Showing papers by "University of Tennessee Health Science Center published in 2002"

Late-Onset Sepsis in Very Low Birth Weight Neonates: The Experience of the NICHD Neonatal Research Network

Abstract: Objective. Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 6956 VLBW (401–1500 g) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period (1998–2000). Methods. The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospective registry of all VLBW neonates admitted to participating centers within 14 days of birth. Expanded infection surveillance was added in 1998. Results. Of 6215 infants who survived beyond 3 days, 1313 (21%) had 1 or more episodes of blood culture-proven late-onset sepsis. The vast majority of infections (70%) were caused by Gram-positive organisms, with coagulase-negative staphylococci accounting for 48% of infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus, prolonged ventilation, prolonged intravascular access, bronchopulmonary dysplasia, and necrotizing enterocolitis. Infants who developed late-onset sepsis had a significantly prolonged hospital stay (mean length of stay: 79 vs 60 days). They were significantly more likely to die than those who were uninfected (18% vs 7%), especially if they were infected with Gram-negative organisms (36%) or fungi (32%). Conclusions. Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently.

Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II)

Abstract: 1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall, 0.99 (0.84-1.17). The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women who were adherent to randomized treatment assignment (RH, 0.96; 95% CI, 0.77-1.19). Conclusions Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.

Hyperglycemia: An Independent Marker of In-Hospital Mortality in Patients with Undiagnosed Diabetes

Abstract: Admission hyperglycemia has been associated with increased hospital mortality in critically ill patients; however, it is not known whether hyperglycemia in patients admitted to general hospital wards is associated with poor outcome. The aim of this study was to determine the prevalence of in-hospital hyperglycemia and determine the survival and functional outcome of patients with hyperglycemia with and without a history of diabetes. We reviewed the medical records of 2030 consecutive adult patients admitted to Georgia Baptist Medical Center, a community teaching hospital in downtown Atlanta, GA, from July 1, 1998, to October 20, 1998. New hyperglycemia was defined as an admission or in-hospital fasting glucose level of 126 mg/dl (7 mmol/liter) or more or a random blood glucose level of 200 mg/dl (11.1 mmol/liter) or more on 2 or more determinations. Hyperglycemia was present in 38% of patients admitted to the hospital, of whom 26% had a known history of diabetes, and 12% had no history of diabetes before the admission. Newly discovered hyperglycemia was associated with higher in-hospital mortality rate (16%) compared with those patients with a prior history of diabetes (3%) and subjects with normoglycemia (1.7%; both P < 0.01). In addition, new hyperglycemic patients had a longer length of hospital stay, a higher admission rate to an intensive care unit, and were less likely to be discharged to home, frequently requiring transfer to a transitional care unit or nursing home facility. Our results indicate that in-hospital hyperglycemia is a common finding and represents an important marker of poor clinical outcome and mortality in patients with and without a history of diabetes. Patients with newly diagnosed hyperglycemia had a significantly higher mortality rate and a lower functional outcome than patients with a known history of diabetes or normoglycemia.

Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).

Abstract: Context Blood pressure control ( Objective To determine the success and predictors of blood pressure control in a large hypertension trial involving a multiethnic population in diverse practice settings. Design The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial is a randomized, double-blind, active-controlled clinical trial with a mean follow-up of 4.9 years. Participant enrollment began in February 1994 and follow-up was completed in March 2002. Setting A total of 623 centers in the United States, Canada, and the Caribbean. Participants A total of 33,357 participants (aged > or =55 years) with hypertension and at least one other coronary heart disease risk factor. Interventions Participants were randomly assigned to receive (double-blind) chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) after other medication was discontinued. Doses were increased within these ranges and additional drugs from other classes were added as needed to achieve blood pressure control ( Main outcome measures The outcome measures for this report are systolic and diastolic blood pressure, the proportion of participants achieving blood pressure control ( Results Mean age was 67 years, 47% were women, 35% black, 36% diabetic; 90% were on antihypertensive drug treatment at entry. At the first of two pre-randomization visits, blood pressure was or =2 drugs was 63%. Blood pressure control varied by geographic regions, practice settings, and demographic and clinical characteristics of participants. Conclusions These data demonstrate that blood pressure may be controlled in two thirds of a multiethnic hypertensive population in diverse practice settings. Systolic blood pressure is more difficult to control than diastolic blood pressure, and at least two antihypertensive medications are required for most patients to achieve blood pressure control. It is likely that the majority of people with hypertension could achieve a blood pressure

Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier.

