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Biomedical subjects

K M Brown

Publications and source records attributed to K M Brown.

At least 19 recordsLinked to original sources
PubMed2003

Life threatening haemorrhage after anterior needle aspiration of pneumothoraces. A role for lateral needle aspiration in emergency decompression of spontaneous pneumothorax.

Needle aspiration is a recognised emergency treatment of spontaneous pneumothorax and in the case of suspected tension is usually performed before chest radiography. Three cases are described of apparent life threatening haemorrhage after anterior aspiration in the second intercostal space, mid-clavicular line (2ICS MCL) requiring resuscitation, and transfer to a cardiothoracic unit. In these patients there was no evidence of haemothorax on initial presentation. Lateral needle aspiration, in the site recommended for chest drain insertion, the 5th intercostal space, anterior axillary line (5ICS ALL) is technically easy and may be a potentially safer option for decompressing pneumothoraces.

Adult↗
PubMed2002

No missense mutation of WKL1 in a subgroup of probands with schizophrenia.

Recently, a Leu309Met mutation in WKL1 (MLC1, KIAA0027), a gene mapped to chromosome 22q13.33, was reported to co-segregate with periodic catatonia, a clinical sub-type of schizophrenia, in seven members of an extended pedigree.(1) WKL1 encodes a putative membrane protein expressed exclusively in the brain, particularly in the amygdala, nucleus caudatus, thalamus, and hippocampus.(1) We screened WKL1 for etiologic mutations in 28 probands from the United States who were given a consensus diagnosis of schizophrenia and met at least one of these criteria: (1) were from multiplex schizophrenia families where at least two schizophrenic subjects were reported to display catatonic behavior at sometime during the course of their illness; or (2) were from multiplex schizophrenia families where, in a genome scan for schizophrenia susceptibility loci, evidence for excess allele sharing among affected family members for markers in the 22q13 region was seen. In addition, 15 affected subjects from 15 German pedigrees were similarly screened for causative mutations. This German cohort exhibited the catatonia phenotype but had ambiguous linkage to 22q13 and included the mutation-positive proband as a positive control. The 43 probands were screened for base changes in WKL1: 15 SNPs in the non-coding regions of the gene, three SNPs in the 3'UTR, four synonymous coding SNPs and two non-synonymous (amino acid changing) SNPs were identified. We were able to rapidly confirm the Leu309Met nucleotide change in the positive control. No missense mutations were detected in any of the other 42 probands studied. These data exclude the role of WKL1 in schizophrenia susceptibility in the subjects studied.

Adolescent↗
PubMed2001

Modification of the beta 2-adrenergic receptor to engineer a receptor-effector complex for gene therapy.

Depressed G-protein-coupled receptor (GPCR) signaling has been implicated as a component of the pathophysiology of a number of complex diseases including heart failure and asthma, and augmentation or restoration of signaling by various means has been shown to improve organ function. Because some properties of native GPCRs are disadvantageous for ectopic therapeutic expression, we utilized the beta(2)-adrenergic receptor (beta(2)AR) as a scaffold to construct a highly modified therapeutic receptor-effector complex (TREC) suitable for gene therapy. Altogether, 19 modifications were made to the receptor. The ligand-binding site was re-engineered in TM-3 so that a beta-hydroxylmethyl side chain acts as a proton donor for the binding of a novel ligand. In addition, sites critical for agonist-promoted down-regulation in the amino terminus and for phosphorylation by GPCR kinases, and protein kinases A and C, in the third intracellular loop and the carboxyl terminus of the receptor were altered. These modifications of the receptor resulted in depressed agonist-stimulated adenylyl cyclase activity (26.8 +/- 2.1 versus 41.4 +/- 8 pmol/min/mg for wild-type beta(2)AR). This was fully restored by fusing the carboxyl terminus of the modified receptor to G alpha(s) (43.3 +/- 2.7 pmol/min/mg). The fully modified fused receptor was not activated by beta-agonists but rather by a nonbiogenic amine agonist that itself failed to activate the wild-type beta(2)AR. This two-way selectivity thus provides targeted activation based on physiologic status. Furthermore, the TREC did not display tachyphylaxis to prolonged agonist exposure (desensitization was 1 +/- 5% versus 55 +/- 4% for wild-type beta(2)AR). Thus, despite extensive alterations in regions of conformational lability, the beta(2)AR can be tailored to have optimal signaling characteristics for gene therapy. As a general paradigm, TRECs for enhancement of other G-protein signaling appear to be feasible for modification of other pathologic states.

