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K Gammon

Publications and source records attributed to K Gammon.

10 recordsLinked to original sources
PubMed2001

Functional genomics of oxidant-induced lung injury.

In summary, acute lung injury is a severe (>40% mortality) respiratory disease associated with numerous precipitating factors. Despite extensive research since its initial description over 30 years ago, questions remain about the basic pathophysiological mechanisms and their relationship to therapeutic strategies. Histopathology reveals surfactant disruption, epithelial perturbation and sepsis, either as initiating factors or as secondary complications, which in turn increase the expression of cytokines that sequester and activate inflammatory cells, most notably, neutrophils. Concomitant release of reactive oxygen and nitrogen species subsequently modulates endothelial function. Together these events orchestrate the principal clinical manifestations of the syndrome, pulmonary edema and atelectasis. To better understand the gene-environmental interactions controlling this complex process, we examined the relative sensitivity of inbred mouse strains to acute lung injury induced by ozone, ultrafine PTFE, or fine particulate NiSO4 (0.2 microm MMAD, 15-150 microg/m3). Measuring survival time, protein and neutrophils in bronchoalveolar lavage, lung wet: dry weight, and histology, we found that these responses varied between inbred mouse strains, and susceptibility is heritable. To assess the molecular progression of NiSO4-induced acute lung injury, temporal relationships of 8734 genes and expressed sequence tags were assessed by cDNA microarray analysis. Clustering of co-regulated genes (displaying similar temporal expression patterns) revealed the altered expression of relatively few genes. Enhanced expression occurred mainly in genes associated with oxidative stress, anti-proteolytic function, and repair of the extracellular matrix. Concomitantly, surfactant proteins and Clara cell secretory protein mRNA expression decreased. Genome wide analysis of 307 mice generated from the backcross of resistant B6xA F1 with susceptible A strain identified significant linkage to a region on chromosome 6 (proposed as Aliq4) and suggestive linkages on chromosomes 1, 8, and 12. Combining of these QTLs with two additional possible modifying loci (chromosome 9 and 16) accounted for the difference in survival time noted in the A and B6 parental strains. Combining these findings with those of the microarray analysis has enabled prioritization of candidate genes. These candidates, in turn, can be directed to the lung epithelium in transgenic mice or abated in inducible and constitutive gene-targeted mice. Initial results are encouraging and suggest that several of these mice vary in their susceptibility to oxidant-induced lung injury. Thus, these combined approaches have led to new insights into functional genomics of lung injury and diseases.

Animals↗
PubMed2001

Pathogenomic mechanisms for particulate matter induction of acute lung injury and inflammation in mice.

To begin identifying genes controlling individual susceptibility to particulate matter, responses of inbred mouse strains exposed to nickel sulfate (NiSO4*) were compared with those of mice exposed to ozone (O3) or polytetrafluoroethylene (PTFE). The A strain was sensitive to NiSO4-induced lung injury (quantified by survival time), the C3H/He (C3) strain and several other strains were intermediate in their responses, and the C57BL/6 (B6) strain was resistant. The strains showed a pattern of response similar to the patterns of response to O3 and PTFE. The phenotype of A x B6 offspring (B6AF1) resembled that of the resistant B6 parental strain, with strains exhibiting sensitivity in the order A > C3 > B6 = B6AF1. Pathology was comparable for the A and B6 mice, and exposure to NiSO4 at 15 microg/m3 produced 20% mortality in A mice. Strain sensitivity for the presence of protein or neutrophils in lavage fluid differed from strain sensitivity for survival time, suggesting that they are not causally linked but are controlled by an independent gene or genes. In the B6 strain, exposure to nickel oxide (NiO) by instillation (40 to 1000 nm) or inhalation (50 nm) produced no changes, whereas inhalation of NiSO4 (60 or 250 nm) increased lavage proteins and neutrophils. Complementary DNA (cDNA) microarray analysis with 8,734 sequence-verified clones revealed a temporal pattern of increased oxidative stress, extracellular matrix repair, cell proliferation, and hypoxia, followed by a decrease in surfactant-associated proteins (SPs). Certain expressed sequence tags (ESTs), clustered with known genes, suggest possible coregulation and novel roles in pulmonary injury. Finally, locus number estimation (Wright equation) and a genomewide analysis suggested 5 genes could explain the survival time and identified significant linkage for a quantitative trait locus (QTL) on chromosome 6, Aliq4 (acute lung injury QTL4). Haplotype analysis identified an allelic combination of 5 QTLs that could explain the difference in sensitivity to acute lung injury between parental strains. Positional candidate genes for Aliq4 include aquaporin-1 (Aqp1), SP-B, and transforming growth factor-alpha (TGF-alpha). Transgenic mice expressing TGF-alpha were rescued from NiSO4 injury (that is, they had diminished SP-B loss and increased survival time). These findings suggest that NiSO4-induced acute lung injury is a complex trait controlled by at least 5 genes (all possibly involved in cell proliferation and surfactant function). Future assessment of these susceptibility genes (including evaluations of human synteny and function) could provide valuable insights into individual susceptibility to the adverse effects of particulate matter.