Abstract: Hearing sensitivity in mammals is enhanced by more than 40 dB (that is, 100-fold) by mechanical amplification thought to be generated by one class of cochlear sensory cells, the outer hair cells. In addition to the mechano-electrical transduction required for auditory sensation, mammalian outer hair cells also perform electromechanical transduction, whereby transmembrane voltage drives cellular length changes at audio frequencies in vitro. This electromotility is thought to arise through voltage-gated conformational changes in a membrane protein, and prestin has been proposed as this molecular motor. Here we show that targeted deletion of prestin in mice results in loss of outer hair cell electromotility in vitro and a 40-60 dB loss of cochlear sensitivity in vivo, without disruption of mechano-electrical transduction in outer hair cells. In heterozygotes, electromotility is halved and there is a twofold (about 6 dB) increase in cochlear thresholds. These results suggest that prestin is indeed the motor protein, that there is a simple and direct coupling between electromotility and cochlear amplification, and that there is no need to invoke additional active processes to explain cochlear sensitivity in the mammalian ear.

First report of the collaborative outcome data project on the effectiveness of psychological treatment for sex offenders.

Abstract: This meta-analytic review examined the effectiveness of psychological treatment for sex offenders by summarizing data from 43 studies (combined n = 9,454). Averaged across all studies, the sexual offence recidivism rate was lower for the treatment groups (12.3%) than the comparison groups (16.8%, 38 studies, unweighted average). A similar pattern was found for general recidivism, although the overall rates were predictably higher (treatment 27.9%, comparison 39.2%, 30 studies). Current treatments (cognitive–behavioral, k = 13; systemic, k = 2) were associated with reductions in both sexual recidivism (from 17.4 to 9.9%) and general recidivism (from 51 to 32%). Older forms of treatment (operating prior to 1980) appeared to have little effect. Future directions for improving the quality of sex offender treatment outcome evaluations are discussed.

Leg Muscle Mass and Composition in Relation to Lower Extremity Performance in Men and Women Aged 70 to 79: The Health, Aging and Body Composition Study

Abstract: OBJECTIVES: The loss of muscle mass with aging, or sarcopenia, is hypothesized to be associated with the deterioration of physical function. Our aim was to determine whether low leg muscle mass and greater fat infiltration in the muscle were associated with poor lower extremity performance (LEP). DESIGN: A cross-sectional study, using baseline data of the Health, Aging and Body Composition study (1997/98). SETTING: Medicare beneficiaries residing in ZIP codes from the metropolitan areas surrounding Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS: Three thousand seventy-five well-functioning black and white men and women aged 70 to 79. MEASUREMENTS: Two timed tests (6-meter walk and repeated chair stands) were used to measure LEP. Muscle cross-sectional area and muscle tissue attenuation (indicative of fat infiltration) were obtained from computed tomography scans at the midthigh. Body fat was assessed using dual-energy x-ray absorptiometry. RESULTS: Blacks had greater muscle mass and poorer LEP than whites. Black women had greater fat infiltration into the muscle than white women. After adjustment for clinic site, age, height, and total body fat, smaller muscle area was associated with poorer LEP in all four race-gender groups. (Regression coefficients, expressed per standard deviation (±55 cm2) of muscle area, were 0.658 and 0.519 in white and black men and 0.547 and 0.435 in white and black women, respectively, P .7) or between race and muscle attenuation (P> .2) were observed. CONCLUSION: Smaller midthigh muscle area and greater fat infiltration in the muscle are associated with poorer LEP in well-functioning older men and women.

Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants.

Abstract: Background It is uncertain whether the rates and causes of early-onset sepsis (that occurring within 72 hours after birth) among very-low-birth-weight infants have changed in recent years, since antibiotics have begun to be used more widely during labor and delivery. Methods We studied 5447 very-low-birth-weight infants (those weighing between 401 and 1500 g) born at centers of the Neonatal Research Network of the National Institute of Child Health and Human Development between 1998 and 2000 who had at least one blood culture in the first three days of life and compared them with 7606 very-low-birth-weight infants born at centers in the network between 1991 and 1993. Results Early-onset sepsis (as confirmed by positive blood cultures) was present in 84 infants in the more recent birth cohort (1.5 percent). As compared with the earlier birth cohort, there was a marked reduction in group B streptococcal sepsis (from 5.9 to 1.7 per 1000 live births of infants weighing 401 to 1500 g, P<0.001) and an increase ...

