Bram P. Wispelwey

A genomic storm in critically injured humans

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes.

Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor.

The diversity of infectious agents capable of inducing meningitis and blood-brain barrier (BBB) injury suggests the potential for a common host mediator. The inflammatory polypeptides, IL-1 and TNF, were tested in an experimental rat model as candidate mediators for induction of meningitis and BBB injury. Intracisternal challenge of rIL-1 beta into rats induced neutrophil emigration into cerebrospinal fluid (CSF) and significantly increased BBB permeability to systemically administered 125I-BSA as early as 3 h later (P less than 0.05). This injury was reversible, dose dependent and significantly inhibited by prior induction of systemic neutropenia (via intraperitoneal cyclophosphamide) or preincubation of the rIL-1 beta inoculum (50 U) with an IgG monoclonal antibody to rIL-1 beta. Similar kinetics and reversibility of CSF inflammation and BSA permeability were observed using equivalent dose inocula of rIL-1 alpha. rTNF-alpha was less effective as an independent inducer of meningitis or BBB injury over an inoculum range of 10(1) U (0.0016 micrograms/kg)-10(6) U (160 micrograms/kg) when injected intracisternally, but inoculum combinations of low concentrations of rTNF alpha (10(3) U) and rIL-1 beta (0.0005-5.0 U) were synergistic in inducing both meningitis and BBB permeability to systemic 125I-BSA. These data suggest that in situ generation of interleukin-1 within CSF (with or without TNF) is capable of mediating both meningeal inflammation and BBB injury seen in various central nervous system infections.

Haemophilus influenzae lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat.

The factors responsible for blood-brain barrier (BBB) injury during bacterial meningitis are incompletely defined. We evaluated the role of Haemophilus influenzae type b (Hib) lipopolysaccharide (LPS) in the alteration of blood-brain barrier permeability (BBBP) in an adult, normal and leukopenic, rat model of meningitis. Intracisternal inoculation of Hib LPS resulted in (a) dose-dependent increases in BBBP from 2 pg to 20 ng, with significant attenuation in the peak response after challenge with 500 ng and 1 microgram; (b) time-dependent increases in BBBP, with a delayed onset of at least 2 h, maximum alteration at 4 h, and complete reversal at 18 h; (c) greater BBBP than after challenge with the live parent strain; (d) and a close correlation (r = 0.86) between CSF pleocytosis and BBBP at 4 h. The LPS effect was significantly inhibited by preincubation with Polymyxin B and neutrophil acyloxyacyl hydrolase, however two different oligosaccharide-specific monoclonal antibodies did not inhibit activity. No change in BBBP after inoculation with Hib LPS occurred in leukopenic rats. Hib LPS, in the setting of an intact leukocyte response, exerts profound effects on BBBP.

Benchmarking outcomes in the critically injured burn patient

Objective:To determine and compare outcomes with accepted benchmarks in burn care at 6 academic burn centers. Background:Since the 1960s, US morbidity and mortality rates have declined tremendously for burn patients, likely related to improvements in surgical and critical care treatment. We describe the baseline patient characteristics and well-defined outcomes for major burn injuries. Methods:We followed 300 adults and 241 children from 2003 to 2009 through hospitalization, using standard operating procedures developed at study onset. We created an extensive database on patient and injury characteristics, anatomic and physiological derangement, clinical treatment, and outcomes. These data were compared with existing benchmarks in burn care. Results:Study patients were critically injured, as demonstrated by mean % total body surface area (TBSA) (41.2 ± 18.3 for adults and 57.8 ± 18.2 for children) and presence of inhalation injury in 38% of the adults and 54.8% of the children. Mortality in adults was 14.1% for those younger than 55 years and 38.5% for those aged 55 years and older. Mortality in patients younger than 17 years was 7.9%. Overall, the multiple organ failure rate was 27%. When controlling for age and % TBSA, presence of inhalation injury continues to be significant. Conclusions:This study provides the current benchmark for major burn patients. Mortality rates, notwithstanding significant % TBSA and presence of inhalation injury, have significantly declined compared with previous benchmarks. Modern day surgical and medically intensive management has markedly improved to the point where we can expect patients younger than 55 years with severe burn injuries and inhalation injury to survive these devastating conditions.