Animals↗
PubMed2001

Aminopeptidase from Sphingomonas capsulata.

A novel aminopeptidase with unique substrate specificity was purified from a culture broth of Sphingomonas capsulata. This is the first reported aminopeptidase to demonstrate broad substrate specificity and yet release glycine and alanine with the highest efficacy. On a series of pentapeptide amides with different N-terminal amino acids, this enzyme efficiently releases glycine, alanine, leucine, proline, and glutamate with the lowest turnover value of 370 min(-1) for glutamate. At pH 7.5 (pH optimum) and 25 degrees C, the kinetic parameters for alanine para-nitroanilide were found to be k(cat) = 7600 min(-1) and K(m) = 14 mm. For alanine beta-naphthylamide, they were k(cat) = 860 min(-1) and K(m) = 6.7 mm. Polymerase chain reaction primers were designed based upon obtained internal sequences of the wild type enzyme. The subsequent product was then used to acquire the full-length gene from an S. capsulata genomic library. An open reading frame encoding a protein of 670 amino acids was obtained. The translated protein has a putative signal peptide that directs the enzyme into the supernatant. A search of the amino acid sequence revealed no significant homology to any known aminopeptidases in the available data bases.

Amino Acid Sequence↗
PubMed2001

Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.

BACKGROUND: Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). METHODS AND RESULTS: In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. CONCLUSIONS: Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.

Base Sequence↗
PubMed2001

Severe autosomal recessive rippling muscle disease.

Rippling muscle disease (RMD) has previously been reported as a skeletal myopathy that was attributed to a defect in the sarcomere. Here we report a new form of RMD that is more severe, characterized by fatal arrhythmic cardiomyopathy and delayed bone age. Mortality has previously not been associated with RMD. With this report we hope to raise awareness that a subset of patients with this clinical entity are predisposed to severe cardiac disease.

Adolescent↗
PubMed2001

Managing birds and controlling aircraft in the kennedy airport-jamaica bay wildlife refuge complex: the need for hard data and soft opinions.

During the 1980s, the exponential growth of laughing gull (Larus atricilla) colonies, from 15 to about 7600 nests in 1990, in the Jamaica Bay Wildlife Refuge and a correlated increase in the bird-strike rate at nearby John F. Kennedy International Airport (New York City) led to a controversy between wildlife and airport managers over the elimination of the colonies. In this paper, we review data to evaluate if: (1) the colonies have increased the level of risk to the flying public; (2) on-colony population control would reduce the presence of gulls, and subsequently bird strikes, at the airport; and (3) all on-airport management alternatives have been adequately implemented. Since 1979, most (2987, 87%) of the 3444 bird strikes (number of aircraft struck) were actually bird carcasses found near runways (cause of death unknown but assumed to be bird strikes by definition). Of the 457 pilot-reported strikes (mean = 23 +/- 6 aircraft/yr, N = 20 years), 78 (17%) involved laughing gulls. Since a gull-shooting program was initiated on airport property in 1991, over 50,000 adult laughing gulls have been killed and the number of reported bird strikes involving laughing gulls has declined from 6.9 +/- 2.9 (1983-1990) to 2.6 +/- 1.3 (1991-1998) aircraft/yr; nongull reported bird strikes, however, have more than doubled (6.4 +/- 2.6, 1983-1990; 14.9 +/- 5.1, 1991-1998). We found no evidence to indicate that on-colony management would yield a reduction of bird strikes at Kennedy Airport. Dietary and mark-recapture studies suggest that 60%-90% of the laughing gulls collected on-airport were either failed breeders and/or nonbreeding birds. We argue that the Jamaica Bay laughing gull colonies, the only ones in New York State, should not be managed at least until all on-airport management alternatives have been properly implemented and demonstrated to be ineffective at reducing bird strikes, including habitat alterations and increasing the capability of the bird control unit to eliminate bird flocks on-airport using nonlethal bird dispersal techniques. Because the gull-shooting program may be resulting in a nonsustainable regional population of laughing gulls (>30% decline), we also recommend that attempts be made to initiate an experimental colony elsewhere on Long Island to determine if colony relocation is a feasible management option.