Aldosterone-Induced Inflammation in the Rat Heart: Role of Oxidative Stress

Abstract: Heart failure and hypertension have each been linked to an induction of oxidative stress transduced by neurohormones, such as angiotensin II and catecholamines. Herein, we hypothesized that aldosterone (ALDO) likewise induces oxidative stress and accounts for a proinflammatory/fibrogenic phenotype that appears at vascular and nonvascular sites of injury found in both right and left ventricles in response to ALDO/salt treatment and that would be sustained with chronic treatment. Uninephrectomized rats received ALDO (0.75 μg/hour) together with 1% dietary NaCl, for 3, 4, or 5 weeks. Other groups received this regimen in combination with an ALDO receptor antagonist, spironolactone (200 mg/kg p.o. daily), or an antioxidant, either pyrrolidine dithiocarbamate (PDTC) (200 mg/kg s.c. daily) or N-acetylcysteine (NAC) (200 mg/kg i.p. daily). Unoperated and untreated age- and gender-matched rats served as controls. We monitored spatial and temporal responses in molecular and cellular events using serial, coronal sections of right and left ventricles. Our studies included: assessment of systolic blood pressure; immunohistochemical detection of NADPH oxidase expression and activity; analysis of redox-sensitive nuclear factor-κB activation; in situ localization of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-α mRNA expression; monitoring cell growth and infiltration of macrophages and T cells; and analysis of the appearance and quantity of fibrous tissue accumulation. At week 3 of ALDO/salt treatment and comparable to controls, there was no evidence of oxidative stress or pathological findings in the heart. However, at weeks 4 and 5 of treatment, increased gp91phox and 3-nitrotyrosine expression and persistent activation of RelA were found in endothelial cells and inflammatory cells that appeared in the perivascular space of intramural coronary arteries and at sites of lost cardiomyocytes in both ventricles. Coincident in time and space with these events was increased mRNA expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-α. Macrophages, lymphocytes, and proliferating endothelial and vascular smooth muscle cells and fibroblast-like cells were seen at each of these sites, together with an accumulation of fibrillar collagen, or fibrosis, as evidenced by a significant increase in ventricular collagen volume fraction. Co-treatment with spironolactone, PDTC, or NAC attenuated these molecular and cellular responses as well as the appearance of fibrosis at vascular and nonvascular sites of injury. Furthermore, elevated systolic blood pressure in ALDO-treated rats was partially suppressed by spironolactone or either antioxidant. Thus, chronic ALDO/salt treatment is accompanied by a time-dependent sustained activation of NADPH oxidase with 3-nitrotyrosine generation and nuclear factor-κB activation expressed by endothelial cells and inflammatory cells. This leads to a proinflammatory/fibrogenic phenotype involving vascular and nonvascular sites of injury found, respectively, in both normotensive and hypertensive right and left ventricles. Spionolactone, PDTC, and NAC each attenuated these responses suggesting ALDO/salt induction of oxidative/nitrosative stress is responsible for the appearance of this proinflammatory phenotype.

Prospective screening for blunt cerebrovascular injuries: analysis of diagnostic modalities and outcomes.

Abstract: Objective To prospectively examine outcomes associated with an aggressive screening protocol for blunt cerebrovascular injury (BCVI), and to compare the accuracy of computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) versus conventional angiography with respect to BCVI diagnosis. Summary Background Data In the past 5 years, BCVI (carotid and vertebral arteries) has been recognized with increasing frequency. Initial studies described blunt carotid injuries and their associated morbidity, while more recent reports have established the devastating potential of blunt vertebral injuries. It has been suggested that early diagnosis and anticoagulation will improve outcomes and that less-invasive diagnostic techniques than conventional angiography are desirable for screening. However, there are neither established screening criteria nor studies comparing optimal diagnostic modalities. Methods The screened population included all patients with cervical spine fractures, LeFort II or III facial fractures, Horner's syndrome, skull base fractures involving the foramen lacerum, neck soft tissue injury, or neurological abnormalities unexplained by intracranial injuries. Patients underwent screening with four-vessel cerebral angiography. During the first half of the study, patients also underwent helical CTA. Selected patients during this same period underwent MRA. At the time of diagnosis, anticoagulant or antiplatelet therapy was instituted unless clinically contraindicated. Results of this screening protocol were compared to a previously published cohort with cerebrovascular injuries (1995-1999) from the authors' institution. Results Two hundred sixteen patients were screened over a 2-year period (3.5% of all blunt trauma admissions). Angiography identified 24 patients with carotid artery injuries (CAI) and 43 patients with vertebral artery injuries (VAl) for an overall screening yield of 29%. While the incidence of CAI remained similar between the current study and the previous study group, the incidence of VAI diagnosis increased. Stroke rates in those with CAI were also similar between the two periods. The stroke rate in VAI, however, was markedly lower at 0% as compared to 14% in the previous group. Comparison of CTA and MRA with cerebral angiography in 143 patients demonstrated sensitivities of 47% and 50%, respectively, for CAI; sensitivities were 53% (CTA) and 47% (MRA) for VAI. Conclusions Aggressive screening of patients with blunt head and neck trauma identified an incidence of BCVI in 1.03% of blunt admissions. Early identification, which led to early treatment, significantly reduced stroke rates in patients with VAI, but provided no outcome improvement with CAI. More encompassing screening may be required to improve outcomes for patients with CAI. However, less-invasive diagnostic techniques (CTA and MRA) are inadequate for screening. Technological advances are necessary before abandonment of conventional angiography, which remains the standard for diagnosis.

