Genetic and Biochemical Predictors of Neonatal Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a common complication of prematurity with a multifactorial etiology, influenced by both genetic susceptibility and environmental factors on the immature lung. Fibroblast growth factor receptor-3 and -4 (FGFR-3 and FGFR-4) are abundantly expressed in both the epithelium and mesenchyme in the developing mammalian lung. FGFR-4 may play a role in developing BPD as it is associated with airway inflammation and remodeling; studies showed a link between BPD and a polymorphism in the FGFR-4 gene. The aim of this study was to study the significance of FGFR-4 in developing BPD and to investigate the correlation between its serum level and its genetic polymorphism in relation to development of BPD in preterms. This case-control study was performed on 80 preterm neonates (<32 weeks) divided into two groups: group I included 50 preterms with respiratory distress syndrome (RDS) who developed BPD and group II included 30 preterms with RDS only. The mean serum level of FGFR-4 was significantly lower in group I than in group II ( p -value < 0.05). There was no significant correlation between the serum levels of FGFR-4 and the degree of severity of BPD. Allele variation in the FGFR-4 gene was similar in both groups. The serum level of FGFR-4 was significantly lower in preterms with BPD, although the gene polymorphism was not significantly different in the studied groups.

Erratum to: Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA).

[This corrects the article DOI: 10.1186/s13017-016-0089-y.].

Recurrent trauma in elderly patients.

HYPOTHESIS: Older patients (those aged > or = 70 years) who have experienced trauma have an increased risk of recurrent trauma. Demographic, medical, and functional factors are potential contributors to the risk of subsequent trauma among injured elderly patients. DESIGN: Retrospective follow-up study. PARTICIPANTS: Study participants were derived from the Longitudinal Study of Aging, an extension of the 1984 National Health Interview Survey focusing on persons who were aged 70 years and older in 1984. A cohort of elderly patients participating in the Longitudinal Study of Aging and hospitalized for injury in 1985 (n = 100) was identified using Medicare hospital discharge data. An uninjured cohort (n = 401) was also identified from the Longitudinal Study of Aging and matched for age (1 year) and sex. MAIN OUTCOME MEASURES: Risk of admission for trauma among the injured cohort compared with the uninjured cohort and associations between demographic, medical, and functional characteristics and trauma recurrence. RESULTS: Following adjustment for potential confounding factors, the injured cohort was 3.25 times more likely (95% confidence interval, 1.99-5.31) to be hospitalized for injury during the follow-up period compared with the uninjured cohort. Among the injured cohort, those at greatest risk of subsequent trauma included women and those with chronic medical conditions or functional impairments, the latter being the only factor independently associated with recurrence. CONCLUSIONS: Elderly patients who have experienced trauma are at increased risk of subsequent injury. Interventions to reduce the likelihood of trauma recurrence should focus on those with chronic illnesses and functional impairments.

Contribution of Escherichia coli alpha-hemolysin to bacterial virulence and to intraperitoneal alterations in peritonitis.

Alpha-hemolysin (Hly) is a common exotoxin produced by Escherichia coli that enhances virulence in a number of clinical infections. The addition of hemolysin production to laboratory bacterial strains is known to increase the lethality of E. coli peritonitis. However, the mechanisms involved have not been determined and the contribution of hemolysin to the alterations in the host intraperitoneal environment and the leukocyte response is not known. Utilizing a rat peritonitis model, we show that wild-type hemolytic E. coli strains have a significant competitive advantage over nonhemolytic strains within the peritoneum. To examine the specific contribution of Hly to E. coli-induced virulence and alterations within the peritoneum, a mixed peritonitis model of E. coli, Bacteroides fragilis, and sterile fecal adjuvant was used. Three transformed E. coli strains were utilized: one strongly secretes active hemolysin (WAF 270), a second secretes active hemolysin but a reduced amount (WAF 260), and the third does not produce hemolysin (WAF 108). After an equal inoculum of each of the three strains, WAF 270 produced a markedly increased lethality and an increased recovery of both E. coli and B. fragilis from the host relative to the other strains. Changes in the intraperitoneal pH, degree of erythrocyte lysis, and recruitment and viability of leukocytes within the peritoneum following the induction of peritonitis differed significantly between the strongly hemolytic and nonhemolytic strains. Induction of peritonitis with WAF 270 caused a pronounced decrease in intraperitoneal pH, lysis of most of the intraperitoneal erythrocytes, and a marked decrease in recoverable viable leukocytes compared to WAF 108. Thus, hemolysin production by E. coli within the peritoneum may alter not only the host's ability to control the hemolytic strain itself but also other organisms.

Endovascular therapy of traumatic injuries of the extracranial cerebral arteries.

The field of neuroendovascular therapy is rapidly growing. New technology and operators' expertise are developing at a pace that will make this discipline progressively more available and successful. For patients who have traumatic injuries of the extracranial arteries, endovascular therapy offers a new dimension to the treatment of these injuries and the prevention of stroke. Because many of these patients are likely to be critically ill, it is important to keep in mind the principles of their management before, during, and after the procedure, thus assuring the best chance for a successful outcome. Furthermore, some of the issues related to their neurointensive care will serve as guides for the need for endovascular therapy, as well as its timing.

