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At least 163 records · Page 9Linked to original sources
PubMed1999

Ziskind-Somerfeld Research Award. Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness.

Understanding the biology of the pharmacological stabilization of mood will undoubtedly serve to provide significant insight into the pathophysiology of manic-depressive illness (MDI). Accumulating evidence from our laboratories and those of other researchers has identified the family of protein kinase C isozymes as a shared target in the brain for the long-term action of both lithium and valproate. In rats chronically treated with lithium, there is a reduction in the hippocampus of the expression of two protein kinase isozymes, alpha and epsilon, as well as a reduction in the expression of a major PKC substrate, MARCKS, which has been implicated in long-term neuroplastic events in the developing and adult brain. In addition, we have been investigating the down-stream impact of these mood stabilizers on another kinase system, GSK-3 beta and on the AP-1 family of transcription factors. Further studies have generated promising preliminary data in support of the antimanic action of tamoxifen, and antiestrogen that is also a PKC inhibitor. Future studies must address the therapeutic relevance of these protein targets in the brain using innovative strategies in both animal and clinical investigations to ultimately create opportunities for the discovery of the next generations of mood stabilizers for the treatment of MDI.

Animals↗
PubMed1995

Transfer of the CFTR gene to the lung of nonhuman primates with E1-deleted, E2a-defective recombinant adenoviruses: a preclinical toxicology study.

This paper describes a preclinical toxicology study designed to investigate the biological efficacy and safety profile of second-generation adenovirus for CFTR gene transfer into the baboon lung. This second-generation virus is deleted of E1 and contains a temperature-sensitive mutation in the E2a gene, which encodes a defective DNA-binding protein. Two distinct projects were undertaken. Group A animals received a first-generation adenovirus (i.e., deleted of E1) in an upper lobe at the time a second-generation virus was instilled into the contralateral upper lobe. The goal of study A was to compare the biology of each construct directly and to determine if an immune response to the first-generation virus affected the performance of the second-generation virus. Group B animals received a lacZ second-generation virus in an upper lobe at the same time the CFTR second-generation virus was instilled in the other upper lobe. Necropsies were performed 4 or 21 days after gene transfer and tissues were evaluated for recombinant gene expression and histopathology. Using a second-generation adenovirus, recombinant gene stability was prolonged and associated with a diminished level of perivascular inflammation as compared to first-generation vectors. Markedly diminished levels of hexon protein were present in tissues infected with second-generation as compared to first-generation virus. No evidence of viral shedding was evident. Furthermore, coadministration of first- and second-generation adenovirus did not affect the stability of transgene expression from the second-generation virus. These data suggest that second-generation adenoviral vectors provide an improved gene delivery vehicle, and thus may be useful in gene therapy for cystic fibrosis.

Adenoviridae↗
PubMed2001

Lectin-functionalized liposomes for pulmonary drug delivery: effect of nebulization on stability and bioadhesion.

The generation of respirable aerosols of a functionalized colloidal carrier has been investigated in this study. Lectin-functionalized liposomes, which proved to show improved cell association (using A549 cell line and primary human alveolar cells) even in the presence of a commercial lung surfactant preparation, have been developed. The stability of non-functionalized liposomes during nebulization using a jet nebulizer (Pari II provocation nebulizer, operated using an air flow of 30 l/min) was firstly investigated, and the experimental and formulation conditions were optimized and applied for the preparation of lectin-functionalized liposomes. The incorporation of cholesterol enhanced the stability of the liposomes during nebulization (from 15-20% leakage of a hydrophilic marker to 8% upon cholesterol incorporation) and upon incubation with lung surfactant preparation. Nebulization of the functionalized liposomes did not significantly influence their physical stability. Their enhanced cell binding capability (compared to non-functionalized liposomes) was also maintained. A drop in cell association compared to fresh functionalized liposomes was detected after nebulization, nevertheless, the binding was still significantly higher than that of the non-functionalized liposomes. The deposition of the liposomal preparation in lung periphery, proved by the deposition of the liposomal preparation on the lower stages of an ASTRA type cascade impinger and a mean median aerodynamic diameter (MMAD) of 2.85 microm, makes it a potential candidate as a macromolecule-drug carrier for local and/or systemic administration.

1,2-Dipalmitoylphosphatidylcholine↗
PubMedDate not supplied

Behavior of Escherichia coli R factors in Salmonella typhi.