How Important Are Gender Differences in Pharmacokinetics

Abstract: Gender-related differences in pharmacokinetics have frequently been considered as potentially important determinants for the clinical effectiveness of drug therapy. The mechanistic processes underlying gender-specific pharmacokinetics can be divided into molecular and physiological factors. Major molecular factors involved in drug disposition include drug transporters and drug-metabolising enzymes. Men seem to have a higher activity relative to women for the cytochrome P450 (CYP) isoenzymes CYP1A2 and potentially CYP2E1, for the drug efflux transporter P-glycoprotein, and for some isoforms of glucuronosyltransferases and sulfotransferases. Women were suggested to have a higher CYP2D6 activity. No major gender-specific differences seem to exist for CYP2C19 and CYP3A. The often-described higher hepatic clearance in women compared with men for substrates of CYP3A and P-glycoprotein, such as erythromycin and verapamil, may be explained by increased intrahepatocellular substrate availability due to lower hepatic P-glycoprotein activity in women relative to men. Physiological factors resulting in gender-related pharmacokinetic differences include the generally lower bodyweight and organ size, higher percentage of body fat, lower glomerular filtration rate and different gastric motility in women compared with men. Although gender disparity in pharmacokinetics has been identified for numerous drugs, differences are generally only subtle. For a few drugs, e.g. verapamil, beta-blockers and selective serotonin reuptake inhibitors, gender-related differences in pharmacokinetics have been shown to result in different pharmacological responses, but their clinical relevance remains unproven. In contrast, gender differences of clinical importance have clearly been identified for pharmacodynamic processes such as QTc prolongation, and intensive future research efforts are needed to assess the full scope and impact of pharmacodynamic gender disparity on applied pharmacotherapy.

Essential, Nonredundant Role for the Phosphoinositide 3-Kinase p110δ in Signaling by the B-Cell Receptor Complex

Abstract: Lymphocyte development and function are regulated through the coordinated action of receptors of the cytokine receptor superfamily and the B-cell antigen-specific receptor (BCR) or T-cell antigen-specific receptors (TCR). Engagement of either receptor complex initiates tyrosine phosphorylation of a variety of intracellular substrates, including receptor chains, resulting in the initiation of cellular responses. Members of the cytokine receptor superfamily utilize JAK family cytoplasmic kinases (14), while the BCR and TCR complexes utilize members of the Src, Tec, and Zap70/Syk families of tyrosine kinases. In BCR signal transduction, the Tec family kinase Btk plays a critical role as evidenced by the loss of a proliferative response to BCR engagement in Btk-deficient B cells (15, 16). Among the substrates typically phosphorylated and recruited to hematopoietic receptor complexes are the regulatory subunits for phosphoinositide 3-kinases (PI3Ks) (9, 10, 30). In mammals there are three genes that encode adapter proteins for PI3K catalytic subunits, including p85α, p85β, and p55γ. The adapter proteins facilitate association of the catalytic subunits with the receptor complex and are proposed to regulate enzyme activity. The disruption of the p85α gene, in a manner that deletes the p85 isoform as well as two splice variants of p55 and p50, results in defective BCR signaling comparable to that seen with Btk deficiency (11, 26). This strongly suggests that PI3K activity is critical in BCR signal transduction. Three of the known PI3Ks, i.e., PI3Kα, PI3Kβ, and PI3Kδ, are regulated through their interaction with regulatory subunits (30). The fourth PI3K, PI3Kγ, functions in the context of heterotrimeric G-protein-coupled receptors and is essential for leukocyte function (12). The critical, nonredundant role that PI3Kα plays in cellular responses has been demonstrated through the derivation of mice lacking the gene. This deficiency results in an embryonic lethality at E9.5 to E10.5 due to a severe proliferative defect in many tissues (2). Similarly, deletion of the PI3Kβ gene alone results in a very early embryonic lethality (1, 2). In contrast to PI3Kα and PI3Kβ, PI3Kδ is expressed primarily in hematopoietic cells (32). To identify proteins that are recruited to cytokine receptor complexes, we have used affinity columns containing phosphopeptides corresponding to the major sites of tyrosine phosphorylation of JAK2. Two complexes which bound to a phosphopeptide affinity column derived from the amino acid sequence surrounding Jak2 Y966 were p85α/p110δ and p85β/p110δ. In order to determine the potential role of PI3Kδ in signaling, we derived a strain of mice in which the gene was disrupted in a manner to yield a protein null mutant. As demonstrated here, a deficiency in PI3Kδ results in a very specific loss of function of the BCR complex, while signaling through the cytokine receptor complexes is unaffected.

