Biomedical subjects

K K Brown

Publications and source records attributed to K K Brown.

At least 19 recordsLinked to original sources

PubMed2007

Organizing pneumonia and lymphoplasmacytic inflammation predict treatment response in idiopathic pulmonary fibrosis.

AIMS: To identify individual histopathological features within usual interstitial pneumonia pattern that predict responsiveness to immunosuppressive therapy. METHODS AND RESULTS: Fifty-six retrospectively confirmed usual interstitial pneumonia pattern surgical lung biopsy specimens from subjects with idiopathic pulmonary fibrosis treated with corticosteroid and cytotoxic therapy were included. Eleven prospectively defined histopathological features were evaluated by two expert pulmonary pathologists. Regression analysis identified predictors of response to therapy, as defined by the change in percent predicted forced vital capacity over 6 months. Additional end-points were change in dyspnoea score over 6 months, and survival time. Improvement in percent predicted forced vital capacity was associated with lymphoplasmacytic inflammation, while worsening of percent predicted forced vital capacity was associated with the presence of organizing pneumonia and fibroblast foci. Worsening dyspnoea was associated with fibroblast foci. Survival time was associated with age and baseline percent predicted forced vital capacity, but not with any individual histopathological feature. CONCLUSIONS: In pathological usual interstitial pneumonia pattern, the presence of lymphoplasmacytic inflammation predicts responsiveness to immunomodulatory therapy, while airspace organization predicts lack of response.

Humans↗

PubMed2006

Lymphoid interstitial pneumonia: clinical features, associations and prognosis.

Lymphoid interstitial pneumonia (LIP) is rare and its clinical course incompletely described. The aim of this study was to examine the clinical features, associations and prognosis of surgical lung biopsy-proven LIP. The study group consisted of 15 subjects encountered over a 14-yr period. The majority of subjects were females (n = 11) and the mean age was 47 yrs (range 17-78 yrs). Underlying systemic immune disorders were frequent, including Sjögren's syndrome (n = 8), rheumatoid arthritis, systemic lupus erythematosus, polymyositis, common variable immunodeficiency and dysproteinaemia. Only three patients were classified as "idiopathic". Presenting symptoms were dominated by dyspnoea and cough. Restrictive physiology, reduced diffusion capacity (62.5+/-18.4% predicted) and bronchoalveolar lavage lymphocytosis (30.5+/-29.1% pred) were noted. Thirteen patients received corticosteroid therapy. Of the nine whose response could be assessed, four showed clinical improvement and four were stable. Overall, median survival was 11.5 yrs. Of the seven patients who died, respiratory problems were the primary cause of death in three. Conversion to lymphoma was not identified. In conclusion, histopathological lymphoid interstitial pneumonia is commonly associated with immune system dysregulation, with idiopathic lymphoid interstitial pneumonia being extremely rare. Clinical stability or improvement with corticosteroids can be expected; however, survival remains impaired.

Adolescent↗

PubMed2006

Comparison of the pharmacology of hydroxamate- and carboxylate-based matrix metalloproteinase inhibitors (MMPIs) for the treatment of osteoarthritis.

OBJECTIVE AND DESIGN: Hydroxamic-and carboxylic-acid based matrix metalloproteinase inhibitors (MMPIs) were compared for their potency against various MMPs, pharmacodynamic properties and in vivo efficacy in a model of cartilage degeneration. MATERIALS AND METHODS: The MMPIs were evaluated for their ability to inhibit human MMPs using the quenched fluorescence assay. The ability of the MMPIs to inhibit the degeneration of the knee joint was evaluated in rats injected intraarticularly with iodoacetate. The amount of MMPI in the plasma and cartilage was determined using liquid chromatography/mass spectrometry/mass spectrometry (LC/ MS/MS). Plasma protein binding was measured by ultrafiltration and unbound MMPI was quantitated using HPLC. RESULTS: The hydroxamic acid based inhibitor PGE-3321996 and the carboxylic acids PGE-2909492 and PGE-6292544 were potent MMP-13 inhibitors, but only the hydroxamic acid PGE 3321996 demonstrated significant inhibition of knee degeneration in the rat iodoacetate model. Both of the carboxylic acids demonstrated superior pharmacokinetic properties and established much higher plasma concentrations than the hydroxamic acid. However, neither of the carboxylic acids was detectable in the cartilage, whereas, the hydroxamic acid was present in both the cartilage and the plasma. The carboxylic acid based MMPIs also demonstrated higher plasma protein binding (>99%) than the hydroxamic acid (79%). CONCLUSIONS: Carboxylic acid-based MMPIs were identified that had superior in vivo plasma exposure compared to a hydroxamic acid inhibitor but lacked in vivo efficacy in the rat iodoacetate model of cartilage degeneration. The lack of in vivo efficacy of the carboxylic acid based MMPIs were probably due to their lack of cartilage penetration which was related to their physicochemical properties.