Seventeen R factors originally found in community-isolated E. coli strains were transferred by in vitro conjugation experiments to three S. typhi strains and to J55, an E. coli J53 pro met derivative strain, in order to analyze R factor stability through 100 generations in liquid cultures at low bacterial density thus avoiding R factor retransfer. Four R factors were maintained in 100% of the S. typhi colonies tested after 100 generations. Four other R factors were completely or almost completely segregated, and nine R factors showed an intermediate segregation rate (average 50%). Resistance stability rate in J55 was high (above 90%) as was expected. Overall R factors in S. typhi tend to segregation and this may partially explain epidemiological data about low antibiotic-resistance incidence in S. typhi.

Drug Resistance, Microbial↗
PubMed1997

Mutations in the small subunit of ribulose-1,5-bisphosphate carboxylase/ oxygenase increase the formation of the misfire product xylulose-1,5-bisphosphate.

The small subunit (S) increases the catalytic efficiency of ribulose-1,5-bisphosphate carboxylase/oxygenase (EC 4.1.1.39) by stabilizing the active sites generated by four large subunit (L) dimers. This stabilization appears to be due to an influence of S on the reaction intermediate 2,3-enediol, which is formed after the abstraction of a proton from the substrate ribulose-1,5-bisphosphate. We tested the functional significance of residues that are conserved among most species in the carboxy-terminal part of S and analyzed their influence on the kinetic parameters of Synechococcus holoenzymes. The replacements in S (F92S, Q99G, and P108L) resulted in catalytic activities ranging from 95 to 43% of wild type. The specificity factors for the three mutant enzymes were little affected (90-96% of wild type), but Km(CO2) values increased 0.5- to 2-fold. Mutant enzymes with replacements Q99G and P108L showed increased mis-protonation, relative to carboxylation, of the 2,3-enediol intermediate, forming 2 to 3 times more xylulose-1,5-bisphosphate per ribulose-1,5-bisphosphate utilized than wild-type or F92S enzymes. The results suggest that specific alterations of the L/S interfaces and of the hydrophobic core of S are transmitted to the active site by long-range interactions. S interactions with L may restrict the flexibility of active-site residues in L.

Amino Acid Sequence↗
PubMed1990

Prediction of rates of inbreeding in selected populations.

A method is presented for the prediction of rate of inbreeding for populations with discrete generations. The matrix of Wright's numerator relationships is partitioned into 'contribution' matrices which describe the contribution of the Mendelian sampling of genes of ancestors in a given generation to the relationship between individuals in later generations. These contributions stabilize with time and the value to which they stabilize is shown to be related to the asymptotic rate of inbreeding and therefore also the effective population size, Ne approximately 2N/(mu 2r + sigma 2r), where N is the number of individuals per generation and mu r and sigma 2r are the mean and variance of long-term relationships or long-term contributions. These stabilized values are then predicted using a recursive equation via the concept of selective advantage for populations with hierarchical mating structures undergoing mass selection. Account is taken of the change in genetic parameters as a consequence of selection and also the increasing 'competitiveness' of contemporaries as selection proceeds. Examples are given and predicted rates of inbreeding are compared to those calculated in simulations. For populations of 20 males and 20, 40, 100 or 200 females the rate of inbreeding was found to increase by as much as 75% over the rate of inbreeding in an unselected population depending on mating ratio, selection intensity and heritability of the selected trait. The prediction presented here estimated the rate of inbreeding usually within 5% of that calculated from simulation.

Animals↗
PubMed1997

The effect of fatigue on multijoint kinematics and load sharing during a repetitive lifting test.

STUDY DESIGN: A repetitive lifting test in the sagittal plane was performed with a submaximal load at a maximal lifting rate to understand the effects of fatigue on kinematic and kinetic measures of performance. OBJECTIVES: To quantify the effect of fatigue during a highly repetitive lifting task, in terms of lifting force transmitted to the load, joint motion patterns, and internal joint load sharing. SUMMARY OF BACKGROUND DATA: Industrial surveillance and epidemiologic data suggest that repetitive lifting is a risk factor for low back pain. Previous studies examining the effect of fatigue have either been constrained to isolated trunk movement, or have not explored the internal load distribution and potential alteration in the loading patterns. METHODS: Sixteen healthy male subjects performed repetitive lifting in the sagittal plane with a load equal to 25% of their maximal lifting capacity, at a maximal lifting rate. Changes in lifting performance were determined from the power transferred to the box, joint kinematics, and joint kinetics. Data from three cycles at the start and end of the exercise were tested for the effect of fatigue using repeated-measures analysis of variance. RESULTS: Fatigue was documented by a reduction in average lifting force and hip and spine torque generation, whereas internal joint load sharing was relatively unchanged. The fatigue was associated with decreased knee and hip motion, and increased lumbar flexion. Decreased postural stability also was evident. CONCLUSIONS: The significant decrease in postural stability and force generation capability because of the repetitive lifting task indicated a higher risk of injury in the presence of unexpected perturbation. Multijoint coordinated lifting tasks provide a more realistic protocol to study neuromuscular fatigue.

