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Biomedical subjects

R Clark

Publications and source records attributed to R Clark.

At least 55 records · Page 3Linked to original sources
PubMed2001

Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage.

To investigate the role of the Lyn kinase in establishing signaling thresholds in hematopoietic cells, a gain-of-function mutation analogous to the Src Y527F-activating mutation was introduced into the Lyn gene. Intriguingly, although Lyn is widely expressed within the hematopoietic system, these mice displayed no propensity toward hematological malignancy. By contrast, analysis of aging cohorts of both loss- and gain-of-function Lyn mutant mice revealed that Lyn(-/-) mice develop splenomegaly, increased numbers of myeloid progenitors, and monocyte/macrophage (M phi) tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells. Loss of such inhibitory signaling may predispose mice lacking this putative protooncogene to tumorigenesis.

Aging↗
PubMed2001

Maternity leave, women's employment, and marital incompatibility.

This research investigated the relationship between the length of women's maternity leave and marital incompatibility, in the context of other variables including the woman's employment, her dissatisfaction with the division of household labor, and her sense of role overload. Length of leave, work hours, and family salience were associated with several forms of dissatisfaction, which in turn predicted role overload. Role overload predicted increased marital incompatibility for experienced mothers but did not for first-time mothers, for whom discrepancies between preferred and actual child care were more important. Length of maternity leave showed significant interactions with other variables, supporting the hypothesis that a short leave is a risk factor that, when combined with another risk factor, contributes to personal and marital distress.

Adult↗
PubMed2001

The relationship of a mother's working model of feeding to her feeding behaviour.

AIMS OF THE STUDY: This study aimed to examine the difference the attunement of a mother's working model of feeding to her infant makes for her positive feeding affect and behaviour, accounting for infant and mother conditions. BACKGROUND/RATIONALE: The concept of a mother's working model of feeding is derived from attachment theory. Caregiving, including feeding, is a component of this theory. The conditions that may influence the attunement of a mother's working model of feeding to her infant include infant birth maturity status (premature, full-term), age at assessment, and robustness, indexed by weight-for-age z score (WAZ). Mother conditions include symptoms of depression and feeding practice (breast feeding or exclusive bottle feeding). DESIGN/METHODS: Participants in this longitudinal study were 99 mothers and their infants (47 full-term, 52 premature, very low birth weight). After written informed consent was given, home assessments were made when infants were approximately 1, 4, 8 and 12 months old (adjusted age for premature infants). Working model attunement was assessed with a video-assisted interview. A mother's positive affect and behaviour, including sensitivity and responsiveness, were rated from videotaped feeding interaction. RESULTS/FINDINGS: Repeated measures analysis with a general linear mixed model showed a significant positive relationship with positive affect and behaviour for both working model attunement and the WAZ score and a significant negative relationship for symptoms of depression. Neither birth maturity status, infant age, nor feeding practice had a significant effect on mother's positive affect and behaviour during feeding. CONCLUSIONS: Nurses' efforts to enhance the attunement of a mother's working model of feeding may help mothers feed with greater positive affect and behaviour. Further study of how the attunement of a mother's feeding expectations and intentions are related to her symptoms of depression and with what she makes of the infant's growth and well-being is needed. The theoretical model needs testing with infants from the entire premature population.

Adult↗
PubMed2001

The effect of multidose antenatal betamethasone on maternal and infant outcomes.

OBJECTIVE: This study was undertaken to determine whether prolonged betamethasone therapy is, as has been suggested, associated with adverse maternal or neonatal outcomes. STUDY DESIGN: A secondary multivariate analysis of a randomized controlled trial was performed to determine whether duration of betamethasone therapy was associated with adverse maternal or neonatal outcomes. RESULTS: There were 414 fetuses whose mothers were randomly assigned to trial groups. Final models included only valid cases without missing or averaged data (N = 367 to N = 412, depending on the model). Three or more sets of weekly betamethasone injections were given in 21.3% of cases and > or =4 sets were given in 12.3% of cases. Prolonged antenatal betamethasone therapy was not associated with increases in incidences of antenatal fever, chorioamnionitis, reduced birth weight, suppressed neonatal adrenal function, neonatal sepsis, or neonatal death. It was associated with larger birth weights (P <.05). CONCLUSION: Prolonged antenatal betamethasone therapy was not associated with higher risks of antenatal maternal fever, chorioamnionitis, reduced birth weight, neonatal adrenal suppression, neonatal sepsis, and neonatal death.

Adrenal Insufficiency↗
PubMed2001

Home apnea monitor use in preterm infants discharged from newborn intensive care units.

PURPOSE: To identify current factors associated with home apnea monitor use in preterm infants and to determine whether home monitor use was associated with a shorter length of hospital stay. SETTING: We evaluated neonates who were < or =34 weeks' estimated gestational age and admitted for neonatal intensive care. We excluded neonates with congenital anomalies, neonates transferred out before discharge, and neonates who died. METHODS: Using a database created with a computer-assisted tool that generates hospital notes, we reviewed the epidemiology of monitor use. Differences between neonates sent home with an apnea monitor and those who were not were evaluated by using stepwise logistic regression analysis to identify which factors were independently associated with a neonate being discharged with a monitor. RESULTS: We studied 14,532 neonates; 1588 (11%) were sent home with monitors and 12,944 (89%) were not. The most important variables associated with being discharged with a monitor were site of care and a diagnosis of apnea. Site variation remained significant when adjusted for gestational age, diagnosis of apnea, and a history of use of methylxanthines. When corrected for gestational age, monitor use was not associated with shorter hospital stays. CONCLUSION: The data suggest that monitor use is more dependent on physician preference than medical indication and is not associated with earlier hospital discharge.

