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Biomedical subjects

M J Schurr

Publications and source records attributed to M J Schurr.

At least 19 recordsLinked to original sources
PubMed2006

Clinical experience with Alloderm: a one-staged composite dermal/epidermal replacement utilizing processed cadaver dermis and thin autografts.

UNLABELLED: Alloderm has been advocated for the management of acute burns. However, few studies have demonstrated the feasibility of this technique. METHODS: We reviewed the medical records of all patients treated in our burn center who received Alloderm since 1999. RESULTS: Alloderm was used in 21 burn patients and 6 patients with traumatic skin loss. The average size of Alloderm used in the burn patients was 517+/-144 cm(2) (range 24-3000 cm(2)). The average Alloderm thickness used was 0.008 in. and autografts were harvested at an average of 0.007 in. Overall, Alloderm was used in a variety of locations including the face in 3 patients (2 burns, 1 traumatic skin loss) and hands in 7 patients (6 burns, 1 traumatic skin loss). Successful take was observed in 26/27 patients. CONCLUSIONS: Alloderm can be used successfully in patients with acute burns requiring grafting.

Adolescent↗
PubMed2005

A549 lung epithelial cells grown as three-dimensional aggregates: alternative tissue culture model for Pseudomonas aeruginosa pathogenesis.

A three-dimensional (3-D) lung aggregate model was developed from A549 human lung epithelial cells by using a rotating-wall vessel bioreactor to study the interactions between Pseudomonas aeruginosa and lung epithelial cells. The suitability of the 3-D aggregates as an infection model was examined by immunohistochemistry, adherence and invasion assays, scanning electron microscopy, and cytokine and mucoglycoprotein production. Immunohistochemical characterization of the 3-D A549 aggregates showed increased expression of epithelial cell-specific markers and decreased expression of cancer-specific markers compared to their monolayer counterparts. Immunohistochemistry of junctional markers on A549 3-D cells revealed that these cells formed tight junctions and polarity, in contrast to the cells grown as monolayers. Additionally, the 3-D aggregates stained positively for the production of mucoglycoprotein while the monolayers showed no indication of staining. Moreover, mucin-specific antibodies to MUC1 and MUC5A bound with greater affinity to 3-D aggregates than to the monolayers. P. aeruginosa attached to and penetrated A549 monolayers significantly more than the same cells grown as 3-D aggregates. Scanning electron microscopy of A549 cells grown as monolayers and 3-D aggregates infected with P. aeruginosa showed that monolayers detached from the surface of the culture plate postinfection, in contrast to the 3-D aggregates, which remained attached to the microcarrier beads. In response to infection, proinflammatory cytokine levels were elevated for the 3-D A549 aggregates compared to monolayer controls. These findings suggest that A549 lung cells grown as 3-D aggregates may represent a more physiologically relevant model to examine the interactions between P. aeruginosa and the lung epithelium during infection.

Antigens↗
PubMed2002

Mechanisms of bacterial pathogenicity.

Pathogenic bacteria utilise a number of mechanisms to cause disease in human hosts. Bacterial pathogens express a wide range of molecules that bind host cell targets to facilitate a variety of different host responses. The molecular strategies used by bacteria to interact with the host can be unique to specific pathogens or conserved across several different species. A key to fighting bacterial disease is the identification and characterisation of all these different strategies. The availability of complete genome sequences for several bacterial pathogens coupled with bioinformatics will lead to significant advances toward this goal.

Adhesins, Bacterial↗
PubMed2001

Geriatric trauma: review and recommendations.

Although the elderly make up about 12% of the US population, they account for nearly 33% of health care resources expended on trauma. A review of the literature in the area of geriatric trauma revealed a number of factors that influence the likelihood of injury in the elderly population. These include age-related changes in postural stability, balance, motor strength, and coordination that may predispose individuals to falls and other accidents. It is important to have a high index of suspicion for injury and a low threshold for invasive monitoring and transfer to an intensive care setting. Considerations in the care of elderly trauma patients include comorbid conditions, pre-injury medications, reduced physiologic reserve, and the physical changes of aging.

Accidental Falls↗
PubMed2000

Dual regulation of mucoidy in Pseudomonas aeruginosa and sigma factor antagonism.

