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Biomedical subjects

R Armstrong

Publications and source records attributed to R Armstrong.

At least 37 records · Page 2Linked to original sources
PubMed1998

Healing bone using recombinant human bone morphogenetic protein 2 and copolymer.

Middiaphyseal 2.5-cm segmental defects in the right femurs of 12 sheep were stabilized with stainless steel plates and implanted with (1) 2 mg recombinant human bone morphogenetic protein 2 and poly[D,L-(lactide-co-glycolide)] bioerodible polymer with autologous blood (n = 7), (2) 4 mg recombinant human bone morphogenetic protein 2 and poly[D,L-(lactide-co-glycolide)] and blood (n = 3), or (3) poly[D,L-(lactide-co-glycolide)] and blood only (n = 2). Bone healing was evaluated for 1 year using clinical, radiographic, gross pathologic, and histologic techniques. Union occurred in three sheep in Group 1, two in Group 2, and none in Group 3. In the animals that healed, new bone first was visible radiographically between Weeks 2 and 6 after implantation; new bone mineral content equaled that of the intact femur not surgically treated by Week 16; recanalization of the medullary cavity approached completion at Week 52; and at necropsy the surgical treated femurs were rigidly healed, the poly[D,L-(lactide-co-glycolide)] was resorbed completely, and woven and lamellar bone bridged the defect site. In two Group 1 sheep euthanized at Weeks 2 and 6, polymer particles were permeated by occasional multinucleated giant cells. Some plasma cells, lymphocytes, and neutrophils were present locally. The poly[D,L-(lactide-co-glycolide)] tended to fragment during surgical implantation. Despite these observations, the recombinant human bone morphogenetic protein 2/poly[D,L-(lactide-co-glycolide)] implant was able to heal large segmental bone defects in this demanding model.

Animals↗
PubMed1997

Arteritis and increased intracellular calcium as a possible mechanism for tacrolimus-related cardiac toxicity in a pediatric transplant recipient.

We recently reported partially to wholly reversible hypertrophic cardiomyopathy, including severe hypertrophic obstructive cardiomyopathy, as a side effect in pediatric transplant recipients receiving tacrolimus immunosuppression. This seemed to be dose related. We describe a pediatric patient receiving tacrolimus who died 3 weeks after liver/bowel transplantation. Postmortem findings revealed arteritis of cardiac arteries and extensive calcification of cardiac tissue suggesting a possible mechanism of tacrolimus cardiac toxicity. This is consistent with recent reports of tacrolimus increasing calcium release into the sarcoplasmic reticulum of cardiac and striated muscle.

Arteritis↗
PubMed1997

Expression of human cathepsin K in Pichia pastoris and preliminary crystallographic studies of an inhibitor complex.

Cathepsin K is a cysteine protease of the papain family, which is predominantly expressed in osteoclasts, and is regarded as a key protease in bone remodeling. To facilitate structural studies of the protein, the wild-type sequence of the protease has been mutated so as to replace a potential N-glycosylation site. We have expressed the mutant human cathepsin K to 190 mg/5 L using the Pichia pastoris expression system. Cathepsin K was inactivated with the mechanism-based inhibitor, APC3328, and crystallized from magnesium formate. A 2.2 A X-ray data set has been collected on crystals belonging to space group P2(1)2(1)2(1), with a = 41.66 A, b = 51.41 A, and c = 107.72 A. There is most likely one molecule per asymmetric unit.

Cathepsin K↗
PubMed1997

Postoperative Serratia marcescens wound infections traced to an out-of-hospital source.

From 25 August to 28 September 1994, 7 cardiovascular surgery (CVS) patients at a California hospital acquired postoperative Serratia marcescens infections, and 1 died. To identify the outbreak source, a cohort study was done of all 55 adults who underwent CVS at the hospital during the outbreak. Specimens from the hospital environment and from hands of selected staff were cultured. S. marcescens isolates were compared using restriction-endonuclease analysis and pulsed-field gel electrophoresis. Several risk factors for S. marcescens infection were identified, but hospital and hand cultures were negative. In October, a patient exposed to scrub nurse A (who wore artificial fingernails) and to another nurse-but not to other identified risk factors-became infected with the outbreak strain. Subsequent cultures from nurse A's home identified the strain in a jar of exfoliant cream. Removal of the cream ended the outbreak. S. marcescens does not normally colonize human skin, but artificial nails may have facilitated transmission via nurse A's hands.