Amino Acids↗

PubMed2005

Small vessel vasculitis of the lung.

The diagnosis and management of SVV remains one of the most challenging clinical scenarios encountered by a clinician. Careful attention to detail and a thorough knowledge of the specific disorders, their therapies, and complications thereof is required to optimally care for these patients. The recent completion of a number of randomized, controlled, multicenter clinical trials has greatly improved our knowledge base and ability to care for vasculitis patient. The next decade holds even more promise.

Humans↗

PubMed2004

Detection of aggrecanase- and MMP-generated catabolic neoepitopes in the rat iodoacetate model of cartilage degeneration.

OBJECTIVE: To characterize the time course of aggrecan and type II collagen degradation in the rat iodoacetate model of cartilage degeneration in relationship to the temporal sequence that has been described in human osteoarthritis (OA). DESIGN: Rats were injected intra-articularly in one knee joint with iodoacetate and damage to the tibial plateau was assessed from digitized images captured using an image analyzer. The articular cartilage from the tibial plateau was harvested, extracted and glycosaminoglycan (GAG) content was measured using the dimethylmethylene blue (DMMB) assay. Cartilage aggrecan neoepitopes were detected in cartilage extracts by Western blotting using antibodies recognizing the aggrecanase-generated C-terminal neoepitope NITEGE (BC-13) and the MMP-generated C-terminal neoepitope DIPEN (BC-4). A type II collagen collagenase-generated neoepitope was detected in cartilage extracts by ELISA using the Col2-3/4Cshort antibody; denatured collagen was detected using the Col2-3/4m antibody. RESULTS: Degenerative joint changes and proteoglycan (GAG) loss progressed with time after iodoacetate injection. Western blotting of cartilage extracts of iodoacetate treated rats demonstrated an increase in both aggrecanase- and MMP-generated epitopes with the NITEGE aggrecanase neoepitope being significantly elevated on days 7, 14 and 21 while DIPEN the MMP neoepitope was significantly elevated on days 7 and 14. The type II collagen neoepitope recognized by Col2-3/4Cshort was significantly increased in cartilage extracts of rats at days 14 and 21 after iodoacetate injection. CONCLUSION: The proteoglycan fragments extracted from the knee cartilage of rats after the intra-articular injection of iodoacetate appeared to result from cleavage at both aggrecanase and MMP sites. Cleavage of type II collagen by collagenase was also detected after iodoacetate injection and occurred subsequent to the initiation of aggrecan loss. These observations serve to demonstrate similarities in the mechanisms of cartilage degeneration induced by iodoacetate to those seen in articular cartilage in OA.

Aggrecans↗

PubMed2004

Autologous biologicals--science/regulations.

There has been increased interest in Targeted Biologicals in the United States for several reasons. First, new technology is available to facilitate science-based isolate selection and manufacture. The science of Autologous/Targeted Biologicals will be discussed later in this presentation. A second reason for the increased interest in Targeted Biologicals is the fact that the livestock production methods have changed to favour herd/flock specific products controlled by a veterinarian. There have been changes in management methods such as segregated early weaning in swine, accelerated feeding and early weaning of dairy calves, and forced moulting in poultry. Herds and flocks have increased in stocking density and size. These factors stress animals and may facilitate mutation, strain variation and increased virulence of pathogens. Under these conditions, Traditional Biologicals may not be relevant to current field isolates. Many veterinarians favour vaccinating only for pathogens isolated from a herd/flock. A third reason for the increased interest in these products is that the licensing procedure for Targeted Biologicals is responsive to the needs of livestock producers. The process is abbreviated, requiring much less time and money. This allows for a more rapid response to emerging pathogens, strain variations and mutations, while facilitating the development of monovalent and multivalent products for limited markets or those for minor species.