The conversion to mucoid, exopolysaccharide alginate-overproducing phenotype in Pseudomonas aeruginosa during chronic respiratory infections in cystic fibrosis patients occurs via mutations that activate the alternative sigma factor AlgU (sigmaE). In this study, we demonstrate that conversion to mucoidy can be caused via a second, algU-independent pathway, in which alginate production and transcription of the critical algD promoter depend on another alternative sigma factor, RpoN (sigma54). The algD promoters dependent on sigma54 and sigmaE showed a complete overlap resulting in identical mRNA 5' ends. The two pathways were not independent, as sigma54 also repressed sigmaE-dependent transcription of algD both in vitro and in vivo. The negative regulatory effect of sigma54 on sigmaE-dependent algD expression was based on sigma54 binding to the algD promoter and its interference with sigmaE-dependent transcription. This phenomenon, referred to here as sigma factor antagonism, reflects the unique properties of sigma54, which lacks an intrinsic ability to form open transcription initiation complexes. We propose that this peculiar feature of sigma54 has evolved in part to allow its recruitment as a repressor of certain promoter subsets. The repression of algD by sigma54 also depends on environmental conditions, supporting the notion that sigma factor antagonism plays a physiological role in controlling alginate production in P. aeruginosa during adaptation to different ecological sites (e.g. biofilm development, stress and other growth conditions) and unique environments in the chronically infected host.

Alginates↗
PubMed1999

Formal swallowing evaluation and therapy after traumatic brain injury improves dysphagia outcomes.

BACKGROUND: The incidence of swallowing dysfunction after brain injury is unknown. The efficacy of dysphagia therapy is also unknown. We reviewed our experience to define the incidence of swallowing dysfunction and efficacy of therapeutic intervention. METHODS: Patients with brain injury sustained between January of 1996 and December of 1997 were reviewed. All were screened with trials of oral intake. Abnormal findings were confirmed with a videofluoroscopic swallow study. Standard therapies included diet, posture, and behavior modifications. RESULTS: A total of 47 patients were evaluated. Bedside evaluations were normal in 14 patients, 2 patients had overt aspiration and underwent gastrostomy, and 31 patients were referred for a videofluoroscopic swallow study (66%). The videofluoroscopic swallow study was abnormal in 22 of 31 patients (71%). Of these, 4 additional patients required gastrostomy, 13 patients had laryngeal penetration or minor aspiration responsive to dysphagia therapy and were fed. Five other patients had silent aspiration and were fed by means of nasogastric tube; these five patients responded to dysphagia therapy and were able to resume oral intake. CONCLUSION: Dysphagia is common after severe head injury. With formal swallowing service intervention, aspiration is avoided. Therapeutic interventions can be used to restore oral intake.

Adolescent↗
PubMed1997

Unexpected action of platelet activating factor antagonism after fluid resuscitation from traumatic shock.

BACKGROUND: We have shown that therapy directed at polymorphonuclear neutrophil (PMN) CD18 receptors attenuates sequelae associated with a post-trauma endotoxin (lipopolysaccharide [LPS]) challenge. Platelet activating factor (PAF) stimulates PMNs by CD18-independent pathways, and WEB-2086, a PAF receptor antagonist, blunts septic symptoms in many experimental models. This study tested the hypothesis that the blockade of non-CD18 dependent PMN adherence attenuates trauma- and LPS-evoked pulmonary dysfunction. METHODS: We performed three experiments. First, anesthetized swine were subjected to hind-limb trauma and 30% hemorrhage. After 1 hour animals were resuscitated with shed blood, lactated Ringer's solution (LRS), and WEB-2086 (10 mg/kg/hr) or vehicle. After a 72-hour recovery period, LPS was administered. LPS was then administered without an earlier episode of traumatic shock to animals treated with WEB-2086 or vehicle. Finally, PAF was infused before and after trauma and a dose response curve was obtained. RESULTS: Surprisingly, PAF blockade increased mortality after trauma (5 of 11 WEB-2086 animals versus 1 of 9 vehicle animals; p = 0.15) and depressed cardiac index and O2 delivery at 72 hours (p < 0.05). After LPS administration WEB-2086 treated pigs were unable to manifest the hyperdynamic circulatory compensation seen in the vehicle pigs. In the absence of traumatic shock, WEB-2086 was associated with reduced mortality (four of five WEB-2086 treated pigs versus two of five vehicle pigs survived 5 hours; p = 0.07) and improved arterial PO2 (p = 0.05) and base excess (p = 0.04) 60 minutes after LPS administration. The dose response curve for PAF infusion on the cardiac index was altered after trauma compared with the nontraumatized state. CONCLUSIONS: Because WEB-2086 had unexpected and fundamentally opposite properties before and after trauma, PAF may have a previously undescribed homeostatic role in the compensatory response to injury. These results also suggest that blockade of endogenous inflammatory mediators can have a positive or negative action, depending on the timing of administration and the preexisting condition.