Accidents, Aviation↗
PubMed2001

Vacuum-assisted closure in the treatment of a 9-year-old child with severe and multiple dog bite injuries of the thorax.

The vacuum-assisted closure (VAC; KCI International, San Antonio, TX) device is a negative pressure dressing, which we have used in the treatment of wounds with devitalized or infected tissues. Although introduced in plastic and reconstructive surgery, its use has extended to orthopedic and cardiothoracic surgical practice in the treatment of infected joint replacement and sternal wound infections, respectively. Although the VAC is becoming more widely used in surgical practice, only a small number of case reports exist in addition to the original case series by Argenta and Morykwas in 1997. Previously, the device was described in treating single wounds in adult patients. We report a case where it was successfully used to treat multiple dog bite injuries in a 9-year-old child.

Animals↗
PubMed2001

Intraluminal biopsy of a superior vena cava mass.

A number of methods have been devised for the biopsy of intracaval tumour masses but all risk damage to the cava and tumour dissemination. We report on a case in which the tumour mass was almost entirely within the superior vena cava and describe an 'endoscopic' technique for biopsy.

Biopsy↗
PubMed2001

The effects of stress, anxiety, and outdoor temperature on the frequency and severity of Raynaud's attacks: the Raynaud's Treatment Study.

It was expected that stress and anxiety would be related to Raynaud's phenomenon (RP) attack characteristics when mild outdoor temperatures produced partial or no digital vasoconstriction. Hypotheses were that in warmer temperature categories, compared to those below 40 degrees F, higher stress or anxiety would be associated with more frequent, severe, and painful attacks. The Raynaud's Treatment Study recruited 313 participants with primary RP. Outcomes were attack rate, severity, and pain. Predictors were average daily outdoor temperature, stress, anxiety, age, gender, and a stress-by-temperature or an anxiety-by-temperature interaction. Outcomes were tested separately in multiple linear regression models. Stress and anxiety were tested in separate models. Stress was not a significant predictor of RP attack characteristics. Higher anxiety was related to more frequent attacks above 60 degrees F. It was also related to greater attack severity at all temperatures, and to greater pain above 60 degrees F and between 40 degrees and 49.9 degrees F.

Adult↗
PubMed2001

The Raynaud's Treatment Study: biofeedback protocols and acquisition of temperature biofeedback skills.

The Raynaud's Treatment Study (RTS) compared temperature biofeedback training and a behavioral control procedure (frontalis EMG biofeedback) with nifedipine-XL and a medication placebo for treatment of primary Raynaud's phenomenon (RP) in a large (N = 313) multicenter trial. The present study describes the RTS biofeedback protocols and presents data on the acquisition of digital skin temperature and frontalis EMG responses in the RTS. The findings point to substantial problems with acquisition of physiological self-regulation skills in the RTS. Only 34.6% of the Temperature Biofeedback group (N = 81) and 55.4% of the EMG Biofeedback group (N = 74) successfully learned the desired physiological response. In contrast, 67.4% of a Normal Temperature Biofeedback group (N = 46) learned hand warming. Multivariate analysis found that coping strategies, anxiety, gender, and clinic site predicted acquisition of hand-warming skills whereas variables related to RP disease severity did not. Physiological data showed vasoconstriction in response to the onset of biofeedback and also found that performance in the initial sessions was critical for successful acquisition. These findings indicate that attention to the emotional and cognitive aspects of biofeedback training, and a degree of success in the initial biofeedback sessions, are important for acquisition.

Adult↗
PubMed2001

Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease.

