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Biomedical subjects

L Graves

Publications and source records attributed to L Graves.

At least 19 recordsLinked to original sources
PubMed2002

Behavioral analysis of CREB alphadelta mutation on a B6/129 F1 hybrid background.

The cyclic AMP (cAMP)-response element binding protein (CREB) is an activity-dependent transcription factor that plays a role in synaptic plasticity and memory storage in Aplysia, Drosophila, and rodents. Mice with targeted deletions of two CREB isoforms (alpha and delta; CREB alphadelta mice) have been characterized on a mixed genetic background of C57BL/6 (B6) and 129/SvEv (129), as well as on a defined F1 hybrid of B6 and FVB/N, and these results suggest that the phenotype of CREB alphadelta mice depends critically on genetic background. In an examination of the hypothesis that the role of CREB in learning and memory can be influenced by strain differences, we analyzed mice with the CREB alphadelta mutation on an F1 hybrid background of B6 and 129 strains. CREB alphadelta mice on this background had impaired short-term and long-term cued and contextual fear conditioning and normal spatial learning in the Morris water maze. Our results suggest that at least some aspects of hippocampal function are normal in CREB alphadelta mice, and that CREB alphadelta mice on the B6/129 F1 background have alterations in amygdala function. These studies underscore the importance of controlling for genetic background in the behavioral analysis of knockout and transgenic mice.

Animals↗
PubMed2001

Protein-tyrosine kinase Pyk2 mediates endothelin-induced p38 MAPK activation in glomerular mesangial cells.

Endothelin-1 (ET-1), a member of a family of 21 amino acid peptides possessing vasoconstrictor properties, is known to stimulate mesangial cell proliferation. In this study, ET-1 (100 nm) induced a rapid activation of p21(ras) in human glomerular mesangial cells (HMC). Inhibition of Src family tyrosine kinase activation with [4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] or chelation of intracellular free calcium with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester significantly decreased ET-1dependent p21(ras) activation and suggested the involvement of the cytoplasmic proline-rich tyrosine kinase Pyk2. We have observed that Pyk2 was expressed in HMC and was tyrosine-phosphorylated within 5 min of ET-1 treatment. ET-1-induced activation of Pyk2 was further confirmed using phospho-specific anti-Pyk2 antibodies. Surprisingly, Src kinase activity was required upstream of ET-1-induced autophosphorylation of Pyk2. To determine whether Pyk2 autophosphorylation mediated ET-1-dependent p21(ras) activation, adenovirus-mediated transfer was employed to express a dominant-negative form of Pyk2 (CRNK). CRNK expression inhibited ET-1-induced endogenous Pyk2 autophosphorylation, but did not abolish ET-1-mediated increases in GTP-bound p21(ras) levels. ET-1-induced activation of the p38 MAPK (but not ERK) pathway was inhibited in HMC and in rat glomerular mesangial cells expressing the dominant-negative form of Pyk2. These findings suggest that the engagement of Pyk2 is important for ET-1-mediated p38 MAPK activation and hence the biological effect of this peptide in mesangial cells.

Adenoviridae↗
PubMed2001

Sleep and memory: a molecular perspective.

This review synthesizes data from behavioral studies examining the role of sleep in memory storage with what is known about the molecular mechanisms of memory consolidation. There are striking similarities in the effects on memory storage of post-training pharmacological manipulations and post-training manipulations of sleep. For example, inhibition of protein synthesis is most effective if it occurs at a time post-training when rapid eye movement (REM) sleep is required for memory consolidation. The neurochemical changes that occur across sleep/wake states, especially the cholinergic changes that occur in the hippocampus during REM sleep, might provide a mechanism by which sleep modulates specific cellular signaling pathways involved in hippocampus-dependent memory storage.

Acetylcholine↗
PubMed1997

Mexiletine in the symptomatic treatment of diabetic peripheral neuropathy.

OBJECTIVE: To evaluate the efficacy and safety of mexiletine in the symptomatic treatment of diabetic peripheral neuropathy (DPN). METHODS: In this prospective, double-blind study, 29 patients were randomized to receive mexiletine 600 mg/d or matching placebo for 3 weeks. A four-item symptom score (FIS), which rated pain, dysesthesias, paresthesias, and nightly exacerbations of symptoms, and a 100-mm visual analog scale (VAS), which rated pain intensity, were completed by patients before and after treatment. At the end of treatment independent patient and investigator global assessments were made. Patients reported adverse effects after 1 and 3 weeks of treatment. RESULTS: Treatment groups were similar at baseline. The difference between the median changes in FIS scores (mexiletine = 5.5, placebo = 2) was not statistically significant. Overall symptom response was similar in both treatment groups as demonstrated by both global assessments (p = 0.19). The mean change in VAS score from baseline to posttreatment was determined for both groups and the difference between these mean scores was 16.5 mm (95% CI, -7.1 to 40.2 mm) (p = 0.16). Inadequate statistical power (1-beta = 0.40) may have resulted from small sample size, small magnitude of effect, or variability in the measured effect. Adverse effects were more common in the mexiletine group, though not statistically significant. One patient receiving mexiletine was hospitalized for palpitations. CONCLUSIONS: Because of conflicting reports of mexiletine's efficacy in the treatment of symptomatic DPN, this drug should be reserved for patients unresponsive or intolerant to standard therapy, without evidence of heart disease, and with sensations of burning heat, formication, or stabbing pain.

