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Biomedical subjects

A Keller

Publications and source records attributed to A Keller.

At least 91 records · Page 5Linked to original sources
PubMed1998

Asthma management: the challenge of equivalence.

Increasing prevalence and severity of asthma worldwide encourage the development of new antiasthmatic drugs, alternative treatment regimens and improved formulations of established drugs. Whereas the efficacy of new chemical entities (NCEs) is usually demonstrated by superiority over placebo or a subtherapeutic dose of the active drug, equivalence concepts have to be used in the following situations: the need to replace chlorofluorocarbon (CFC) propellants for inhalative asthma medications by suitable alternatives, and the need to demonstrate that an alternative treatment regimen is not clinically inferior to an established reference treatment. To cover both situations, the recent ICH guidance on biostatistics clearly distinguishes between two-sided equivalence trials and one-sided non-inferiority trials. In this context, non-inferiority always means "not inferior by a clinically relevant amount". After having confirmed non-inferiority, superiority of the alternative test treatment over the reference treatment can additionally be tested without the need to adjust the significance level. The definition of equivalence acceptance limits becomes crucial, particularly in studies conducted in the flat range of the dose-response curve of inhaled steroids. In order to assess the non-inferiority of steroid sparing add-on treatments we propose a one-sided test based on post-/pre-ratios which have substantially reduced coefficients of variation compared to the post-treatment values themselves. The non-inferiority acceptance limit of 0.90 - as opposed to 0.80 in bioequivalence assessment - reflects clinically irrelevant changes of lung function variables. The proposed methodology is illustrated by 2 examples from randomized, double-blind, parallel-group studies comparing inhaled steroid plus theophylline versus doubling the steroid dose in asthmatics who are symptomatic on low-dose inhaled steroid.

Administration, Inhalation↗
PubMed1998

The ASE Web page.

Explore the source record for details and available documents.

Computer Communication Networks↗
PubMed1998

[Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma].

The anti-asthmatic effect of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 micrograms/day. The trial was designed as a randomized, double-blind, parallel-group study in several European countries. 69 patients were treated for 6 weeks with theophylline plus BDP 400 micrograms/day, compared to 64 patients treated with BDP 800 micrograms/day. The mean +/- SD serum theophylline concentration was 10.1 +/- 4.2 mg/l. Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow rate (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p < 0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p < 0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 micrograms/day and beclomethasone dipropionate 800 micrograms/day in patients whose asthma is not controlled on beclomethasone dipropionate 400 micrograms/d. The results support the use of theophylline as steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate asthma.

Adolescent↗
PubMed1997

Differential distribution of inositol 1,4,5-triphosphate receptors in the rat olfactory bulb.

The inositol 1,4,5-triphosphate receptor (IP3R) regulates the release of calcium from intracellular stores. In the present study, the distribution of IP3R in the rat main olfactory bulb was determined by immunohistochemistry. Immunofluorescence was used to double label for IP3R and for gamma-aminobutyric acid (GABA) or for projection neurons, which were retrogradely labeled following dextran injection into the lateral olfactory tract (LOT). The expression profile of IP3R changes dramatically during development. In the glomerular layer of adults, many juxtaglomerular neurons are IP3R immunoreactive [IP3R(+)]; the majority of these cells are also GABA immunoreactive [GABA(+)]. Scattered sparsely throughout the external plexiform layer are small numbers of IP3R(+) neurons, a small number of which are LOT-projecting tufted cells. Significant numbers of IP3R(+) neurons are in the granule cell layer; however, most of these cells are GABA(-). The vast majority of mitral cells contain little or no IP3R immunoreactivity. These findings indicate that, in the olfactory bulb of adult rats, IP3R is preferentially localized in specific classes of intrinsic neurons and that it is rarely expressed in projection neurons. In contrast, during the first postnatal week, the receptor is detected almost exclusively in mitral cells. Expression of IP3R in subclasses of intrinsic neurons begins during the second and third weeks, concomitant with a decrease in immunostaining of mitral cells. Adult patterns of IP3R immunostaining are apparent by the fourth postnatal week. These observations raise the possibility that the expression of IP3R in specific classes of neurons during development is activity dependent.

Aging↗
PubMed1997

Biochemical characterization of the mouse muscle-specific enolase: developmental changes in electrophoretic variants and selective binding to other proteins.