Biological Products↗

PubMed2003

Procedure for the quantification of the biomarker (2-methoxyethoxy)acetic acid in human urine samples.

An accurate and precise procedure was developed for the detection and quantification of (2-methoxyethoxy)acetic acid (MEAA), a metabolite and biomarker for human exposure to 2-(2-methoxyethoxy)ethanol. The compound 2-(2-methoxyethoxy)ethanol has a wide array of industrial applications including its use as an additive in military jet fuel. Exposure to 2-(2-methoxyethoxy)ethanol is a health concern owing to its toxicity which includes developmental and teratogenic properties. Sample preparation consisted of liquid-liquid extraction (LLE) and esterification of MEAA to produce the ethyl ester. Measurement was by a gas chromatograph (GC) equipped with a mass selective detector (MSD) using a HP-1 capillary column. Recovery studies of spiked blank urine demonstrated good accuracy and precision; recovery varied between 95 and 103% with relative standard deviations of 8.6% and less. The limit of detection (LOD) for this procedure was found to range from 0.02 to 0.08 microg/ml equivalent levels of MEAA in urine. These data and other aspects of the validation of this procedure will be discussed.

Acetates↗

PubMed2003

Interferon-gamma for delayed pulmonary toxicity syndrome resistant to steroids.

Delayed pulmonary toxicity syndrome, characterized by interstitial pneumonia and pulmonary fibrosis, is common following high-dose bischloroethylnitrosourea (BCNU) (carmustine, [1,3-bis (2-chloroethyl)-1-nitrosourea]) containing chemotherapeutic regimens. Depending upon the treatment protocol, it may develop in over 70% of patients. Early and aggressive corticosteroid treatment leads to improvement in the majority of patients. However, up to 8% of affected patients may fail to respond to corticosteroids and develop progressive respiratory failure leading to death. No alternatives to corticosteroids have thus far been shown useful. We report the symptomatic and physiological improvement of a patient with severe steroid-resistant delayed pulmonary toxicity syndrome, following treatment with interferon-gamma.

Adrenal Cortex Hormones↗

PubMed2002

High-resolution CT features of severe asthma and bronchiolitis obliterans.

AIM: To evaluate the high-resolution CT findings of severe asthma (SA) and bronchiolitis obliterans (BO) and determine whether any reliable discriminating HRCT features exist. MATERIALS AND METHODS: HRCT examinations of the chest of 30 patients with SA and 14 patients with BO were analysed. Images were scored for the presence and extent of 21 CT findings. RESULTS: The most consistent HRCT features in SA were bronchial wall thickening in 30 (100%), expiratory air trapping in 19 of 22 examinations with expiratory images (87%), inspiratory decreased attenuation in 18 (60%), and bronchial luminal narrowing in 12 (40%). The most consistent HRCT features in BO were expiratory air trapping in 10 of 10 examinations with expiratory images (100%), bronchial wall thickening in 13 (93%), inspiratory decreased attenuation in 11 (79%), ground glass opacity in seven (50%), and mosaic pattern of attenuation in seven (50%). Decreased attenuation was more extensive in BO than in SA on both inspiratory and expiratory images. The mosaic pattern of attenuation was present in seven (50%) BO patients but in only one (3%) SA patients (P=0.0006). CONCLUSIONS: Mosaic pattern of attenuation, when present, is highly suggestive of BO, but SA and BO may be indistinguishable.

Acute Disease↗

PubMed2002

Induction of osteoarthritis in the rat by surgical tear of the meniscus: Inhibition of joint damage by a matrix metalloproteinase inhibitor.

