusion.

Nosocomial infections in combined medical-surgical intensive care units in the United States.

OBJECTIVE: To describe the epidemiology of nosocomial infections in combined medical-surgical (MS) intensive care units (ICUs) participating in the National Nosocomial Infection Surveillance (NNIS) System. DESIGN: Analysis of surveillance data on 498,998 patients with 1,554,070 patient-days, collected between 1992 and 1998 from 205 MS ICUs following the NNIS Intensive Care Unit protocol, representing 152 participating NNIS hospitals in the United States. RESULTS: Infections at three major sites represented 68% of all reported infections (nosocomial pneumonia, 31%; urinary tract infections (UTIs), 23%; and primary bloodstream infections (BSIs), 14%: 83% of episodes of nosocomial pneumonia were associated with mechanical ventilation, 97% of UTIs occurred in catheterized patients, and 87% of primary BSIs in patients with a central line. In patients with primary BSIs, coagulase-negative staphylococci (39%) were the most common pathogens reported; Staphylococcus aureus (12%) was as frequently reported as enterococci (11%). Coagulase-negative staphylococcal BSIs were increasingly reported over the 6 years, but no increase was seen in candidemia or enterococcal bacteremia. In patients with pneumonia, S. aureus (17%) was the most frequently reported isolate. Of reported isolates, 59% were gram-negative bacilli. In patients with UTIs, Escherichia coli (19%) was the most frequently reported isolate. Of reported isolates, 31% were fungi. In patients with surgical-site infections, Enterococcus (17%) was the single most frequently reported pathogen. Device-associated nosocomial infection rates for BSIs, pneumonia, and UTIs did not correlate with length of ICU stay, hospital bed size, number of beds in the ICU, or season. Combined MS ICUs in major teaching hospitals had higher device-associated infection rates compared to all other hospitals with combined medical-surgical units. CONCLUSIONS: Nosocomial infections in MS ICUs at the most frequent infection sites (bloodstream, urinary, and respiratory tract) almost always were associated with use of an invasive device. Device-associated infection rates were the best available comparative rates between combined MS ICUs, but the distribution of device-associated rates should be stratified by a hospital's major teaching affiliation status.

Pathogenesis of axonal degeneration: parallels between Wallerian degeneration and vincristine neuropathy.

Peripheral neuropathies and Wallerian degeneration share a number of pathological features; the most prominent of which is axonal degeneration. We asked whether common pathophysiologic mechanisms are involved in these 2 disorders by directly comparing in vitro models of axonal degeneration after axotomy or exposure to the neurotoxin vincristine. Embryonic rat dorsal root ganglia (DRG) were allowed to extend neurites for 5 days in culture, and then were either axotomized or exposed to 0.01 microM vincristine. Neurites universally degenerated by 3 days after axotomy or after 6 days of vincristine exposure. The neuroprotective effects of a low calcium environment or pharmacologic inhibition of the cysteine protease calpain were compared in these 2 models of axonal degeneration. Addition of EGTA or growth in zero-calcium media provided significant protection against axonal degeneration after either axotomy or vincristine exposure. Treatment with the experimental calpain inhibitor AK295 was equally protective in both models. Chronic exposure to AK295 was not toxic to the cultures. These data suggest that common mechanisms involving calcium and calpains are involved in both axotomy-induced and vincristine-induced axonal degeneration. In addition, calpain inhibition may provide a strategy for preventing axonal degeneration and preserving neurologic function in a variety of PNS and CNS disorders.

Determinants of vancomycin use in adult intensive care units in 41 United States hospitals.

We analyzed data from a prospective observational cohort study that included 108 adult intensive care units (ICUs) in 41 United States hospitals. Use of vancomycin (defined daily doses per 1,000 patient-days), nosocomial infection rates, and proportion of all Staphylococcus aureus isolates resistant to methicillin (MRSA rate) were recorded from January 1996 through November 1997. The median rate of vancomycin use was lowest in coronary care ICUs and highest in general surgical ICUs. Prior approval before use of vancomycin was required in only 26 (24%) of the 108 ICUs. In a multivariate linear regression model, rates of MRSA, central line-associated bloodstream infection, and the type of ICU were independent predictors of vancomycin use. None of the vancomycin control practices was associated with lower rates of vancomycin use; however, it is important to recognize that this database was not designed to measure rates of inappropriate use. Vancomycin use is heavily determined by rates of endemic MRSA and central line-associated bloodstream infection. Efforts to reduce these rates through infection control activities should be included in hospitals' efforts to reduce vancomycin use.

Generation of spectrin breakdown products in peripheral nerves by addition of M-calpain.

Identification of spectrin breakdown products (SBP) in tissues of the central nervous system (CNS) has been used to monitor calpain activity in models of neurodegeneration. We investigated the use of this technique in the peripheral nervous system (PNS) in order to use it as a marker of calpain-mediated proteolysis during axonal degeneration. Using in vitro methods for activation of calpains, we compared brains and sciatic nerves from rats for the presence of calpain-specific SBP. The 150-kDa SBP identified on western blots was demonstrated in brain and nerve homogenates subjected to membrane disruption in the presence of calcium. Incubation of tissues with recombinant m-calpain generated SBP in a dose-dependent fashion, and calpastatin inhibited the generation of SBP by either paradigm. In contrast to brain, sciatic nerves showed the presence of SBP even in noninjured tissues, suggesting a basal level of calpain activity in peripheral nerves. Time-course experiments showed that the generation of SBP in sciatic nerves correlated with the breakdown of axonal neurofilaments. SBP peaked within minutes after addition of m-calpain and disappeared in the homogenates before 1 h, indicating that identification of SBP is a transient phenomenon. These data provide a potential new way for studying axonal degeneration in both experimental and human neuropathies.

Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System.

OBJECTIVE: To describe the epidemiology of nosocomial infections in medical intensive care units (ICUs) in the United States. DESIGN: Analysis of ICU surveillance data collected through the National Nosocomial Infections Surveillance (NNIS) System between 1992 and 1997. SETTING: Medical ICUs in the United States. PATIENTS: A total of 181,993 patients. MEASUREMENTS AND MAIN RESULTS: Nosocomial infections were analyzed by infection site and pathogen distribution. Urinary tract infections were most frequent (31%), followed by pneumonia (27%) and primary bloodstream infections (19%). Eighty-seven percent of primary bloodstream infections were associated with central lines, 86% of nosocomial pneumonia was associated with mechanical ventilation, and 95% of urinary tract infections were associated with urinary catheters. Coagulase-negative staphylococci (36%) were the most common bloodstream infection isolates, followed by enterococci (16%) and Staphylococcus aureus (13%). Twelve percent of bloodstream isolates were fungi. The most frequent isolates from pneumonia were Gram-negative aerobic organisms (64%). Pseudomonas aeruginosa (21%) was the most frequently isolated of these. S. aureus (20%) was isolated with similar frequency. Candida albicans was the most common single pathogen isolated from urine and made up just over half of the fungal isolates. Fungal urinary infections were associated with asymptomatic funguria rather than symptomatic urinary tract infections (p < .0001). Certain pathogens were associated with device use: coagulase-negative staphylococci with central lines, P. aeruginosa and Acinetobacter species with ventilators, and fungal infections with urinary catheters. Patient nosocomial infection rates for the major sites correlated strongly with device use. Device exposure was controlled for by calculating device-associated infection rates for bloodstream infections, pneumonia, and urinary tract infections by dividing the number of device-associated infections by the number of days of device use. There was no association between these device-associated infection rates and number of hospital beds, number of ICU beds, or length of stay. There is a considerable variation within the distribution of each of these infection rates. CONCLUSIONS: The distribution of sites of infection in medical ICUs differed from that previously reported in NNIS ICU surveillance studies, largely as a result of anticipated low rates of surgical site infections. Primary bloodstream infections, pneumonia, and urinary tract infections associated with invasive devices made up the great majority of nosocomial infections. Coagulase-negative staphylococci were more frequently associated with primary bloodstream infections than reported from NNIS ICUs of all types in the 1980s, and enterococci were a more frequent isolate from bloodstream infections than S. aureus. Fungal urinary tract infections, often asymptomatic and associated with catheter use, were considerably more frequent than previously reported. Invasive device-associated infections were associated with specific pathogens. Although device-associated site-specific infection rates are currently our most useful rates for performing comparisons between ICUs, the considerable variation in these rates between ICUs indicates the need for further risk adjustment.

Axonal neurofilaments are resistant to calpain-mediated degradation in the WLD(S) mouse.

The biological basis for the phenotype of delayed Wallerian degeneration in the WLDs mouse has yet to be elucidated, although it is known that the characteristic is intrinsic to the axon. Previous data suggested that nerves from the WLD(S) are relatively resistant to proteolytic degradation. We investigated the time-course of neurofilament degradation in response to addition of the calcium-activated protease m-calpain, comparing nerves from WLD(S) and wild-type mice. During 10 min of in vitro proteolysis, neurofilaments from the WLD(S) were consistently slower to degrade than were neurofilaments from wild-type mice. Direct comparisons were performed on Western blots, with statistically significant differences in neurofilament immunoreactivity at 2, 4, and 6 min of reaction time (p < 0.01). These findings suggest that the mutation leading to the WLD(S) phenotype may affect the proteolytic interaction between calpain and neurofilaments.

Nosocomial infections in pediatric intensive care units in the United States. National Nosocomial Infections Surveillance System.

OBJECTIVES: To describe the epidemiology of nosocomial infections in pediatric intensive care units (ICUs) in the United States. BACKGROUND: Patient and ICU characteristics in pediatric ICUs suggest the pattern of nosocomial infections experienced may differ from that seen in adult ICUs. METHODS: Data were collected between January 1992 and December 1997 from 61 pediatric ICUs in the United States using the standard surveillance protocols and nosocomial infection site definitions of the National Nosocomial Infections Surveillance System's ICU surveillance component. RESULTS: Data on 110 709 patients with 6290 nosocomial infections were analyzed. Primary bloodstream infections (28%), pneumonia (21%), and urinary tract infections (15%) were most frequent and were almost always associated with use of an invasive device. Primary bloodstream infections and surgical site infections were reported more frequently in infants aged 2 months or less as compared with older children. Urinary tract infections were reported more frequently in children >5 years old compared with younger children. Coagulase-negative staphylococci (38%) were the most common bloodstream isolates, and aerobic Gram-negative bacilli were reported in 25% of primary bloodstream infections. Pseudomonas aeruginosa (22%) was the most common species reported from pneumonia and Escherichia coli (19%), from urinary tract infections. Enterobacter spp. were isolated with increasing frequency from pneumonia and were the most common Gram-negative isolates from bloodstream infections. Device-associated infection rates for bloodstream infections, pneumonia, and urinary tract infections did not correlate with length of stay, the number of hospital beds, or season. CONCLUSIONS: In pediatric ICUs, bloodstream infections were the most common nosocomial infection. The distribution of infection sites and pathogens differed with age and from that reported from adult ICUs. Device-associated infection rates were the best rates currently available for comparisons between units, because they were not associated with length of stay, the number of beds in the hospital, or season.