The glycolytic enzyme enolase (EC 4.2.1.11) is active as dimers formed from three subunits encoded by different genes. The embryonic alphaalpha isoform remains distributed in many adult cell types, whereas a transition towards betabeta and gammagamma isoforms occurs in striated muscle cells and neurons respectively. It is not understood why enolase exhibits tissue-specific isoforms with very close functional properties. We approached this problem by the purification of native betabeta-enolase from mouse hindlimb muscles and by raising specific antibodies of high titre against this protein. These reagents have been useful in revealing a heterogeneity of the beta-enolase subunit that changes with in vivo and in vitro maturation. A basic carboxypeptidase appears to be involved in generating an acidic beta-enolase variant, and may regulate plasminogen binding by this subunit. We show for the first time that pure betabeta-enolase binds with high affinity the adjacent enzymes in the glycolytic pathway (pyruvate kinase and phosphoglycerate mutase), favouring the hypothesis that these three enzymes form a functional glycolytic segment. betabeta-Enolase binds with high affinity sarcomeric troponin but not actin and tropomyosin. Some of these binding properties are shared by the alphaalpha-isoenolase, which is also expressed in striated muscle, but not by the neuron-specific gammagamma-enolase. These results support the idea that specific interactions with macromolecules will address muscle enolase isoforms at the subcellular site where ATP, produced through glycolysis, is most needed for contraction. Such a specific targeting could be modulated by post-translational modifications.

Animals↗
PubMed1997

Intrinsic circuitry and physiological properties of pyramidal neurons in rat barrel cortex.

Pyramidal neurons in the rat posteromedial barrel subfield (PMBSF) were characterized physiologically and filled with biocytin in in vitro brain slices. Intrinsic axons belonging to supragranular neurons projected horizontally and vertically, arborizing in layers II/III and V, but had few or no projections to layers IV or VI. These axons projected horizontally for up to 2 mm, spanning two to seven barrel columns. Layer V neurons had more diffuse axon arbors that projected either vertically, arborizing in layers III to V, or horizontally, branching profusely in layers V and VI. The basal dendritic trees of neurons in layers II/III, V and VI spanned one or two barrel columns without being skewed toward particular barrel columns. Physiologically, regular-spiking neurons were classified as "RS1" or "RS2" according to their degree of late spike frequency adaptation. RS1 neurons were found in superficial and deep layers, whereas RS2 neurons were significantly more prevalent in the latter. Infragranular, but not supragranular neurons showed slow, inward rectification at hyperpolarized potentials. All neurons generated fast and medium afterhyperpolarizations following individual spikes; however, only infragranular pyramids had depolarizing afterpotentials interposed between the two afterhyperpolarizations. RS1 neurons had larger cell bodies, longer total basal dendritic lengths, and more densely branched proximal dendritic trees than RS2 neurons. These findings indicate that pyramidal neurons in the deep and superficial layers of the rat PMBSF have distinct patterns of intracortical axon arbors and distinct physiological properties. These features are probably involved in shaping and modulating the response properties of PMBSF neurons.

Animals↗
PubMed1997

Correspondence between the effect of zidovudine plus lamivudine on plasma HIV level/CD4 lymphocyte count and the incidence of clinical disease in infected individuals. North American Lamivudine HIV Working Group.

OBJECTIVES: To investigate whether apparently beneficial changes in plasma HIV RNA level and CD4 lymphocyte count that are induced by antiretroviral therapy are associated with a corresponding clinical benefit. METHODS: For 620 patients in two randomized, double-blind trials of lamivudine (3TC) and zidovudine (ZDV) plasma HIV RNA and CD4 lymphocyte count changes were compared in patients randomized to 3TC plus ZDV and patients randomized to other treatment arms. The effect of therapy on the HIV RNA level and CD4 count was compared with the effect of therapy on clinical endpoints over the same time period. RESULTS: Median baseline values for all subjects were 42 420 copies/ml for HIV RNA and 277 x 10(6)/l for CD4 count. During the trial a significantly lower HIV RNA level and higher CD4 count was sustained in the ZDV/3TC group compared with the other group, with a difference in the median area under the curve from baseline per month of follow-up of 0.38 log10 copies/ml HIV RNA and 0.18 log2 x 10(6)/l CD4 cells (P < 0.001 in each case). For patients who were initially asymptomatic or in CDC stage B, the adjusted relative hazard (RH) of AIDS for a twofold lower CD4 count was 3.14 [95% confidence interval (CI), 1.44-6.83] and for a 10-fold higher HIV RNA level was 3.22 (1.20-8.59). The RH progression to AIDS expected with ZDV/3TC compared with the control treatments, given the observed effects of treatment on CD4 cell counts and HIV RNA levels, is 0.52, whereas the observed value was 0.16 (0.03-0.74). After adjustment for HIV RNA and CD4 changes over time the observed RH of progression to AIDS for ZDV/3TC treatment compared with controls was increased to 0.36 and was no longer significant (95% CI, 0.07-1.85). CONCLUSION: In this analysis of two trials, the effects of ZDV/3TC in reducing plasma HIV RNA and raising peripheral blood CD4 counts were associated with concurrent clinical benefits and the effect of treatment on these markers could account for at least part of the clinical benefits of therapy that were observed.