Venous Thrombosis in Patients with Solid Tumors: Determination of Frequency and Characteristics

Abstract: Deep venous thrombosis (DVT) and pulmonary embolism (PE) are well recognized complications of cancer. However, our current knowledge of this association is derived from studies conducted more than a decade ago. In light of the changes in medical practice and the improvement in cancer care in recent years, a re-evaluation of the relationship between malignancy and venous thrombosis is in order. Of a total of 1041 patients with solid tumors admitted to 3 major medical centers, there were 81 (7.8%) diagnosed with DVT/PE. Patients were more likely to develop DVT/PE during chemotherapy (p = .0001). Advanced malignancies (p = .001), renal carcinoma (p = .005), pancreatic (p = .001), gastric (p = .014) and brain tumors (p = .001) were independent variables strongly associated with the occurrence of venous thrombosis. The occurrence of thrombotic events in the population tested in this study did not adversely affect survival (p = .082). The study identifies subset of patients with cancer at high risk for venous thrombosis. Early prophylaxis with anticoagulants in these patients may be warranted. Most importantly, further clinical trials are desperately awaited to detect possible new trends in the frequency and types of thrombotic events and to better define prevention strategies in cancer patients at risk for thrombosis. The association between venous thromboembolic disease (VTD) and malignant neoplastic disorders is well known and has been the subject of several reports for more than a century. There is a general agreement among investigators that thrombotic complications in patients with cancer occur at a rather high frequency, and that other circumstantial factors such as surgery or chemotherapy potentiates this risk. However, several important considerations pertaining to cancer and thrombosis continue to be shrouded in controversy. For example, there are inexplicable differences in the proportion of patients with cancer diagnosed with deep venous thrombosis (DVT) or pulmonary embolism (PE) reported in the literature. In the absence of large well-controlled studies, one may only postulate on the reasons that contributed to these differences. The inclusion of different types of VTD such as superficial, venous, arterial or vascular access device-induced thrombosis may have led to overestimation of the incidence of these events in patients with underlying malignancy. Another possible explanation for this discrepancy relates to the use of a variety of diagnostic and methodological criteria ranging from observation and clinical suspicion to more invasive procedures resulting in considerable differences in the rate of reported clotting events. Along the same line of discussion, one may argue whether VTD is a random event or constitutes a complication that occurs more commonly in patients with distinct characteristics and certain tumor types. To further investigate the association between malignancy and thrombosis, we evaluated 1041 patients with solid tumors for the risk of DVT/PE. The main objectives of the study were to determine the frequency of DVT/PE based on validated diagnostic criteria and to identify patients with cancer at high risk for developing these thrombotic episodes. Also, we evaluated the impact of VTD on the survival of these patients.

An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections.

Abstract: The role of host genetic factors in conferring predisposition or protection in infectious diseases has become evident. Infection with group A streptococci causes a wide spectrum of disease ranging from pharyngitis to streptococcal toxic shock syndrome. The release of inflammatory cytokines triggered by streptococcal superantigens has a pivotal role in invasive streptococcal disease. However, individuals infected with the same strain can develop very different manifestations. We report here that the immunogenetics of the host influence the outcome of invasive streptococcal infection, and demonstrate the underlying mechanism for these genetic associations. Specific human leukocyte antigen class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1*1501/DQB1*0602 haplotype mounted significantly reduced responses and were less likely to develop severe systemic disease (P < 0.0001). We propose that human leukocyte antigen class II allelic variation contributes to differences in severity of invasive streptococcal infections through their ability to regulate cytokine responses triggered by streptococcal superantigens.