Adult↗
PubMed1999

ELAV proteins stabilize deadenylated intermediates in a novel in vitro mRNA deadenylation/degradation system.

We have developed an in vitro mRNA stability system using HeLa cell cytoplasmic S100 extracts and exogenous polyadenylated RNA substrates that reproduces regulated aspects of mRNA decay. The addition of cold poly(A) competitor RNA activated both a sequence-specific deadenylase activity in the extracts as well as a potent, ATP-dependent ribonucleolytic activity. The rates of both deadenylation and degradation were up-regulated by the presence of a variety of AU-rich elements in the body of substrate RNAs. Competition analyses demonstrated that trans-acting factors were required for RNA destabilization by AU-rich elements. The approximately 30-kD ELAV protein HuR specifically bound to RNAs containing an AU-rich element derived from the TNF-alpha mRNA in the in vitro system. Interaction of HuR with AU-rich elements, however, was not associated with RNA destabilization. Interestingly, recombinant ELAV proteins specifically stabilized deadenylated intermediates generated from the turnover of AU-rich element-containing substrate RNAs. These data suggest that mammalian ELAV proteins play a role in regulating mRNA stability by influencing the access of degradative enzymes to RNA substrates.

Adenosine Triphosphate↗
PubMed1998

Relative stability of a minimal CTG repeat expansion in a large kindred with myotonic dystrophy.

The genetic basis for myotonic dystrophy (DM) is a CTG trinucleotide repeat expansion. The number of CTG repeats commonly increases in affected individuals of successive generations, in association with anticipation. We identified a large DM family in which multiple members had minimal CTG repeat expansions, and in which the number of CTG repeats remained in the minimally expanded range through at least three, and possibly four, generations. This relative stability of minimal CTG repeat expansions may help to maintain the DM mutation in the population.

Aged↗
PubMed1992

Promoter methylation and progressive transgene inactivation in Arabidopsis.

Agrobacterium-transformed Arabidopsis plants were generated and the stability of their T-DNA-encoded resistance to kanamycin was examined. Of seven families, each homozygous for a single insertion event, two showed progressive inactivation of resistance over four generations of inbreeding. Loss of resistance was associated with methylation of an Sst II site in the nos promoter of the kanamycin resistance gene. Treatment of plant roots from inactive lines with the demethylating agent 5-azacytidine restored the ability of such lines to form callus on kanamycin-containing media. These observations are consistent with the view that methylation is a factor in the progressive inactivation of transgenes in Arabidopsis.

DNA, Bacterial↗
PubMed1993

The antimicrobial activity and beta-lactamase stability of cefpirome, a new fourth-generation cephalosporin in comparison with other agents.

The antimicrobial activity of cefpirome was compared with amoxycillin/clavulanic acid, ampicillin/sulbactam, cefuroxime, ceftazidime, gentamicin and amikacin against 743 non-duplicate clinical isolates. MIC50 and MIC90 showed that the antibiotic was active against both Gram-negative and Gram-positive organisms. Cefpirome was highly active against most of the Enterobacteriaceae, including indole-positive Proteus spp., Aeromonas spp. (MIC < or = 1 mg/L) and Salmonella spp. (MIC < or = 0.5 mg/L). Neisseria gonorrhoeae and Haemophilus influenzae (including beta-lactamase producers) were all susceptible, with MIC less than 0.5 and 0.25 mg/L respectively. Cefpirome was more active than cefuroxime and ceftazidime against Campylobacter spp. (MIC < or = 2 mg/L), but less active than ceftazidime against Pseudomonas aeruginosa. Cefpirome was active against Streptococcus pneumoniae. Streptococcus bovis and coagulase-negative staphylococci (MIC < or = 0.5 mg/L) and methicillin-sensitive Staphylococcus aureus (MIC < or = 2 mg/L). Methicillin-resistant S. aureus, Gram-positive and Gram-negative anaerobes were resistant to cefpirome. The stability of cefpirome to TEM-1, TEM-2, PSE-1, SHV-1 and the chromosomal-mediated P99 and K-1 beta-lactamases was comparable to ceftazidime.

Acinetobacter↗
PubMed1985

Stability of atrial sensing and pacing after dual chamber pulse generator implantation.