Prognostic factors in patients with inferior vena cava injuries.

Inferior vena cava (IVC) injuries are potentially devastating insults that continue to be associated with high mortality despite advances in prehospital and in-hospital critical care. Between 1987 and 1996, 37 patients (32 males and 5 females; average age, 30 years) were identified from the trauma registry as having sustained IVC trauma. Overall mortality was 51 per cent (n = 19), with 13 intraoperative deaths and five patients dying within the first 48 hours. Blunt IVC injuries (n = 8) had a higher associated mortality than penetrating wounds (63% versus 48%). Of the 29 patients with penetrating IVC trauma, the wounding agent influenced mortality (shotgun-100% versus gunshot-43% versus stab-0%). Anatomical location of injury was also predictive of death [suprahepatic (n = 3)-100% versus retrohepatic (n = 9)-78% versus suprarenal (n = 6)-33% versus juxtarenal (n = 2)-50% versus infrarenal (n = 15)-33%]. A direct relationship existed between outcome and the number of associated injuries: nonsurvivors averaged four and survivors averaged three. Eighty per cent of patients sustaining four or more associated injuries died, by contrast to a 33 per cent mortality in those suffering less than four injuries. Physiological factors were also predictive of outcome. Patients in shock (systolic blood pressure < 80) on arrival had a higher mortality than those who were hemodynamically stable (76% versus 30%). Preoperative lactate levels were of prognostic value for death (> or = 4.0-59% versus < 4.0-0%), as was base deficit (< 4-22%, > or = 4, and < 10-36%, > or = 10-73%). Interestingly, neither time from injury to hospital arrival (47.4 minutes versus 33.0 minutes) nor time in the emergency department before surgery (45.6 minutes versus 42.6 minutes) differed between survivors and fatalities. Mortality remained high in the 34 patients who had operative control of their IVC injuries [lateral repair (n = 27)-44% versus ligation (n = 6)-66% versus Gortex graft (n = 1)-0%]. As wounding agent, anatomical location, associated injuries, and physiological status seem to most directly impact mortality, future efforts must focus both on establishing prevention programs directed at reducing the incidence of this injury, as well as on advancing the management of those who do survive to hospitalization, if we are to improve on the outcome of these devastating injuries.

Hemolytically active (acylated) alpha-hemolysin elicits interleukin-1beta (IL-1beta) but augments the lethality of Escherichia coli by an IL-1- and tumor necrosis factor-independent mechanism.

Many pathogenic Escherichia coli produce the toxin alpha-hemolysin (Hly), and lipopolysaccharide (LPS), interleukin-1 (IL-1), and tumor necrosis factor (TNF) have all been recognized as important effector molecules during infections by gram-negative organisms. Despite the characterization of many in vitro effects of hemolysin, no direct relationship has been established between hemolysin, LPS, proinflammatory cytokine production, and E. coli-induced mortality. Previously, we have shown in vivo that hemolysin elicits a distinct IL-1alpha spike by 4 h into a lethal hemolytic E. coli infection. Using three transformed E. coli strains, WAF108, WAF270, and WAH540 (which produce no Hly [Hlynull], acylated Hly [Hlyactive], or nonacylated Hly [Hlyinactive], respectively), we sought to determine the specific roles of hemolysin acylation, LPS, IL-1, and TNF in mediating the lethality of E. coli infection in mice. WAF270 was 100% lethal in BALB/c, C3H/HeJ, and C57BL/6 mice; in mice pretreated with antibody to the type 1 IL-1 receptor; in type 1 IL-1 receptor-deficient mice; and in dual (type 1 IL-1 receptor-type 1 TNF receptor)-deficient mice at doses which were nonlethal (0%) with both WAF108 and WAH540. At lethal doses, WAF270 killed by 6 +/- 2.3 h while WAF108 and WAH540 killed at 36 +/- 9.4 and 36 +/- 13.8 h, respectively. These differences in mortality were not due to IL-1 or TNF release, and the enhanced expression of LPS, which corresponded to Hly expression, was not likely the primary factor causing mortality. We demonstrate that bacterial fatty acid acylation of hemolysin is required in order for it to elicit IL-1 release by monocytes and to confer its virulence on E. coli.

Emerging evidence of selection of fluconazole-tolerant fungi in surgical intensive care units.