Adult↗
PubMed1996

Intravenous pamidronate for hypercalcemia of primary hyperparathyroidism.

Intravenous pamidronate disodium has been used successfully in the treatment of malignancy-associated hypercalcemia and Paget's disease of bone. Although the definitive treatment of primary hyperparathyroidism (PHPT) is surgical, intravenous pamidronate has been used to treat hypercalcemia of PHPT when surgery was contraindicated. We report two cases of PHPT in which intravenous pamidronate effectively reduced hypercalcemia and significantly improved the clinical symptoms. The results of our study and the experience in the literature suggest that pamidronate is a safe and effective method of reducing serum calcium in patients with PHPT when definitive surgery is contraindicated or must be postponed.

Aged↗
PubMed1995

Judicial decision-making in contested custody cases: the influence of reported child abuse, spouse abuse, and parental substance abuse.

This study examined the relationship between allegations of maltreatment and substance abuse, and custody awards in Florida. Information concerning the presence, or absence, of these reports was collected on 60 contested initial disposition, or disposition modification cases, and was used to model judicial decision-making. Substantiated reports of child and spouse abuse occurred very infrequently in our sample. Conversely, substance abuse allegations occurred much more frequently. Judges appeared responsive to allegations of abuse with regard to awards of primary physical residence, despite the lack of substantiated evidence. Maltreatment allegations had no apparent impact, however, on awards of shared, versus sole, custody. Additionally, reports of parental substance abuse also had no apparent impact on judicial decision-making. Implications of these results are discussed.

Adolescent↗
PubMed1993

Speak up!

Explore the source record for details and available documents.

Attitude of Health Personnel↗
PubMed1992

Herbimycin A blocks IL-1-induced NF-kappa B DNA-binding activity in lymphoid cell lines.

The mechanism by which interleukin-1 alpha (IL-1 alpha) activates NF-kappa B DNA-binding activity is not completely understood. While it is well established that protein kinase C can activate NF-kappa B, neither protein kinase C nor protein kinase A appears to be critical in the induction of NF-kappa B by IL-1 alpha. Since a number of growth factors signal via protein tyrosine kinase, in this study we examined a possible involvement of protein tyrosine kinase in the IL-1 alpha-induced NF-kappa B. The results showed that in the murine pre-B cell line 70Z/3 and in the murine T cell line EL-4 6.1 C10 IL-1 alpha-induced NF-kappa B was associated with transient increase in protein tyrosine kinase activity. Pre-treatment of these cell lines with herbimycin A, an inhibitor of tyrosine kinase activity, blocked the IL-1 alpha-enhanced protein tyrosine kinase activity and the IL-1 alpha-induced NF-kappa B DNA-binding activity. Herbimycin A at concentrations sufficient to block IL-1 alpha-induced NF-kappa B did not block the phorbol 12-myristate 13-acetate (PMA)-induced NF-kappa B. The data suggest that IL-1 alpha and PMA activate NF-kappa B by different pathways and that induction of NF-kappa B DNA-binding activity by IL-1 might be dependent on protein tyrosine phosphorylation.

Amino Acid Sequence↗
PubMed1990

Inhibition of mediator release in systemic mastocytosis is associated with reversal of bone changes.

A 59-year-old male presented with systemic mastocytosis with extensive skeletal involvement resulting in vertebral compression fractures and bone pain. Histomorphometric analysis of bone revealed increased mast cells, elevated static parameters of bone resorption, and low bone formation. Serum calcium, phosphorus, and alkaline phosphatase were normal; however, serum 1,25-dihydroxyvitamin D3 and osteocalcin levels were low. Histamine levels in plasma and urine were elevated. Following therapy with ketotifen, the patient had resolution of bone pain along with decreased flushing and pruritus. Elevated plasma and urine histamine levels normalized, as did 1,25-dihydroxyvitamin D3 and osteocalcin levels. Indices of low bone formation improved on therapy. Eroded surfaces improved but remained elevated. This case is the first demonstration that bone symptoms and histomorphometric change in systemic mastocytosis are reversed with inhibition of mast cell degranulation. The role of mast cells and their products in bone metabolism is poorly understood, but the therapy of bone disease in systemic mastocytosis should include inhibition of the release of mast cell products along with the use of histamine antagonist.