Animals↗
PubMed1997

Microbial pathogenesis in cystic fibrosis: co-ordinate regulation of heat-shock response and conversion to mucoidy in Pseudomonas aeruginosa.

Conversion of Pseudomonas aeruginosa to the mucoid phenotype plays a major role in the pathogenesis of respiratory infections in cystic fibrosis (CF). One mechanism responsible for mucoidy is based on mutations that inactivate the anti-sigma factor, MucA, which normally inhibits the alternative sigma factor, AIgU. The loss of MucA allows AIgU to freely direct transcription of the genes responsible for the production of the exopolysaccharide alginate resulting in mucoid colony morphology. In Escherichia coli, a close homologue of AIgU, sigma(E), directs transcription of several genes under conditions of extreme heat shock. Here we examined whether AIgU, besides its role in controlling alginate production, affects the heat-shock response in P. aeruginosa. The P. aeruginosa rpoH gene encoding a homologue of the major heat-shock sigma factor, sigma32, was found to be transcribed by AIgU containing RNA polymerase from one of its promoters (P3) identified in this study. Transcription of rpoH from P3 was elevated upon exposure to extreme heat shock in an aIgU-dependent manner. Importantly, the AIgU-dependent promoter of rpoH was found to be activated in mucoid mucA mutants. In keeping with this observation, introduction of a wild-type mucA gene abrogated AIgU-dependent rpoH transcription in mucoid P. aeruginosa laboratory isolates and CF isolates. These results suggest that conversion to mucoidy and the heat-shock response are co-ordinately regulated in P. aeruginosa. The simultaneous activation of both systems in mucA mutants, selected in the lungs of CF patients, may have significance for the inflammatory processes characteristic of the establishment of chronic infection and ensuing clinical deterioration in CF.

Bacterial Proteins↗
PubMed1997

Dehydroepiandrosterone, an endogenous immune modulator, after traumatic shock.

Dehydroepiandrosterone (DHEA), an endogenous immune modulator, reduces mortality after endotoxin (lipopolysaccharide (LPS)) administration in rodents. However, there have been no studies in clinically relevant large-animal models. A unique experimental model is used to study the effects of DHEA in resuscitated trauma and to evaluate the protective effect of DHEA on the systemic inflammatory response induced by a delayed LPS challenge. Anesthetized, ventilated pigs were instrumented and then subjected to local hind-limb trauma and 35% hemorrhage. After 1 h, animals were resuscitated with shed blood, supplemental Ringers solution, and in a randomized, blinded fashion, 4 mg/kg of DHEA or vehicle. Two additional groups received 10 mg/kg or 20 mg/kg of DHEA. Animals were dosed again at 24, 48, and 72 h. After 75 h, Escherichia coli LPS was administered. LPS caused a fall in DHEA levels (0.23 +/- .05 ng/mL (60 min post-LPS) versus .94 +/- 35 ng/mL (72 h), p = .01). DHEA levels 60 min post-LPS were significantly higher in treated animals (p < .002). After LPS, all groups manifested progressive septic symptoms with a hyperdynamic state and pulmonary failure. These symptoms were not blunted by the administration of DHEA. DHEA levels are suppressed by LPS in this two-stage model of trauma and delayed sepsis; however, exogenous DHEA administration fails to blunt the associated systemic inflammatory response and pulmonary failure.

Animals↗
PubMed1997

Pseudomonas aeruginosa in cystic fibrosis: role of mucC in the regulation of alginate production and stress sensitivity.