Adult↗
PubMed1997

Treatment strategies for lower third molars following orthodontic care.

To examine the extent to which orthodontists consider it appropriate to refer post-orthodontic patients for lower third molar treatment. The subjects were 10 orthodontists from hospital, specialist practice and community setting. Participants were presented with 15 case histories of orthodontic patients (including full records) and asked to state whether they would have referred the case to an oral surgeon for management of their third molars. Data were analysed using multi-kappa measure. Two-hundred-and-sixty-two decisions of 300 (88%) were not to refer cases for third molar management. Little consensus was seen between orthodontists on which post-orthodontic cases referral (kappa = 0.14). Some clinicians referred cases much more frequently than others (Kruskall-Wallis = 46.84, P < 0.001) and some clinicians referred much more frequently (Kruskall-Wallis = 85.57, P < 0.001). This group of orthodontists did not refer post-orthodontic cases for third molar management and little consensus was observed regarding which cases did warrant removal.

Adolescent↗
PubMed1997

Occupational asthma in New Zealanders: a population based study.

OBJECTIVES: To examine the effect of occupation on respiratory symptoms in a randomly selected adult population aged 20-44 years. METHODS: It is based on the phase II sampling of the New Zealand part of the European Community respiratory health survey. 1609 people (63.9% response rate) completed a detailed respiratory questionnaire. Of those responding, 1174 (73%) underwent skin tests and 1126 (70%) attended to undergo methacholine bronchial challenge. Current occupation was recorded and a previous occupation was also recorded if it had led to respiratory problems. 21 occupational groups were used for analysis for the five definitions of asthma wheezing in the previous 12 months; symptoms related to asthma; bronchial hyperresponsiveness (BHR); BHR with wheezing in the previous 12 months; and BHR with symptoms related to asthma. RESULTS: Prevalence odds ratios (ORs) were significantly increased for farmers and farm workers (OR 4.16, 95% confidence interval (95% CI) 1.33 to 13.1 for the combination of wheezing and BHR). Increased risks of prevalence of asthma were also found for laboratory technicians, food processors (other than bakers), chemical workers, and plastic and rubber workers. Workers had also been divided into high and low risk exposure categories according to relevant publications. The prevalence of wheezing was greater in the high risk group (OR 1.57, 95% CI 0.83 to 2.95) than in the low risk group. Atopy was associated with asthma, but the prevalence of atopy did not differ significantly between occupational exposure groups. The attributable risk of wheezing that occurred after the age of 15 years and that was estimated to be due to occupational exposure (based on the defined high risk group) was 1.9%, but this increased to 3.1% when farmers and food processors (other than bakers) were also included in the high risk group. CONCLUSIONS: This population based study has identified certain occupations significantly associated with combinations of asthmatic symptoms and BHR.

Adult↗
PubMed1997

Chronic bronchitis, shortness of breath, and airway obstruction by occupation in New Zealand.

The objectives of this study were to measure the population prevalence of symptoms of chronic obstructive lung disease and mild airway obstruction and to compare these between occupational groups. There were 1,609 subjects (63.9% response rate) who completed a respiratory questionnaire. Of these, 1,132 (70.4%) underwent pulmonary function testing (FEV1 and FVC). Twenty-one categories of current occupation were used for analysis. Four definitions of chronic obstructive pulmonary disease (COPD) were used: (1) chronic bronchitis, (2) chronic bronchitis with airway obstruction, (3) shortness of breath, and (4) shortness of breath with airway obstruction. For chronic bronchitis, adjusted prevalence odds ratios were significantly elevated for food processors other than bakers (OR = 2.83; 95% CI, 1.27 to 6.29) and chemical processors (OR = 18.84; 3.71 to 95.64). The combination of chronic bronchitis and mild airway obstruction (FEV1/FVC < 0.75) was associated with bakers (OR = 25.5; 3.86 to 168.53) and spray painters (OR = 14.40; 2.85-72.69). Shortness of breath was associated with hairdressers (OR = 2.75; 0.80 to 9.42) and bakers (OR = 6.72; 0.57 to 79.66), and nursing was associated with lower levels of shortness of breath (OR = 0.42; 0.16 to 1.15). Working ever with vapors, gases, dust, or fumes was significantly associated with chronic bronchitis and airway obstruction (OR = 3.13; 1.07 to 9.12). This population-based study has identified certain occupations with increased prevalence of chronic bronchitis and COPD.