Noninvasive vs. conventional mechanical ventilation in patients with chronic obstructive pulmonary disease after failure of medical treatment in the ward: a randomized trial

Abstract: Objective. We conducted a randomized prospective study comparing noninvasive positive pressure ventilation (NPPV) with conventional mechanical ventilation via endotracheal intubation (ETI) in a group of patients with chronic obstructive pulmonary disease who failed standard medical treatment in the emergency ward after initial improvement and met predetermined criteria for ventilatory support. Design and setting. Prospective randomized study in a university hospital 13-bed general ICU. Patients. Forty-nine patients were randomly assigned to receive NPPV (n=23) or conventional ventilation (n=26). Results. both NPPV and conventional ventilation significantly improved gas exchanges. The two groups had similar length of ICU stay, number of days on mechanical ventilation, overall complications, ICU mortality, and hospital mortality. In the NPPV group 11 (48%) patients avoided intubation, survived, and had a shorter duration of ICU stay than intubated patients. One year following hospital discharge the NPPV group had fewer patients readmitted to the hospital (65% vs. 100%) or requiring de novo permanent oxygen supplementation (0% vs. 36%). Conclusions. The use of NPPV in patients with chronic obstructive pulmonary disease and acute respiratory failure requiring ventilatory support after failure of medical treatment avoided ETI in 48% of the patients, had the same ICU mortality as conventional treatment and, at 1-year follow-up was associated with fewer patients readmitted to the hospital or requiring for long-term oxygen supplementation. An editorial regarding this article can be found in the same issue (http://dx.doi.org/10.1007/s00134-002-1503-3).

The maternal lifestyle study: effects of substance exposure during pregnancy on neurodevelopmental outcome in 1-month-old infants.

Abstract: Objective. This was a prospective longitudinal multisite study of the effects of prenatal cocaine and/or opiate exposure on neurodevelopmental outcome in term and preterm infants at 1 month of age. Methods. The sample included 658 exposed and 730 comparison infants matched on race, gender, and gestational age (11.7% born Results. On the NICU Network Neurobehavioral Scale, cocaine exposure was related to lower arousal, poorer quality of movement and self-regulation, higher excitability, more hypertonia, and more nonoptimal reflexes with most effects maintained after adjustment for covariates. Some effects were associated with heavy cocaine exposure, and effects were also found for opiates, alcohol, marijuana, and birth weight. Acoustic cry characteristics that reflect reactivity, respiratory, and neural control of the cry sound were also compromised by prenatal drug exposure, including cocaine, opiates, alcohol, and marijuana and by birth weight. Fewer cry effects remained after adjustment for covariates. Conclusions. Cocaine effects are subtle and can be detected when studied in the context of polydrug use and level of cocaine exposure. Effects of other drugs even at low thresholds can also be observed in the context of a polydrug model. The ability to detect these drug effects requires a large sample and neurobehavioral tests that are differentially sensitive to drug effects. Long-term follow-up is necessary to determine whether these differences develop into clinically significant deficits.

The prediction of visceral fat by dual-energy X-ray absorptiometry in the elderly: a comparison with computed tomography and anthropometry.

Abstract: Introduction: Effective methods for assessing visceral fat are important to investigate the role of visceral fat for the increased health risks in obesity. Techniques for direct measurement of soft tissue composition such as CT or MRI are expensive, time-consuming or require a relatively high radiation dose. Simple anthropometric methods, such as waist-to-hip ratio, waist circumference or sagittal diameter are widely used. However, these methods cannot differentiate between visceral and subcutaneous fat and are less accurate. The aim of the present study is to investigate whether the dual-energy X-ray absorptiometry (DXA) method, possibly combined with anthropometry, offers a good alternative to CT for the prediction of visceral fat in the elderly. Methods: Subjects were participants in the Health ABC-study, a cohort study of black and white men and women aged 70–79, investigating the effect of weight-related health conditions on disablement. Total body fat and trunk fat were measured by DXA using a Hologic QDR 1500. A 10 mm CT scan at the L4–L5 level was acquired to measure visceral fat and total abdominal fat. Weight, height, sagittal diameter and waist circumference were measured using standard methods. Fat in a manually defined DXA subregion (4 cm slice at the top of iliac crest) at the abdomen was calculated in a sub-group of participants (n=150; 50% male; 45.3% Afro-American/54.7% Caucasian, age 70–79 y). This subregion, the standard trunk region and total fat were used as indicators of visceral fat. Results: Total abdominal fat by DXA (subregion) was strongly correlated with total abdominal fat by CT (r ranging from 0.87 in white men to 0.98 in black women). The DXA subregion underestimated total abdominal fat by 10% compared to the CT slice. The underestimation by DXA was seen especially in people with less abdominal fat. The association of visceral fat by CT with the DXA subregion (r=0.66, 0.78, 0.79 and 0.65 for white and black men and women, respectively) was comparable with the association of the CT measure with the sagittal diameter (r=0.74, 0.70, 0.84 and 0.68). Combining DXA measurements with anthropometry gave only limited improvement for the prediction of visceral fat by CT compared to univariate models (maximal increase of r2 4%). Conclusion: DXA is a good alternative to CT for predicting total abdominal fat in an elderly population. For the prediction of visceral fat the sagittal diameter, which has a practical advantage compared to DXA, is just as effective.