Anti-HIV Agents↗
PubMed1997

Distribution and activation of intracellular Ca2+ stores in cultured olfactory bulb neurons.

The presence and distribution of intracellular Ca2+ release pathways in olfactory bulb neurons were studied in dissociated cell cultures. Histochemical techniques and imaging of Ca2+ fluxes were used to identify two major intracellular Ca2+ release mechanisms: inositol 1, 4,5-triphosphate receptor (IP3R)-mediated release, and ryanodine receptor-mediated release. Cultured neurons were identified by immunocytochemistry for the neuron-specificmarker beta-tubulin III. Morphometric analyses and immunocytochemistry for glutamic acid-decarboxylase revealed a heterogeneous population of cultured neurons with phenotypes corresponding to both projection (mitral/tufted) and intrinsic (periglomerular/granule) neurons of the in vivo olfactory bulb. Immunocytochemistry for the IP3R, and labeling with fluorescent-tagged ryanodine, revealed that, irrespective of cell type, almost all cultured neurons express IP3R and ryanodine binding sites in both somata and dendrites. Functional imaging revealed that intracellular Ca2+ fluxes can be generated in the absence of external Ca2+, using agonists specific to each of the intracellular release pathways. Local pressure application of glutamate or quisqualate evoked Ca2+ fluxes in both somata and dendrites in nominally Ca2+ free extracellular solutions, suggesting the presence of IP3-dependent Ca2+ release. These fluxes were blocked by preincubation with thapsigargin and persisted in the presence of the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Local application of caffeine, a ryanodine receptor agonist, also evoked intracellular Ca2+ fluxes in the absence of extracellular Ca2+. These Ca2+ fluxes were suppressed by preincubation with ryanodine. In all neurons, both IP3- and ryanodine-dependent release pathways coexisted, suggesting that they interact to modulate intracellular Ca2+ concentrations.

Animals↗
PubMed1997

Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma.

The anti-asthmatic effects of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 microg x day(-1). The trial was designed as a randomized, double-blind, parallel-group study in several European countries. Sixty nine patients were treated for 6 weeks with theophylline plus BDP 400 microg x day(-1), compared to 64 patients treated with BDP 800 micro x day(-1). The mean+/-SD serum theophylline concentration was 10.1+/-4.2 mg x L(-1). Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p<0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p<0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 microg x day(-1) and beclomethasone dipropionate 800 microg x day(-1) in patients whose asthma is not controlled on beclomethasone dipropionate 400 microg x day(-1). The results support the use of theophylline as a steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate asthma.

Administration, Inhalation↗
PubMed1997

[Iatrogenic hepatitis B, non-A non-B, and C virus infections acquired in health service institutions of the Gdansk province in 1986-1995].

The aim of this study is estimation of the frequency of nosocomial infections caused by HBV, NANB virus, HCV in health service institutions of Gdańsk province. Relationship between medical procedures and acute viral hepatitis was examined among 4268 patients hospitalized in Clinic of Infectious Diseases and Provincial Hospital of Infectious Diseases in Gdańsk, from 1986 to 1995. The analysis of results showed that 1915 (44.9%) cases of viral hepatitis caused by HBV, NANB virus, HCV were probably connected with diagnostic or therapeutic procedures. Within ten years number of HBV, NANB, HCV infections decreased but at the same time relative increase of nosocomial infections caused by those pathogens was observed. Transfusion anamnesis was noted among 129 patients (8.5% of all persons with acute viral hepatitis probably infected in hospitals).

Adolescent↗
PubMed1996

Intrinsic inhibitory pathways in mouse barrel cortex.