Bone Resorption↗
PubMed1990

Comparison of bone and parathyroid hormone as stimulators of osteoclast development and activity in calvarial cell cultures from normal and osteopetrotic (mi/mi) mice.

Osteoclast development was studied in cell cultures prepared from calvaria of neonatal osteopetrotic (mi/mi) mice or their normal littermates, using tartrate-resistant acid phosphatase (TRAPase), as an osteoclast marker. In cultures from normal mice, treatment with 10 nM PTH for 4-5 days stimulated the formation of osteoclasts. However in cultures from mi/mi mice, this response was only 7% +/- 5% that of normal mice and they were significantly smaller than osteoclasts of normal mice. Mineralized bone particles elicited osteoclast development in cultures from both normal and mi/mi mice, and osteoclast size was identical for both genotypes. Seventy-eight to 96% of the TRAPase-positive cells bound 125I-CT, as demonstrated by autoradiography. 125I-CT binding characteristics were identical in cultures from both genotypes treated with bone particles, exhibiting a Kd of 3.3-3.6 x 10(-10) M. Addition of PTH stimulated 45Ca release from the added bone particles only in the case of cultures prepared from normal mice, and CT inhibited this response. Cells from normal mice were capable of excavating bone from the surface of smooth cortical bone wafers, but such excavations were rarely seen in the case of calvarial cells from mi/mi mice. Thus, PTH-driven differentiation of osteoclasts is arrested in calvarial cell cultures from mi/mi mice, but mi/mi preosteoclasts retain the ability to express certain osteoclast markers in response to bone derived signals. We hypothesize that the lack of activity of mi/mi osteoclasts is due to the failure of mi/mi preosteoclasts to respond appropriately to resorptive agents, or to cytokines elicited by these agents.

Acid Phosphatase↗
PubMed1989

Expression and characterization of the tau subunit of phosphorylase kinase.

A cDNA encoding the entire tau subunit of rabbit skeletal muscle phosphorylase kinase was reconstructed and inserted into a plasmid containing the Escherichia coli ptac promoter and a constructed plasmid containing the ptac promoter and bacterial chloramphenicol acetyl transferase (CAT) gene, respectively. A significant phosphorylase kinase activity was found, in the first case. In the second case, a fused protein containing 73 amino acids from the CAT protein was obtained. After renaturation, the CAT-tau subunit protein shows enzymatic activity similar to the HPLC-purified and renatured tau subunit.

Animals↗
PubMed1989

Increase in the activity of tryptophan hydroxylase from cortex and midbrain of male Fischer 344 rats in response to acute or repeated sound stress.

Exposure of male Fischer 344 rats to an acute sound stress consisting of 100 dB tones of 2-s duration presented at random 60-s intervals for 2 h, increased cortical and midbrain tryptophan hydroxylase activity, measured in vitro, 50% over that from sham-stressed animals. This increase in enzyme activity was observed when animals were killed immediately, but not 1 h, after termination of the sound stress. It was non-additive with the increase in activity induced by incubation of enzyme under phosphorylating conditions and could be reversed in vitro with alkaline phosphatase. Graded increases in enzyme activity were obtained with increments of sound intensity (90-120 dB). In contrast to acute stress, chronic sound stress (110 dB) repeated over a period of 1, 2 or 6 weeks (3 sessions per week each of 2-h duration) produced a 50% increase in cortical enzyme activity that persisted 24 h after the termination of the stress and was not reversed by alkaline phosphatase. However, a further increase in enzyme activity could be produced if the chronically stressed animals were exposed to an acute 2-h stress (110 dB) immediately before being killed. This additional increase in activity was reversible in vitro by alkaline phosphatase and non-additive with that produced by incubation under phosphorylating conditions. In summary, acute sound stress produced a prompt, reversible activation of tryptophan hydroxylase. Repeated exposure to sound stress induced a persistent increase in enzyme activity that was detected 24 h after the last stress.

Acoustic Stimulation↗
PubMed1986

Behavioural differences of school-age children who were small-for-dates babies.

Twenty-one children aged between five and nine years who were small for gestational age (SFD) at birth and whose intra-uterine head growth was shown by ultrasonography to be slowing before 35 weeks were observed in a special room, using video-cameras. Their behaviour was compared with that of 21 matched control children who had had normal birthweight. The children in the SFD group were quieter, more compliant and less active than the control group, and their play behaviour suggested that they were less advanced developmentally. The behaviour of the mothers of the SFD group showed that they were aware of their child's problems and tried to compensate for it by teaching the child while they were waiting for the observational session to start, by sitting closer to the child during a drawing test, and by using more words to explain it.

Body Height↗