Little is known about the genetic regulation of medulloblastoma dissemination, but metastatic medulloblastoma is highly associated with poor outcome. We obtained expression profiles of 23 primary medulloblastomas clinically designated as either metastatic (M+) or non-metastatic (M0) and identified 85 genes whose expression differed significantly between classes. Using a class prediction algorithm based on these genes and a leave-one-out approach, we assigned sample class to these tumors (M+ or M0) with 72% accuracy and to four additional independent tumors with 100% accuracy. We also assigned the metastatic medulloblastoma cell line Daoy to the metastatic class. Notably, platelet-derived growth factor receptor alpha (PDGFRA) and members of the downstream RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway are upregulated in M+ tumors. Immunohistochemical validation on an independent set of tumors shows significant overexpression of PDGFRA in M+ tumors compared to M0 tumors. Using in vitro assays, we show that platelet-derived growth factor alpha (PDGFA) enhances medulloblastoma migration and increases downstream MAP2K1 (MEK1), MAP2K2 (MEK2), MAPK1 (p42 MAPK) and MAPK3 (p44 MAPK) phosphorylation in a dose-dependent manner. Neutralizing antibodies to PDGFRA blocks MAP2K1, MAP2K2 and MAPK1/3 phosphorylation, whereas U0126, a highly specific inhibitor of MAP2K1 and MAP2K2, also blocks MAPK1/3. Both inhibit migration and prevent PDGFA-stimulated migration. These results provide the first insight into the genetic regulation of medulloblastoma metastasis and are the first to suggest a role for PDGFRA and the RAS/MAPK signaling pathway in medulloblastoma metastasis. Inhibitors of PDGFRA and RAS proteins should therefore be considered for investigation as possible novel therapeutic strategies against medulloblastoma.

Butadienes↗
PubMed2001

A novel carbohydrate:acceptor oxidoreductase from Microdochium nivale.

A Microdochium nivale carbohydrate:acceptor oxidoreductase was purified, cloned, heterologously expressed, and characterized. The gene encoding the protein showed one intron, and the ORF showed a sequence with low homology (< or = 25% identity or 65% similarity) to other known flavin-containing carbohydrate oxidases. The maturation of the protein required the cleavage of a tetrameric propeptide in addition to an 18 amino-acid signal peptide. The enzyme was found to have a relative molecular mass of 55 000 Da, an isoelectric point of 9, and one FAD per protein. It could oxidize mono-, oligo-, or polymeric saccharides, and transfer their electrons to O2 or other acceptors. When D-glucose served as electron-donating substrate, an activity of 2 s(-1) was observed at pH 5.5 and 23 degrees C. Among various oligosaccharides, the enzyme preferred tetrameric dextrins, indicating a favorable interaction of four linked glucose units with the substrate pocket. The unique structure and ability of oxidizing oligo/polymeric saccharides suggest a promising prospect of this enzyme for various industrial/medicinal applications.

Alcohol Oxidoreductases↗
PubMed2001

Selenium, selenoproteins and human health: a review.

Selenium is of fundamental importance to human health. It is an essential component of several major metabolic pathways, including thyroid hormone metabolism, antioxidant defence systems, and immune function. The decline in blood selenium concentration in the UK and other European Union countries has therefore several potential public health implications, particularly in relation to the chronic disease prevalence of the Western world such as cancer and cardiovascular disease. Ten years have elapsed since recommended dietary intakes of selenium were introduced on the basis of blood glutathione peroxidase activity. Since then 30 new selenoproteins have been identified, of which 15 have been purified to allow characterisation of their biological function. The long term health implications in relation to declining selenium intakes have not yet been thoroughly examined, yet the implicit importance of selenium to human health is recognised universally. Selenium is incorporated as selenocysteine at the active site of a wide range of selenoproteins. The four glutathione peroxidase enzymes (classical GPx1, gastrointestinal GPx2, plasma GPx3, phospholipid hydroperoxide GPx4)) which represent a major class of functionally important selenoproteins, were the first to be characterised. Thioredoxin reductase (TR) is a recently identified seleno-cysteine containing enzyme which catalyzes the NADPH dependent reduction of thioredoxin and therefore plays a regulatory role in its metabolic activity. Approximately 60% of Se in plasma is incorporated in selenoprotein P which contains 10 Se atoms per molecule as selenocysteine, and may serve as a transport protein for Se. However, selenoprotein-P is also expressed in many tissues which suggests that although it may facilitate whole body Se distribution, this may not be its sole function. A second major class of selenoproteins are the iodothyronine deiodinase enzymes which catalyse the 5'5-mono-deiodination of the prohormone thyroxine (T4) to the active thyroid hormone 3,3'5-triiodothyronine (T3). Sperm capsule selenoprotein is localised in the mid-peice portion of spermatozoa where it stabilises the integrity of the sperm flagella. Se intake effects tissue concentrations of selenoprotein W which is reported to be necessary for muscle metabolism. It is of great concern that the health implications of the decline in Se status in the UK over the past two decades have not been systematically investigated. It is well recognised that dietary selenium is important for a healthy immune response. There is also evidence that Se has a protective effect against some forms of cancer; that it may enhance male fertility; decrease cardiovascular disease mortality, and regulate the inflammatory mediators in asthma. The potential influence of Se on these chronic diseases within the European population are important considerations when assessing Se requirement.