The organization of intrinsic connections in the mouse somatosensory cortex was studied by combining tract-tracing and immunocytochemical techniques. Injections of HRP or fluorescent beads were made into the supragranular or infragranular layers of the posteriomedial barrel subfield. Numerous cells were retrogradely labeled within a vertical column centered on each injection site. Retrogradely labeled cells were also found > 3 mm horizontal to the injection. Dual-label immunocytochemistry identified the population of inhibitory, GABAergic cells forming intrinsic horizontal connections. Double-labeled cells were found predominantly within a 200 microns radius horizontal to an injection site. These findings indicate that intrinsic inhibitory pathways in the barrel cortex do not provide a substrate for direct GABAergic interactions among barrel columns, and that inter-columnar interactions are primarily excitatory.

Animals↗
PubMed1996

Tactile experience determines the organization of movement representations in rat motor cortex.

We mapped movement representations in motor cortex of rats that had their mystacial vibrissae (whiskers) clipped continually for various periods during their development. In animals clipped since birth, and in adult animals clipped for 5 days, there was a significant reduction in the ratio of whisker to forelimb representation areas. Allowing the whiskers to regrow for at least 72 h resulted in normal-appearing representation patterns. The plasticity of motor representations induced by whisker clipping, and that following whisker regrowth, were not age dependent. These findings indicate that a relatively innocuous procedure that restricts sensory and motor functions results in pronounced, and reversible, changes in the functional organization of the motor cortex.

Age Factors↗
PubMed1996

Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group.

BACKGROUND: Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. METHODS: Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration > or = 12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly. RESULTS: Among 392 treated patients, the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo. The proportion of patients who had any skeletal events was significantly lower in the pamidronate group (24 percent) than in the placebo group (41 percent, P < 0.001), and the reduction was evident in both stratum 1 (P = 0.04) and stratum 2 (P = 0.004). The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life. Pamidronate was tolerated well. CONCLUSIONS: Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma.

Aged↗
PubMed1996

Insulin-like growth factor-I in man enhances lipid mobilization and oxidation induced by a growth hormone pulse.

Growth hormone (GH) secretion is suppressed during insulin-like growth factor-I (IGF-I) administration. The aim of the study was to examine whether IGF-I alters the metabolic response to a GH pulse. Seven healthy male subjects (age 27 +/- 4 years, BMI 21.8 +/- 1.7 kg/m2) were treated with NaCl 0.9% (saline) or IGF-I (8 micrograms.kg-1.h-1) for 5 days by continuous subcutaneous infusion in a randomized, crossover fashion while receiving an isocaloric diet (30 kcal.kg-1.day-1). On the third treatment day an intravenous bolus of 0.5 U GH was administered. Forearm muscle metabolism was examined by measuring arterialized and deep venous blood samples, forearm blood flow by occlusion plethysmography and substrate oxidation by indirect calorimetry. IGF-I treatment significantly reduced insulin concentrations by 80% (p < 0.02) and C-peptide levels by 78% (p < 0.02), as assessed by area under the curve. Non-esterified fatty acid (NEFA), glycerol and 3-OH-butyrate levels were elevated and alanine concentration decreased. Forearm blood flow rose from 2.10 +/- 0.43 (saline) to 2.79 +/- 0.37 ml.100ml-1. min-1 (IGF-I) (p < 0.02). GH-pulse: 10 h after i.v. GH injection serum GH peaked at 40.9 +/- 7.4 ng/ml. GH did not influence circulating levels of total IGF-I, C-peptide, insulin or glucose, but caused a further increase in NEFA, glycerol and 3-OH-butyrate levels, indicating enhanced lipolysis and ketogenesis. This effect of GH was much more pronounced during IGF-I: NEFA rose from 702 +/- 267 (saline) and 885 +/- 236 (IGF-I) to 963 +/- 215 (saline) (p < 0.05) and 1815 +/- 586 mumol/l (IGF-I) (p < 0.02), respectively; after 5 h, 3-OH-butyrate rose from 242 +/- 234 (saline) and 340 +/- 280 (IGF-I) to 678 +/- 638 (saline) (p < 0.02) and 1115 +/- 578 mumol/l (IGF-I) (p < 0.02) respectively. After injection of GH, forearm uptake of 3-OH-butyrate was markedly elevated only in the subjects treated with IGF-I: from 44 +/- 195 to 300 +/- 370 after 20 min (p < 0.03) and to 287 +/- 91 nmol.100 ml-1. min-1 after 120 min (p < 0.02). In conclusion, the lipolytic and ketogenic response to GH was grossly enhanced during IGF-I treatment, and utilization of ketone bodies by skeletal muscle was increased.

Adult↗