Adult↗
PubMed1996

Measurement of cardiac output with first-pass determination during rubidium-82 PET myocardial perfusion imaging.

In addition to providing useful clinical information, cardiac output determined during rubidium-82 positron emission tomographic (PET) myocardial perfusion studies can be used in the measurement of absolute regional myocardial blood flow using Sapirstein's method. This investigation was conducted to compare cardiac output values obtained by post-processing data acquired in a list mode PET myocardial perfusion study with those obtained using a technetium-99m-labeled red blood cell method on the same patients. Results from 14 patients showed that cardiac output can be accurately measured simultaneously in a 82Rb PET myocardial study, allowing determination of multiple perfusion and functional parameters of the heart, thus improving the cost-effectiveness of the 82Rb PET study.

Cardiac Output↗
PubMed1996

Regulation of somatostatin gene transcription by cyclic adenosine monophosphate.

Cyclic adenosine monophosphate (cAMP) stimulates transcription of somatostatin and other target genes with burst-attenuation kinetics. The kinetics of protein kinase (PK-A)-dependent cAMP response element binding protein (CREB) phosphorylation closely parallel the changes in transcription of cAMP-responsive genes by run-on assay. Nuclear translocation of PK-A, visualized by microinjection of fluorescently labeled PK-A holoenzyme, appears to represent the rate-limiting step in CREB phosphorylation and transcriptional activation. We and others have recently characterized a CREB-binding protein (CBP), which specifically recognizes sequences within the Ser133 phosphorylated form of CREB. CBP does not regulate the DNA binding, dimerization, or nuclear targeting properties of CREB, but binds selectively to the kinase-inducible 60 amino acid trans-activation domain (KID) of CREB, critical for PK-A-inducible transcription. We developed an antiserum directed against amino acid 634-648 within the CREB-binding domain of CBP. We detected a 265-kd polypeptide by Western blot as predicted from the cDNA, which coincided with the predominant phospho-CREB-binding activity in Hela nuclear extracts by "Far Western" blot assay. An identical phospho-CREB-binding activity was also found in NIH-3T3 cells. This phospho-CREB-binding protein appeared to be specific for Ser133-phosphorylated CREB, because no such band was detected with CREB labeled to the same specific activity at a nonregulatory phosphoacceptor site (Ser156) by casein kinase II (CKII). Following microinjection into nuclei of NIH-3T3 cells, a cAMP response element (CRE)-lacZ reporter was markedly induced by treatment with 8-Br cAMP plus isobutyl methyl xanthine (IBMX). Coinjection of CBP antiserum with the CRE-lacZ plasmid inhibited cAMP-dependent activity in a dose-dependent manner, but control immunoglobulin G (lgG) had no effect on this response. We can now begin reconstituting PK-A-dependent transcription in vitro, using well-characterized proteins such as CREB, TAF 110, and CBP. The assembly of such factors on cAMP-regulated promoters like somatostain may enable responsiveness to a variety of hormonal stimuli that employ cAMP as their second messenger.

3T3 Cells↗
PubMed1995

Mch3, a novel human apoptotic cysteine protease highly related to CPP32.

Recent evidence suggests that mammalian cysteine proteases related to Caenorhabditis elegans CED-3 are key components of mammalian programmed cell death or apoptosis. We have shown recently that the CPP32 and Mch2 alpha cysteine proteases cleave the apoptotic markers poly(ADP-ribose) polymerase (PARP) and lamins, respectively. Here we report the cloning of a new Ced-3/interleukin 1 beta-converting enzyme-related gene, designated Mch3, that encodes a protein with the highest degree of homology to CPP32 compared to other family members. An alternatively spliced isoform, named Mch3 beta, was also identified. Bacterially expressed recombinant Mch3 has intrinsic autocatalytic/autoactivation activity. The specific activity of Mch3 alpha toward the peptide substrate DEVD-7-amino-4-methylcoumarin and PARP resembles that of CPP32. Like interleukin 1 beta-converting enzyme and CPP32, the active Mch3 alpha is made of two subunits derived from a precursor (proMch3 alpha). It was of interest that recombinant CPP32-p17 subunit can form an active heteromeric enzyme complex with recombinant Mch3 alpha-p12 subunit and vice versa, as determined by the ability of the heteromeric complexes to induce apoptosis in Sf9 cells. These data suggest that proMch3 alpha and proCPP32 can interact to form an active Mch3 alpha/CPP32 heteromeric complex. We also provide evidence that CPP32 can efficiently cleave proMch3 alpha, but not the opposite, suggesting that Mch3 alpha activation in vivo may depend in part on CPP32 activity. The high degree of conservation in structure and specific activity and the coexistence of Mch3 alpha and CPP32 in the same cell suggests that the PARP cleavage activity observed during apoptosis cannot solely be attributed to CPP32 but could also be an activity of Mch3 alpha.