Glutathione Peroxidase↗
PubMed2001

Effects of beta-estradiol and bisphenol A on heat shock protein levels and localization in the mouse uterus are antagonized by the antiestrogen ICI 182,780.

Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these can be attenuated by antiestrogens. This suggests the involvement of alternate pathways of BPA action that do not involve the estrogen receptor (ER). An examination of the in vivo effects of BPA on uterine gene expression and protein levels should contribute to an understanding of its mechanism of action. In this study we examined the dose-related effects of BPA on levels of a suite of heat shock proteins (hsps) and on the localization of hsp90alpha, a chaperone of the ER, in uteri of ovariectomized B6C3F1 mice and compared these effects with those of beta-estradiol (E2). The antiestrogen ICI 182,780 (ICI) was co-administered with BPA or E2 in order to examine the potential role of the ER. BPA, although less potent than E2, increased hsp90alpha and grp94 to similar levels, but was much less effective than E2 in increasing levels of hsp72. Treatment with 100 mg BPA/kg/day or 2 microg E2/kg/day increased hsp90alpha to 300% of control levels and altered its tissue expression pattern. In uteri of corn oil (control)-treated mice, hsp90alpha predominantly localized in the cytoplasm and nuclei of epithelial cells. Upon treatment with BPA or E2 there was increased intensity of staining in the stroma and myometrium, and in the epithelium hsp90alpha was localized almost exclusively in the cytoplasm. The effects of BPA or E2 on hsp levels and hsp90alpha localization were attenuated by ICI. These results suggest an involvement of the ER in BPA- and E2-induced increases in uterine levels of hsp90alpha, grp94, and hsp72, and localization of hsp90alpha.

Animals↗
PubMed2001

Bupropion sustained release in adolescents with comorbid attention-deficit/hyperactivity disorder and depression.

OBJECTIVE: To determine whether bupropion sustained release (SR) is effective and well-tolerated in adolescents with comorbid attention-deficit/hyperactivity disorder (ADHD) and depression. METHOD: Subjects were 24 adolescents (aged 11-16 years old) with ADHD and either major depressive disorder or dysthymic disorder. After a 2-week, single-blind placebo lead-in, subjects were treated for 8+ weeks with bupropion SR at doses flexibly titrated up to 3 mg/kg b.i.d. (mean final doses: 2.2 mg/kg q A.M. and 1.7 mg/kg q P.M.). Outcomes were global improvement in ADHD and depression (clinician-rated), along with changes in depressive symptomatology (parent- and child-rated), ADHD symptomatology (parent- and teacher-rated), and functional impairment (parent-rated). RESULTS: Clinicians rated 14 subjects (58%) responders in both depression and ADHD, 7 (29%) responders in depression only, and 1 (4%) a responder in ADHD only. Compared with post-placebo ratings, final parents' (p < .0005) and children's (p = .016) ratings of depressive symptomatology improved significantly, as did parents' (p < .0005) but not teachers' (p = .080) ratings of ADHD symptomatology. Final ratings of functional impairment improved significantly from enrollment (p < .0005). No subject discontinued medication because of side effects. CONCLUSIONS: Bupropion SR may be effective and well-tolerated in adolescents with comorbid ADHD and depressive disorders. However, randomized, placebo-controlled studies are needed.

Administration, Oral↗