Alginate production in Pseudomonas aeruginosa and the associated mucoid phenotype of isolates from cystic fibrosis patients are under the control of the algU mucABCD cluster. This group of genes encodes AlgU, the P. aeruginosa equivalent of the extreme heat shock sigma factor sigma E in Gram-negative bacteria, the AlgU-cognate anti-sigma factor MucA, the periplasmic protein MucB and a serine protease homologue, MucD. While mucA, mucB or mucD act as negative regulators of AlgU, the function of mucC is not known. In this study the role of mucC in P. aeruginosa physiology and alginate production has been addressed. Insertional inactivation of mucC in the wild-type P. aeruginosa strain PAO1 did not cause any overt effects on alginate synthesis. However, it affected growth of P. aeruginosa under conditions of combined elevated temperature and increased ionic strength or osmolarity. Inactivation of mucC in mucA or mucB mutant backgrounds resulted in a mucoid phenotype when the cells were grown under combined stress conditions of elevated temperature and osmolarity. Each of the stress factors tested separately did not cause comparable effects. The combined stress factors were not sufficient to cause phenotypically appreciable enhancement of alginate production in mucA or mucB mutants unless mucC was also inactivated. These findings support a negative regulatory role of mucC in alginate production by P. aeruginosa, indicate additive effects of muc genes in the regulation of mucoidy in this organism and suggest that multiple stress signals and recognition systems participate in the regulation of algU-dependent functions.

Alginates↗
PubMed1997

Identification of the algZ gene upstream of the response regulator algR and its participation in control of alginate production in Pseudomonas aeruginosa.

Alginate production in mucoid Pseudomonas aeruginosa isolates from cystic fibrosis patients is under direct control by AlgU, the P. aeruginosa equivalent of the extreme heat shock sigma factor sigma(E) in gram-negative bacteria, and AlgR, a response regulator from the superfamily of two-component signal transduction systems. In this report, we describe the identification of the algZ gene, located immediately upstream of algR, which is involved in the control of alginate production. The predicted product of the algZ gene showed similarity to a subset of sensory components from the superfamily of signal transduction systems but lacked several of the highly conserved motifs typical of histidine protein kinases. Inactivation of algZ in the wild-type standard genetic strain PAO1 did not affect its nonmucoid morphology. However, inactivation of algZ in a mucoid mutant P. aeruginosa strain, which had AlgU freed from control by the anti-sigma factor MucA, resulted in increased alginate production under growth conditions which did not permit expression of mucoidy in the parental algZ+ strain. The observed effects were abrogated when algR was inactivated in the algZ::Tc(r) background. These findings indicate that algZ plays a regulatory role in alginate production, possibly interacting with AlgR, and that it may have negative effects on expression of the mucoid phenotype under the conditions tested. The presented results suggest that elements of negative regulation exist at the levels of both the alternative sigma factor AlgU and the transcriptional activator AlgR which, once relieved from that suppression, cooperate to bring about the expression of the alginate system.

Alginates↗
PubMed1996

Delayed presentation of a tracheoesophageal fistula after blunt chest trauma.

Traumatic tracheoesophageal fistula is an uncommon injury after blunt chest injury. Rapid deceleration against the steering wheel during a high-speed motor vehicle crash is the usual mechanism of injury. Previous reports document few cases of delayed diagnosis and repair of tracheoesophageal fistula. We report a case of delayed diagnosis of tracheoesophageal fistula more than 20 years after the original trauma and describe the subsequent operative repair.

Accidents, Traffic↗
PubMed1996

A prospective analysis of transesophageal echocardiography in the diagnosis of traumatic disruption of the aorta.

OBJECTIVE: Recently, transesophageal echocardiography (TEE) has been proposed as the standard for the diagnosis of traumatic disruption of the aorta (TDA), replacing aortography. The purpose of this study was to evaluate the accuracy and practicality of TEE in the diagnosis of TDA. DESIGN: Prospective clinical trial. MATERIALS AND METHODS: Patients with blunt trauma admitted with a suspected diagnosis of TDA were evaluated with TEE and aortography. MEASUREMENTS AND MAIN RESULTS: Thirty-four patients were evaluated with TEE and aortography. TEE was unsuccessful in five patients (15%). Of the remaining 29 patients, TEE results were true-positive in four and true-negative in 20. TEE results were false-positive in two patients, and three injuries were missed (two were proximal to the left subclavian artery, and one was a localized aortic disruption). Sensitivity and specificity of TEE were 57% and 91%, respectively, compared with aortography, for which sensitivity was 89% and specificity was 100%. CONCLUSION: Although the use of TEE in the diagnosis of TDA has several advantages, it is not more accurate than aortography. TEE should not replace aortography as the standard for the diagnosis of TDA.

Adult↗
PubMed1996

Control of AlgU, a member of the sigma E-like family of stress sigma factors, by the negative regulators MucA and MucB and Pseudomonas aeruginosa conversion to mucoidy in cystic fibrosis.