Cesarean delivery in obese women: a comprehensive review

Background: Obesity (BMI ≥30) is a significant independent risk factor for many gestational complications, including cesarean delivery (CD). While CD rates are increasing in women of every BMI, the trend is more pronounced as maternal weight increases. Objective: This review seeks to describe the risk modulators that explain the high prevalence of CD in obese women, as well as to discuss the excess complications of the procedure in this group of parturients. In assessing the rationale for the procedure and weighing this against the excess risks involved, a clearer indication of when to perform CD in obese women might be developed. Results: A thorough review of the literature indicates that a decreased cervical dilation rate, an increased induction rate, the presence of comorbid conditions, concern about shoulder dystocia, and weight gain in excess of recommendations during pregnancy all may contribute to the high rate of CD in obese women. Obese women are at increased risk of CD-related complications including anesthetic complications, wound complications, venous thromboembolism (VTE), and failure of vaginal birth after CD. Conclusions: Given the excess risks associated with CD in obese women, and that some of the rationale for the procedure (e.g. slower labor, concern about shoulder dystocia) may not be justified based on current evidence, a reassessment of the threshold at which obese women are recommended for CD is necessary.

Econutrition and Utilization of Food-Based Approaches for Nutritional Health

Background Macronutrient and micronutrient deficiencies continue to have a detrimental impact in lower-income countries, with significant costs in morbidity, mortality, and productivity. Food is the primary source of the nutrients needed to sustain life, and it is the essential component that links nutrition, agriculture, and ecology in the econutrition framework. Objective To present evidence and analysis of food-based approaches for improving nutritional and health outcomes in lower-income countries. Methods Review of existing literature. Results and conclusions The benefits of food-based approaches may include nutritional improvement, food security, cost-effectiveness, sustainability, and human productivity. Food-based approaches require additional inputs, including nutrition education, gender considerations, and agricultural planning. Although some forms of malnutrition can be addressed via supplements, food-based approaches are optimal to achieve sustainable solutions to multiple nutrient deficiencies.

Inflammatory bowel disease and preterm delivery.

BackgroundThe association between inflammatory bowel disease (IBD) and preterm delivery is controversial. Study size, quality, and design have been inconsistent, making it difficult to assess the relationship between IBD and preterm delivery.ObjectiveUtilizing a systematic search of Pubmed for all relevant literature, this review seeks to clarify the correlation between IBD and preterm delivery and to assess the impact of disease activity and medication usage on this outcome.ResultsThe available evidence is inadequate to make any robust claims about the association between IBD and preterm delivery. IBD in pregnant women may represent a risk for preterm delivery, and it is probable that IBD activity augments this risk. Many of the medications used to treat IBD also have a correlation with preterm delivery.ConclusionsWhile an association between IBD and preterm delivery may exist, further well-designed prospective studies are necessary to determine how the course and management of disease may impact this outcome.

The transplantation of solid organs from HIV-positive donors to HIV-negative recipients: ethical implications

HIV-positive individuals have traditionally been barred from donating organs due to transmission concerns, but this barrier may soon be lifted in the USA in limited settings when recipients are also infected with HIV. Recipients of livers and kidneys with well-controlled HIV infection have been shown to have similar outcomes to those without HIV, erasing ethical concerns about poorly chosen beneficiaries of precious organs. But the question of whether HIV-negative patients should be disallowed from receiving an organ from an HIV-positive donor has not been adequately explored. In this essay, we will discuss the background to this scenario and the ethical implications of its adoption from the perspectives of autonomy, beneficence/non-maleficence and justice.