OBJECTIVE: Characterize a model of osteoarthritis (OA) induced by a surgically transecting the medial collateral ligament and meniscus. Evaluate the effectiveness of a matrix metalloproteinase (MMP) inhibitor in this model. METHODS: The medial collateral ligament of the right knee of rats was transected and a single full thickness cut was made through meniscus. Rats were sacrificed at various times after the surgery to assess the severity of gross cartilage damage using an image analyser and microscopically by histology. The effect of an MMP inhibitor in this model was assessed by administering compound twice daily for the 21 days and evaluating gross and histological joint damage at day 21. The in vitro potency of the MMP inhibitor (MMPI) against a panel of human recombinant MMPs was assessed kinetically using a quenched fluorescent substrate. RESULTS: Surgical transection of the medial collateral ligament and meniscus resulted in a time dependent increase in the severity of the cartilage lesion (depth) as measured histologically but only a slight increase in the area of the lesion as assessed grossly by image analysis. Administration of a MMPI orally twice daily (b.i.d.) at 25mg/kg to rats in the meniscal tear model resulted in significant inhibition of cartilage degradation and osteophyte formation (total joint score) of 39+/-7% (mean+/-S.E.M., from four separate experiments). CONCLUSION: These results demonstrate that MMP inhibition is effective in reducing the joint damage that occurs in the meniscal tear model of OA and support a potential therapeutic role for MMP inhibition in the treatment of human OA.

Animals↗

PubMed2002

Obliterative bronchiolitis: varying presentations and clinicopathological correlation.

In obliterative bronchiolitis, inflammation and fibrosis lead to narrowing or occlusion of bronchiolar lumina. To determine how bronchiolar structural alterations relate to lung physiology, 19 patients with a pathological diagnosis of obliterative bronchiolitis were studied. The bronchiolar inflammatory and fibrotic features were correlated to the clinical presentation, and lung function tests. Eleven patients demonstrated airflow limitation, one had a restrictive pattern and one had a mixed pattern, two had isolated gas trapping, but four had normal spirometry. Mild-to-moderate bronchiolar inflammation was invariably present. It involved 60% of bronchioles subepithelially and 54% in the adventitia. Subepithelial fibrosis was observed in 15 patients and adventitial in 12. Adventitial bronchiolar inflammation correlated with forced expiratory volume in one second and forced vital capacity and inversely correlated with residual volume. Subepithelial fibrosis inversely correlated with subepithelial and adventitial inflammation. High-resolution computed tomography in 10 patients revealed inspiratory (five out of 10) and expiratory air trapping (five out of five), ground glass opacities (seven out of 10), bronchial wall thickening (five out of 10), bronchiectasis (two out of 10) and centrilobular nodules (two out of 10). The present study suggests that inflammation and fibrosis occurs in bronchioles at different time points in the disease process, or that there is no transition between these types of pathology in the same patient. No correlation was observed between the degree of bronchiolar fibrosis and the degree of airflow limitation.

Adult↗

PubMed2001

Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists.

Elevated levels of the hormone resistin, which is secreted by fat cells, are proposed to cause insulin resistance and to serve as a link between obesity and type 2 diabetes. In this report we show that resistin expression is significantly decreased in the white adipose tissue of several different models of obesity including the ob/ob, db/db, tub/tub, and KKA(y) mice compared with their lean counterparts. Furthermore, in response to several different classes of antidiabetic peroxisome proliferator-activated receptor gamma agonists, adipose tissue resistin expression is increased in both ob/ob mice and Zucker diabetic fatty rats. These data demonstrate that experimental obesity in rodents is associated with severely defective resistin expression, and decreases in resistin expression are not required for the antidiabetic actions of peroxisome proliferator-activated receptor gamma agonists.

Adipocytes↗

PubMed2001

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16alpha-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7alpha-hydroxylase (Cyp7a1) and the Na(+)-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

Animals↗

PubMed2001

Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors.

OBJECTIVE: To determine the effect of matrix metalloproteinase (MMP) inhibitors in mono-iodoacetate-induced arthritis in rats. DESIGN: The ability of compounds to inhibit MMPs in vitro was assessed kinetically using a quenched fluorescent substrate. Rats were injected with iodoacetate intraarticularly in one knee joint and damage to the tibial plateau was evaluated from digitized images captured using an image analyser and by histology. Collagenase and gelatinase activity in cartilage from iodoacetate injected knees were evaluated using(3)H-rat type I collagen and gelatin zymography, respectively. RESULTS: Collagenase and gelatinase activity significantly increased in the knee cartilage of rats injected with iodoacetate with peak activity by day 7. Three MMP inhibitors were examined for their efficacy in the rat iodoacetate-induced arthritis model. Significant (P< 0.05) inhibition of cartilage damage was observed in animals treated orally with 35 mg/kg b.i.d. of the three different MMP inhibitors. Inhibition of cartilage damage by the MMP inhibitors ranged from 36-42%. CONCLUSION: MMP inhibitors are partially protective against cartilage and subchondral bone damage induced by iodoacetate. These results support an important role for MMPs in mediating the joint damage in this model of arthritis.