Alternative Splicing↗
PubMed1995

A K edge filter technique for optimization of the coherent-to-Compton scatter ratio method.

The ratio method involves forming the ratio of the elastic to inelastic x-ray scatter signals from a localized region of a scattering medium to determine its mean atomic number. An analysis is presented of two major error sources influencing the ratio method: firstly statistical (photon) noise and secondly multiple scattering and self-attenuation of the primary and scatter radiations in the medium. It is shown that a forward scattering geometry minimizes errors of both types for substances composed of elements with low and medium atomic number. However, owing to the small energy separation (approximately 100 eV) of coherent and Compton scatter for this geometry, they cannot be distinguished directly with semiconductor (e.g., Ge) detectors. A novel K edge filter technique is described which permits separation of the elastic and Compton signals in the forward-scatter geometry. The feasibility of this method is demonstrated by experimental results obtained with Ta fluorescence radiation provided by a fluorescent x-ray source filtered with an Er foil. The extension of this technique to the "in vivo" measurement of low momentum transfer inelastic scattering from biological tissues, possibly providing useful diagnostic information, is briefly discussed.

Biophysical Phenomena↗
PubMed1995

In vitro sulfotransferase activity of NodH, a nodulation protein of Rhizobium meliloti required for host-specific nodulation.

Early stages of nodulation involve the exchange of signals between the bacterium and the host plant. Bacterial nodulation (nod) genes are required for Rhizobium spp. to synthesize lipooligosaccharide morphogens, termed Nod factors. The common nod genes encode enzymes that synthesize the factor core structure, which is modified by host-specific gene products. Here we show direct in vitro evidence that Rhizobium meliloti NodH, a host-specific nodulation gene, catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate to the terminal 6-O position of Nod factors, and we show substrate requirements for the reaction. Our results indicate that polymerization of the chitooligosaccharide backbone likely precedes sulfation and that sulfation is not absolutely dependent on the presence or the particular structure of the N-acyl modification. NodH sulfation provides a tool for the enzymatic in vitro synthesis of novel Nod factors, or putative Nod factors intermediates, with high specific activity.

Bacterial Proteins↗
PubMed1995

A refractory phase in cyclic AMP-responsive transcription requires down regulation of protein kinase A.

Cyclic AMP (cAMP) stimulates the expression of numerous genes through the protein kinase A (PK-A)-mediated phosphorylation of the nuclear factor CREB at Ser-133 (G. A. Gonzalez and M. R. Montminy, Cell 59:675-680, 1989). Like other signal transduction pathways, cAMP induces gene expression with burst-attenuation kinetics; cAMP-dependent transcription and CREB phosphorylation peak within 30 min and decline steadily over the next 4 to 6 h via the protein phosphatase 1-mediated dephosphorylation of CREB (M. Hagiwara, A. Alberts, P. Brindle, J. Meinkoth, J. Feramisco, T. Deng, M. Karin, S. Shenolikar, and M. Montminy, Cell 70:105-113, 1992). Here we characterize a third phase in cAMP-responsive transcription--a refractory period during which hormone-treated cells become transcriptionally unresponsive to subsequent stimulation by cAMP. This refractory period begins 6 to 8 h after stimulation and lasts 3 to 5 days after the removal of hormone. In contrast to the earlier attenuation phase, transcription of cAMP-responsive genes during the refractory period is not restored by inhibitors of protein phosphatase 1 activity. Rather, the establishment and maintenance of this phase rely on a marked reduction in PK-A catalytic subunit expression at the translational level. As overexpression of C-subunit protein can reactive transcription of cAMP-responsive genes during the refractory period, our results suggest that hormone-responsive cells may stimulate, attenuate, and then silence signal-dependent genes through distinct regulatory mechanisms.

Animals↗