Air Pollutants↗
PubMed2000

Differential gene expression in the initiation and progression of nickel-induced acute lung injury.

Acute lung injury, an often fatal condition, can result from a wide range of insults leading to a complex series of biologic responses. Despite extensive research, questions remain about the interplay of the factors involved and their role in acute lung injury. We proposed that assessing the temporal and functional relationships of differentially expressed genes after pulmonary insult would reveal novel interactions in the progression of acute lung injury. Specifically, 8,734 sequence-verified murine complementary DNAs were analyzed in mice throughout the initiation and progression of acute lung injury induced by particulate nickel sulfate. This study revealed the expression patterns of genes previously associated with acute lung injury in relationship to one another and also uncovered changes in expression of a number of genes not previously associated with acute lung injury. The overall pattern of gene expression was consistent with oxidative stress, hypoxia, cell proliferation, and extracellular matrix repair, followed by a marked decrease in pulmonary surfactant proteins. Also, expressed sequence tags (ESTs), with nominal homology to known genes, displayed similar expression patterns to those of known genes, suggesting possible roles for these ESTs in the pulmonary response to injury. Thus, this analysis of the progression and response to acute lung injury revealed novel gene expression patterns.

Animals↗
PubMed1988

Bedside data system aids pharmacy.

The challenge of managing quality in the healthcare field is becoming increasingly difficult. New technology is now available that provides computerized record keeping in the patient-care area. These bedside information systems, also known as point-of-care systems, have many applications in hospital pharmacies, especially in relation to the administration of medications.

Colorado↗
PubMed1985

Ozone inhibits prostacyclin synthesis in pulmonary endothelium.

The effects of ozone on lung arachidonate metabolism in-vitro were studied in cultured bovine pulmonary endothelial cells exposed for 2 hours to ozone in concentrations up to 1.0 ppm. A concentration-dependent decrease in prostacyclin synthesis was found (90% decrease at the highest ozone level of 1.0 ppm). The inhibition of prostacyclin synthesis was not due to a decreased release of arachidonic acid from membrane lipids. We also examined the hypoxic pulmonary vasoconstrictive response to 10% oxygen inhalation in anesthetized dogs in-vivo after exposure to 1.0 ppm ozone for 1 hour. Pulmonary vascular resistance was significantly increased after ozone exposure, similar to the findings in dogs given indomethacin (15 mg/kg). The percentage change in the hypoxic pulmonary pressor response was similar between the ozone exposure and indomethacin-treated groups, although due to the variance of the pulmonary vascular resistance values during hypoxia the results did not reach statistical significance. These results suggest that ozone inhalation affects pulmonary endothelial arachidonate metabolism in-vivo as well as in-vitro.

Animals↗
PubMed1985

Management of hydrocephalus in infancy: use of acetazolamide and furosemide to avoid cerebrospinal fluid shunts.

Despite its effectiveness, cerebrospinal shunting for hydrocephalus continues to be accompanied by considerable complications and morbidity. Medical therapy with acetazolamide 100 mg/kg/day and furosemide 1 mg/kg/day can be an effective alternative to shunting by halting progression of hydrocephalus until such time as sutures can become fibrosed and spontaneous arrest can occur. In an appropriately selected population older than 2 weeks with hydrocephalus of varied origin, our success rate in avoiding shunting is greater than 50%. The dramatic difference between the number of hospitalizations of patients with shunts and those treated medically, and the potential to avoid shunt dependence would appear to make an initial trial with medical therapy worthwhile.

Acetazolamide↗
PubMed1985

Tubular proteinuria in children without other defects of renal function.

3 patients are described in whom proteinuria was detected on routine urine analysis and subsequently shown to be predominantly tubular in origin. Renal biopsies showed only minor changes. Hypercalciuria was also noted in 1 of the 3 patients but no other tubular abnormalities were demonstrated. The precise diagnosis remains uncertain, but an unusual presentation of idiopathic hypercalciuria or of the adult Fanconi syndrome must be considered. These patients may alternatively have a previously undescribed disorder.

Calcium↗
PubMedDate not supplied

Haloperidol, fluphenazine and clonidine in Tourette syndrome: controversies in treatment.

The value of haloperidol, fluphenazine and clonidine as therapeutic agents for Tourette's syndrome was retrospectively reviewed. Haloperidol improved tic symptoms in 50/60 patients, but side effects often nullified these benefits. Fluphenazine was an effective drug for tic suppression in 24/31 patients. Direct comparison of these drugs in 23 patients confirmed the efficacy of fluphenazine and showed it to produce fewer adverse effects than haloperidol. Clonidine was helpful in 47% and caused few side effects. These results support the use of clonidine for the treatment of tics and suggest that fluphenazine can be considered an alternative to other neuroleptic drugs.

Child↗