Serotoninergic and melatoninergic systems are fully expressed in human skin

Abstract: SPECIFIC AIMSThe skin can metabolize serotonin to N-acetylserotonin (NAS) and possibly melatonin as recently shown in the hamster. We investigated these biosynthetic pathways in normal and pathological human skin, cultured normal and malignant keratinocytes and melanocytes derived from epidermal or follicular compartments, and follicular and dermal fibroblasts.PRINCIPAL FINDINGS1. RT-PCR detection of TPH, AANAT, and HIOMT mRNAsThe 380 bp TPH transcript was present in pituitary, adrenal gland, myometrium, and all samples of normal skin and skin containing basal cell carcinoma; it was also present in cultured normal epidermal and follicular melanocytes, all melanoma cell lines, normal neonatal and adult epidermal and follicular keratinocytes, squamous cell carcinoma cells, and dermal and dermal follicular fibroblasts; the only cells that tested negative for the transcript were HaCaT immortalized keratinocytes. Transcripts of AANAT showed the expected 176 bp fragment spanning exon 2 and 3, and an aberrant 22...

Immunogenicity of a 26-valent group A streptococcal vaccine

Abstract: A multivalent vaccine containing amino-terminal M protein fragments from 26 different serotypes of group A streptococci was constructed by recombinant techniques. The vaccine consisted of four different recombinant proteins that were formulated with alum to contain 400 μg of protein per dose. Rabbits were immunized via the intramuscular route at 0, 4, and 16 weeks. Immune sera were assayed for the presence of type-specific antibodies against the individual recombinant M peptides by enzyme-linked immunosorbent assay and for opsonic antibodies by in vitro opsonization tests and indirect bactericidal tests. The 26-valent vaccine was highly immunogenic and elicited fourfold or greater increases in antibody levels against 25 of the 26 serotypes represented in the vaccine. The immune sera were broadly opsonic and were bactericidal against the majority of the 26 different serotypes. Importantly, none of the immune sera cross-reacted with human tissues. Our results indicate that type-specific, protective M protein epitopes can be incorporated into complex, multivalent vaccines designed to elicit broadly protective opsonic antibodies in the absence of tissue-cross-reactive antibodies.

Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids.

Abstract: Nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor-alpha (GR-alpha) have diametrically opposed functions in regulating inflammation. We investigated whether unresolving acute respiratory distress syndrome (ARDS) is associated with systemic inflammation- induced glucocorticoid resistance and whether prolonged methylprednisolone administration accelerates the suppression of systemic inflammatory indices and normalizes the sensitivity of the immune system to glucocorticoids. Patients enrolled into a randomized trial evaluating prolonged methylprednisolone administration in unresolving ARDS had serial plasma samples collected before and after randomization. In the plasma, we measured the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) IL-1beta and IL-6, adrenocorticotropic hormone (ACTH), and cortisol. The ability of patient plasma to influence the NF-kappaB and GR-signal transduction systems of normal peripheral blood leukocytes (PBL) was examined. Patients treated with methylprednisolone had progressive and sustained reductions of TNF-alpha, IL-1beta, IL-6, ACTH, and cortisol concentrations over time. Normal PBL exposed to plasma samples collected during methylprednisolone exhibited significant progressive increases in all aspects of GR-mediated activity and significant reductions in NF-kappaB DNA-binding and transcription of TNF-alpha and IL-1beta. These findings provide support for the presence of endogenous glucocorticoid inadequacy in the control of inflammation and systemic inflammation-induced peripheral glucocorticoid resistance in ARDS. Prolonged methylprednisolone administration accelerated the resolution of both systemic inflammation and peripheral acquired glucocorticoid resistance in ARDS.

Cardiac Fibrosis as a Cause of Diastolic Dysfunction

Abstract: Diastolic dysfunction is increasingly recognized as a cause of symptomatic heart failure, including the clinical syndrome congestive heart failure (CHF). Metaanalyses of earlier studies of this disorder suggest 40–50% of patients with congestive heart failure have preserved left ventricular systolic function. Conditions associated with diastolic dysfunction are diverse and most commonly include ischemic cardiomyopathy with previous myocardial infarction(s) and hypertensive heart disease.