OBJECTIVE: To determine whether increased use of fluconazole has coincided with a shift in the relative proportion of fluconazole-tolerant species isolated from critically ill surgical patients in 2 university hospitals. DESIGN: Microbiological data and fluconazole administration frequencies were reviewed among patients treated in the surgical intensive care units (SICUs) from January 1, 1990, through December 31, 1995. SETTING: The SICUs of the University of Virginia Medical Center, Charlottesville, and the Hospital of the University of Pennsylvania, Philadelphia. MAIN OUTCOME MEASURES: The number and species types of all fungal isolates and the number of patients treated with fluconazole for each of the 6 years were determined. RESULTS: A sharp increase in the use of fluconazole among critically ill surgical patients has occurred at both medical centers from 1990-1995. The culture results of most patients treated with fluconazole were negative for fungi (73% and 63% at the University of Virginia Medical Center and the Hospital of the University of Pennsylvania, respectively); there was a greater tendency to use fluconazole at the University of Virginia Medical Center compared with the Hospital of the University of Pennsylvania (2.2% vs 1.8% of patients admitted to the SICU received it, respectively; P = .007). There was a significant increase in the proportion of Candida glabrata isolated at the University of Virginia Medical Center (P < .01) from 1990-1995, but a similar change was not detectable at the Hospital of the University of Pennsylvania. CONCLUSIONS: These data justify concern that the increased use of fluconazole in SICUs may be promoting a shift in the fungal flora that cause nosocomial infections toward species that are more difficult to treat. Prospective studies about the use of fluconazole for prophylaxis and empirical therapy among SICU patients are warranted before its widespread use in these settings continues.

In vivo cytokine response to Escherichia coli alpha-hemolysin determined with genetically engineered hemolytic and nonhemolytic E. coli variants.

Alpha-hemolysin is an Escherichia coli exotoxin that enhances bacterial virulence, has profound effects on leukocytes in vitro, and induces the release of interleukin-1 (IL-1) but not tumor necrosis factor (TNF) from human monocytes in vitro. The purpose of this study was to examine alpha-hemolysin's influence on virulence and TNF and IL-1 production in vivo. Two genetically engineered, isogeneic strains of E. coli were used; one variant produces alpha-hemolysin, and the other does not. Male BALB/c mice were injected with either of the two variants and serum TNF and IL-1 were assayed. These results were compared with those obtained from the injection of either of two serotypes of lipopolysaccharide (LPS). The nonhemolytic E. coli strain produced no mortality and no significant elevation of serum TNF or IL-1 levels. In contrast, equal inocula of the hemolytic E. coli strain produced significant mortality and elevation of serum IL-1 levels. No significant elevation of TNF levels was detected in this group despite high-level mortality. A pattern of induction of mortality and elevation of serum IL-1 levels without elevation of serum TNF levels is distinct from the pattern typical of LPS. In these experiments, both serotypes of LPS caused elevations of TNF and IL-1 levels whether or not mortality was induced. Thus, alpha-hemolysin produces a cytokine response in vivo that is similar to that previously demonstrated in vitro by Bhakdi et al. (S. Bhakdi, M. Muhly, S. Korom, and G. Schmidt, J. Clin. Invest. 85:1746-1753, 1990) and appears to induce mortality independently of serum TNF.

Enhanced virulence of Escherichia coli bearing a site-targeted mutation in the major structural subunit of type 1 fimbriae.

Type 1 fimbriae promote enterobacterial adherence to a variety of mammalian cells and are thought to play an important role in the establishment of various extraintestinal infections. Whether or not this adhesin has a role in the pathogenesis of peritoneal Escherichia coli infections, such as those initiated by bowel leakage during intraabdominal surgery, is unclear. By using two genetically engineered E. coli strains, each bearing an antibiotic resistance element inserted at a different site within the type 1 fimbria operon, we examined the role of type 1 fimbriation in intraperitoneal infection in rats. A permanently nonfimbriated insertion mutant was compared with an analogously constructed normally fimbriated one. After intraperitoneal inoculation of adult rats, the permanently nonfimbriated mutant produced mortality more rapidly and resulted in a greater number of culturable organisms from both the peritoneum and the blood. Moreover, the differences between these two insertion mutants were dramatically enhanced by preinoculation growth conditions favoring fimbrial expression. After growth under these conditions, 10(3) CFU of the fimbriation-proficient strain inoculated intraperitoneally caused no mortality; in sharp contrast, the permanently nonfimbriated insertion mutant resulted in death in 60% of the animals inoculated. Notwithstanding evidence that type 1 fimbriae mediate enterobacterial adherence to mammalian oropharyngeal and bladder mucosae, the results presented here demonstrate that type 1 fimbrial expression can lead to diminution of the number of E. coli organisms within the peritoneum.

Anti-tumor necrosis factor antibody reduces mortality in the presence of antibiotic-induced tumor necrosis factor release.

The systemic tumor necrosis factor (TNF) response has been extensively studied during infection. In addition, antibiotics that cause cell-wall lysis have been associated with endotoxinemia and, therefore, could trigger TNF release. We studied the effects of pretreatment with cefoxitin and/or anti-TNF antibody on mortality and early (90 minutes) and delayed (6 hours) serum TNF levels in a murine model of mixed Escherichia coli/Bacteroides fragilis peritonitis. At low and intermediate inocula levels, cefoxitin, but not anti-TNF antibody, prevented death, and low serum TNF levels were noted in all groups. At the highest inoculum level, mortality was uniform in control, cefoxitin, and anti-TNF antibody groups, and a significant elevation in serum TNF levels was seen only at the 6-hour point in animals receiving cefoxitin. The addition of anti-TNF antibody to cefoxitin at this inoculum level abrogated the 6-hour rise in serum TNF levels and reduced mortality to 40%. These results emphasize that the cytokine response in disease is dependent on both the nature of the insult and other forms of therapeutic interventions.