The alternative sigma factor AlgU (Pseudomonas aeruginosa sigma E) is required for full resistance of P. aeruginosa to oxidative stress and extreme temperatures. AlgU also controls conversion of P. aeruginosa to the mucoid, alginate-overproducing phenotype associated with lethal infections in cystic fibrosis patients. Mutations that cause conversion to mucoidy in cystic fibrosis isolates occur frequently in mucA, the second gene within the algU mucABCD gene cluster. Here we analyze the biochemical basis of conversion to mucoidy. MucA was shown to act as an anti-sigma factor by binding to AlgU and inhibiting its activity. MucB, another negative regulator of AlgU, was localized in the periplasm. MucB exerts its function from this compartment, since deletion of the leader peptide and the cytoplasmic location of MucB abrogated its ability to inhibit mucoidy. These data support a model in which a multicomponent system, encompassing an anti-delta factor and elements in the periplasmic compartment, modulates activity of AlgU. Since factors controlling AlgU are conserved in other gram-negative bacteria, the processes controlling conversion to mucoidy in P. aeruginosa may be applicable to the regulation of AlgU (sigma E) equivalents in other organisms.

Bacterial Proteins↗
PubMed1996

Two distinct loci affecting conversion to mucoidy in Pseudomonas aeruginosa in cystic fibrosis encode homologs of the serine protease HtrA.

Conversion to a mucoid, exopolysaccharide alginate-overproducing phenotype in Pseudomonas aeruginosa is associated with chronic respiratory infections in cystic fibrosis. Mucoidy is caused by muc mutations that derepress the alternative sigma factor AlgU, which in turn activates alginate biosynthetic and ancillary regulatory genes. Here we report the molecular characterization of two newly identified genes, algW and mucD, that affect expression of mucoidy. The algW gene, mapping at 69 min, was isolated on the basis of its ability to suppress mucoidy and reduce transcription of the alginate biosynthetic gene algD. The predicted primary structure of AlgW displayed similarity to HtrA (DegP), a serine protease involved in proteolysis of abnormal proteins and required for resistance to oxidative and heat stress in enteric bacteria. Inactivation of algW on the chromosome of the wild-type nonmucoid strain PAO1 caused increased sensitivity to heat, H2O2, and paraquat, a redox cycling compound inducing intracellular levels of superoxide. This mutation also permitted significant induction of alginate production in the presence of subinhibitory concentrations of paraquat. Two new genes, mucC and mucD, were identified immediately downstream of the previously characterized portion (algU mucA mucB) of the gene cluster at 67.5 min encoding the alternative sigma factor AlgU and its regulators. Interestingly, the predicted gene product of mucD also showed similarities to HtrA. Inactivation of mucD on the PAO1 chromosome resulted in conversion to the mucoid phenotype. The mutation in mucD also caused increased sensitivity to H2O2 and heat killing. However, in contrast to algW mutants, no increase in susceptibility to paraquat was observed in mucD mutants. These findings indicate that algW and mucD play partially overlapping but distinct roles in P. aeruginosa resistance to reactive oxygen intermediates and heat. In addition, since mutations in mucD and algW cause conversion to mucoidy or lower the threshold for its induction by reactive oxygen intermediates, these factors may repress alginate synthesis either directly by acting on AlgU or its regulators or indirectly by removing physiological signals that may activate this stress response system.

Alginates↗
PubMed1995

Biochemical characterization and posttranslational modification of AlgU, a regulator of stress response in Pseudomonas aeruginosa.

AlgU is homologous to the extreme heat shock sigma factor sigma E from enteric bacteria. In this work, AlgU was overproduced and purified and its function investigated at the biochemical level. AlgU was shown to associate with RNA polymerase and direct transcription of a target promoter. AlgU also exhibited multiple isoforms detected by 2D gel analysis. Treatment with a Ser/Thr phosphatase shifted the distribution of isoforms towards the basic side on 2D gels, suggesting that posttranslational modifications of AlgU may involve phosphorylation. The underphosphorylated forms of AlgU copurified with RNA polymerase. It is possible that phosphorylation affects AlgU activity or its stability.

Amino Acid Sequence↗
PubMed1995

Pseudomonas aeruginosa, mucoidy and the chronic infection phenotype in cystic fibrosis.

During chronic infections in cystic fibrosis, persistence of Pseudomonas aeruginosa is associated with conversion into forms that are associated with conversion into forms that are characterized by a mucoid colony morphology, rough lipopolysaccharide and, paradoxically, decreased systemic virulence. The mutations underlying these changes occur in global regulators, such as alternative sigma factors and their accessory elements.

Bacterial Capsules↗