Whole-Body Hypothermia for Neonatal Encephalopathy: Animal Observations as a Basis for a Randomized, Controlled Pilot Study in Term Infants

Abstract: OBJECTIVE: Modest reduction in brain temperature is a promising therapy to reduce brain damage after neonatal encephalopathy as a result of acute perinatal asphyxia. The efficacy of modest hypothermia may in part be dependent on the stability of the desired brain temperature. The objective of this study was 1) to evaluate in newborn animals a commercially available cooling system (Blanketrol II Hyperthermia-Hypothermia system) to control brain temperature during whole-body hypothermia and 2) to use the results of the animal experiments to perform a pilot study evaluating the feasibility of whole-body hypothermia as a neuroprotective therapy for newborns with encephalopathy at birth. METHODS: In the animal investigation, 3 miniature swine were instrumented and ventilated, and temperature probes were placed in the esophagus and the brain (1 cm and 2 cm beneath the parietal cortical surface and the dura). Body cooling was achieved using the automatic control mode (servo) of the cooling system. In the human investigation, 19 term infants with moderate or severe encephalopathy were randomized to either normothermia (n = 10) or hypothermia (n = 9) within 6 hours of birth. Whole-body hypothermia was achieved using the hyperthermia-hypothermia cooling system with servo control of esophageal temperature to 34.5 degrees C for 72 hours followed by slow rewarming. RESULTS: In the animal investigation, body cooling with the animal lying on a single blanket resulted in rapid cooling of the body within 90 minutes. Repetitive cyclical swings in esophageal temperature of 1.7 +/- 0.2 degrees C (mean +/- standard deviation) around the set point of 33.5 degrees C were reduced to 0.7 +/- 0.2 degrees C when a second, larger blanket was attached and suspended. Esophageal temperature was a good marker of deep brain temperature (esophageal to 2-cm brain difference: 0.1 +/- 0.3 degrees C). In the human investigation, the infants were randomized at 4.1 +/- 1.3 hours (mean +/- standard deviation) after birth. Age at randomization was similar in the 2 groups. Cooling was initiated at an average age of 5.3 hours. Target temperature of 34.5 degrees C was achieved within 30 minutes and remained constant throughout the intervention period. Heart rate decreased to 108 +/- 14 beats per minute (bpm) at 60 minutes and remained between 115 and 130 bpm for the duration of cooling compared with 130 to 145 bpm in the normothermia group. Blood pressure was similar in the 2 groups. No adverse events occurred during 72 hours of cooling. The mortality rate and frequency of persistent pulmonary hypertension, renal failure, hepatic dysfunction, and need for pressor support were similar in both groups. CONCLUSIONS: Animal studies showed that a simple modification of a commercially available cooling system (2 blankets attached, subject lying on 1 and the second hanging freely) results in stable core body and brain temperature when used in the automatic control mode. The pilot study in term infants with encephalopathy using this cooling system demonstrates feasibility of initiating whole-body hypothermia at <6 hours of age to a constant esophageal temperature using servo control and provides no evidence that hypothermia involved greater hazard than benefit.

A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa.

Abstract: X-linked retinitis pigmentosa (XLRP) is a clinically and genetically heterogeneous degenerative disease of the retina. At least five loci have been mapped for XLRP; of these, RP2 and RP3 account for 10%–20% and 70%–90% of genetically identifiable disease, respectively. However, mutations in the respective genes, RP2 and RPGR, were detected in only 10% and 20% of families with XLRP. Mutations in an alternatively spliced RPGR exon, ORF15, have recently been shown to account for 60% of XLRP in a European cohort of 47 families. We have performed, in a North American cohort of 234 families with RP, a comprehensive screen of the RP2 and RPGR (including ORF15 ) genes and their 5′ upstream regions. Of these families, 91 (39%) show definitive X-linked inheritance, an additional 88 (38%) reveal a pattern consistent with X-linked disease, and the remaining 55 (23%) are simplex male patients with RP who had an early onset and/or severe disease. In agreement with the previous studies, we show that mutations in the RP2 gene and in the original 19 RPGR exons are detected in RPGR-ORF15 mutations in an additional 30% of 91 well-documented families with X-linked recessive inheritance and in 22% of the total 234 probands analyzed. We suggest that mutations in an as-yet-uncharacterized RPGR exon(s), intronic changes, or another gene in the region might be responsible for the disease in the remainder of this North American cohort. We also discuss the implications of our studies for genetic diagnosis, genotype-phenotype correlations, and gene-based therapy.