Animals↗

PubMed2001

Acute interstitial pneumonitis: current understanding regarding diagnosis, pathogenesis, and natural history.

Acute interstitial pneumonitis (AIP) is a fulminant disease culminating in acute respiratory failure and often death. Originally described in 1935 by the pathologists Hamman and Rich, this rare syndrome is characterized by rapidly progressive pulmonary fibrosis, leading to frequent confusion with idiopathic pulmonary fibrosis. In fact, the eponym Hamman-Rich syndrome became synonymous with idiopathic pulmonary fibrosis despite clear differences in clinical presentation, radiography, pathology, and survival. In 1986, Katzenstein described eight patients with acute respiratory failure of unknown etiology. On biopsy, organizing diffuse alveolar damage was present in all specimens. Given the idiopathic nature of the disease, Katzenstein coined the phrase acute interstitial pneumonitis to distinguish it from the fibroproliferative stage of the acute respiratory distress syndrome (ARDS), which has an identical pathology. Olson et al retrospectively examined Hamman and Rich's original cases, compared them to contemporary cases of AIP, and found the two identical. Since then, little progress into understanding this disease has been made. Many questions still linger regarding the epidemiology, pathogenesis, and outcome. We recently published our experience with AIP providing new information regarding natural history. This review summarizes the current literature on AIP emphasizing diagnostic criteria, pathogenesis, and natural history.

Journal Article↗

PubMed2001

Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPAR gamma ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPAR gamma in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPAR gamma activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPAR gamma agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPAR gamma-mediated increases in glucose utilization in muscle. In liver, PPAR gamma activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPAR gamma agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.

Adipose Tissue↗

PubMed2001

Mitochondrial disease: a pulmonary and critical-care medicine perspective.

The clinical spectrum of mitochondrial diseases has expanded dramatically in the last decade. Abnormalities of mitochondrial function are now thought to participate in a number of common adult diseases, ranging from exercise intolerance to aging. This review outlines the common presentations of mitochondrial disease in ICUs and in the outpatient setting and discusses current diagnostic and therapeutic options as they pertain to the pulmonary and critical-care physician.

Adult↗

PubMed2000

Role of p38 mitogen-activated protein kinase in a murine model of pulmonary inflammation.

Early inflammatory events include cytokine release, activation, and rapid accumulation of neutrophils, with subsequent recruitment of mononuclear cells. The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway plays a central role in regulating a wide range of inflammatory responses in many different cells. A murine model of mild LPS-induced lung inflammation was developed to investigate the role of the p38 MAPK pathway in the initiation of pulmonary inflammation. A novel p38 MAPK inhibitor, M39, was used to determine the functional consequences of p38 MAPK activation. In vitro exposure to M39 inhibited p38 MAPK activity in LPS-stimulated murine and human neutrophils and macrophages, blocked TNF-alpha and macrophage inflammatory protein-2 (MIP-2) release, and eliminated migration of murine neutrophils toward the chemokines MIP-2 and KC. In contrast, alveolar macrophages required a 1000-fold greater concentration of M39 to block release of TNF-alpha and MIP-2. Systemic inhibition of p38 MAPK resulted in significant decreases in the release of TNF-alpha and neutrophil accumulation in the airspaces following intratracheal administration of LPS. Recovery of MIP-2 and KC from the airspaces was not affected by inhibition of p38 MAPK, and accumulation of mononuclear cells was not significantly reduced. When KC was instilled as a proinflammatory stimulus, neutrophil accumulation was significantly decreased by p38 MAPK inhibition independent of TNF-alpha or LPS. Together, these results demonstrate a much greater dependence on the p38 MAPK cascade in the neutrophil when compared with other leukocytes, and suggest a means of selectively studying and potentially modulating early inflammation in the lung.

Aminopyridines↗