The continued efficacy of dual chamber pacing is predicated on the stability of both atrial and ventricular electrodes. The introduction of the tined atrial J lead has decreased the incidence of atrial lead dislodgment, allowing for continued effective sensing and pacing. To study the evolution of atrial pacing and sensing threshold, 54 patients with identical pulse generators and atrial electrodes were evaluated for 58 +/- 29 weeks (mean +/- SD). Immediately after pacemaker implantation in 39 patients, the amplitude of the atrial signal was measured by programming the pulse generator to the lowest sensitivity that assured pacing in the atrial synchronous mode. Three levels of atrial sensing were possible: high (0.5 mV), intermediate (1.3 mV) and low (2.5 mV) sensitivity. Three patients had a high, 16 patients had a medium and 20 patients had a low atrial sensitivity. The P wave amplitude and slew rate measured on a physiologic recorder did not differ significantly between the latter two groups. The atrial charge threshold increased from 1.8 +/- 1.3 microcoulombs (microC) to a maximal value of 2.5 +/- 1.3 microC, 3 days to 1 week after implantation (p = 0.02). This remained elevated for 1 to 3 months (p = 0.05) and then decreased, remaining stable over the ensuing year. The atrial sensitivity for the group with noninvasive measurement did not change significantly, although there was considerable patient variation. For 54% of the patients, atrial sensing remained stable or improved. In 26% of the patients, further programming to higher sensitivity settings ws required. In the remaining 20% of the patients, the atrial sensitivity setting fluctuated.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1996

The construction of a stable starch-fermenting yeast strain using genetic engineering and rare-mating.

To develop a yeast strain that is able to produce ethanol directly from starch, alpha-amylase cDNA (originated from mouse salivary glands) was introduced into the hyploid Saccharomyces diastiticus cells secreting glucoamylase by using a linearized integrating vector. The integrating vector contains a LEU2 gene and the inside of the LEU2 gene was cut by KpnI to make the linearized vector. One of the transformants exhibited 100% mitotic stability after 100 generations of cell multiplication. To improve its ethanol-fermentability, the haploid transformant was rare-mated with a polyploid industrial strain having no amylase activity. The resulting hybrid RH51 produced 7.5 (w/v) ethanol directly from 20% (w/v) soluble starch and its mitotic stability was 100% at the end of fermentation.

Animals↗
PubMed1989

Age, period and cohort effects on the risk of major depression: results from five United States communities.

Rates of major depression are presented from the recently completed Epidemiologic Catchment Area (ECA) Study based on probability samples of over 18,000 adults, 18 years of age and older, living in five U.S. communities. These rates were analyzed to describe simultaneously the changes affecting successive birth cohorts and the changes associated with the period in which the onset of the disorder occurred, using age-period-cohort (APC) models. The non-identifiability problem inherent in all APC models was resolved by assuming that the linear period effect and linear cohort effect were non-negative. This assumption is consistent with our a priori substantive knowledge of the disease. Under this assumption, as the linear period effect varies from its minimum to its maximum values, a family of curves representing the possible effects of a factor was generated for each of the time factors--age, period and cohort. The results of the analysis showed a sharp increase in rates of major depression among both men and women in the birth cohort born during the years 1935-1945. The rates among females, however, seemed to have stabilized in the generations born since 1945, while the rates in males continued to rise sharply among the cohorts born in the following decade, after which, in 1955, they also levelled off. In contrast, the rates associated with period of onset of major depression continued to increase between the years 1960-1980 among both men and women of all ages studied. These findings are considered in light of the persistent concentration of depression in women and in biologically related members of families of affected individuals.

Adolescent↗
PubMed1986

Long-term maintenance of hepatocyte functional activity in co-culture: requirements for sinusoidal endothelial cells and dexamethasone.

Sinusoidal cells isolated from adult rat liver have been established in primary culture and in cell line. The presence of factor VIII R:Ag and peroxidatic/phagocytosis activities were the criteria used to distinguish in freshly isolated cells the endothelial cells from the Kupffer cells and suggested the endothelial origin of the cell line. Using a co-culture system, the effect of sinusoidal liver cells on hepatocyte functional activity was characterized. A plateau in which the state of differentiation was stabilized could be generated for co-cultured hepatocytes isolated from adult rat and a disappearance of the initial expression of alpha 1-fetoprotein (AFP) and the increase and/or maintenance of albumin secretion were measured with co-cultured hepatocytes isolated from suckling rat. The presence of dexamethasone was required for such beneficial effect. The hepatocyte-stabilizing activity was also produced by a pulmonary endothelial cell line.

Cell Communication↗