Apgar Score↗
PubMed2001

Are very low birth weight infants born at high altitude at greater risk for adverse outcomes?

OBJECTIVE: To determine if neonatal intensive care at higher altitudes was associated with any variation in mortality or morbidity. METHODS: We reviewed demographic and outcome data on 5450 neonates with birth weights between 500 and 1500 g cared for in 76 different level II and III neonatal intensive care units (NICUs). The altitude break point of 4300 feet was prospectively chosen. Care was provided at 63 NICUs located below 4300 feet, "low-altitude," (n = 4534 neonates) and at 13 NICUs at or above 4300 feet, "high-altitude" (n = 916 neonates). RESULTS: Compared with neonates cared for at low altitude, neonates cared for at high altitude were more often non-Hispanic white and exposed to prenatal steroids. Neonates born at high altitude were more often treated with surfactant (60% vs 53%, P <.01). At 28 days of age, neonates cared for at high altitude were less often in room air (33% vs 50%, P <.01) compared with neonates cared for at low altitude. However, when corrected for barometric pressure, the calculated partial pressure of inspired oxygen at 28 days of age was lower for neonates cared for at high altitude compared with low altitude (165 +/- 80 vs 183 +/- 57, P <.01). There were no differences in the rates of mortality, severe intraventricular hemorrhage (grades 3 and 4), severe retinopathy of prematurity (stages 3 and 4), or necrotizing enterocolitis requiring surgical treatment. CONCLUSIONS: Being cared for at NICUs located above 4300 feet above sea level was not associated with any increase in adverse events compared with NICUs located below 4300 feet.

Altitude↗
PubMed2001

Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor alpha or beta.

Cardiac myocytes express the two thyroid hormone receptors (T(3)Rs), T(3)Ralpha and T(3)Rbeta. However, which isoform contributes to specific, T(3)-induced alterations of cardiac function remains unclear. Here, we used individual T(3)R isoform knockout (KO) mice to study the effects of T(3)Ralpha and T(3)Rbeta in the heart. Our findings indicate that potassium channel genes that code for K(+) channels involved in action potential repolarization, like KV 4.2 and minK, are T(3)Ralpha targets. Both are markedly regulated by thyroid status. The recently identified cyclic nucleotide-gated channels, HCN2 and HCN4, are targets of T(3)Ralpha and are unchanged in a euthyroid T(3)Rbeta KO. However, these transcripts respond markedly to altered T(3) signaling concomitant with bradycardia in T(3)Ralpha KO and hypothyroid animals, as well as tachycardia in hyperthyroid T(3)Rss KO mice. SERCA2a and myosins are T(3) regulated and were also targets of T(3)Ralpha, and the papillary muscles of alphaKO animals showed a slowed rate of force development. Because of the absence of significant cardiac effects in euthyroid T(3)Rss KO mice, we determined messenger RNA levels for both T(3)Ralpha and T(3)Rss in the heart. We found that T(3)Rss is present at a 1:3 ratio to T(3)Ralpha1. We conclude that the cardiac phenotype regulated by T(3) is predominantly mediated by T(3)Ralpha and that the lack of T(3)Ralpha cannot be compensated by T(3)Rss in the heart.

Animals↗
PubMed2001

Fas ligand is targeted to secretory lysosomes via a proline-rich domain in its cytoplasmic tail.

Fas ligand (FasL) induces apoptosis through its cell surface receptor Fas. T lymphocytes and natural killer cells sort newly synthesised FasL to secretory lysosomes but, in cell types with conventional lysosomes, FasL appears directly on the plasma membrane. Here, we define a proline-rich domain (PRD) in the cytoplasmic tail of FasL that is responsible for sorting FasL to secretory lysosomes. Deletion of this PRD results in cell surface expression of FasL in cells with secretory lysosomes. Positively charged residues flanking the PRD are crucial to the sorting motif and changing the charge of these residues causes mis-sorting to the plasma membrane. In cells with conventional lysosomes, this motif is not recognised and FasL is expressed at the plasma membrane. The FasL PRD is not required for endocytosis in any cell type, as deletion mutants lacking this motif are endocytosed efficiently to the lysosomal compartment. Endogenous FasL cannot internalise extracellular antibody, demonstrating that FasL does not transit the plasma membrane en route to the secretory lysosomes. We propose that an interaction of the PRD of FasL with an SH3-domain-containing protein, enables direct sorting of FasL from the Golgi to secretory lysosomes.

Amino Acid Sequence↗
PubMed2001

A highly conserved c-fms gene intronic element controls macrophage-specific and regulated expression.

The c-fms gene encodes the receptor for macrophage colony-stimulating factor-1. This gene is expressed selectively in the macrophage cell lineage. Previous studies have implicated sequences in intron 2 that control transcript elongation in tissue-specific and regulated expression of c-fms. Four macrophage-specific deoxyribonuclease I (DNase I)-hypersensitive sites (DHSs) were identified within mouse intron 2. Sequences of these DHSs were found to be highly conserved compared with those in the human gene. A 250-bp region we refer to as the fms intronic regulatory element (FIRE), which is even more highly conserved than the c-fms proximal promoter, contains many consensus binding sites for macrophage-expressed transcription factors including Sp1, PU.1, and C/EBP. FIRE was found to act as a macrophage-specific enhancer and as a promoter with an antisense orientation preference in transient transfections. In stable transfections of the macrophage line RAW264, as well as in clones selected for high- and low-level c-fms mRNA expression, the presence of intron 2 increased the frequency and level of expression of reporter genes compared with those attained using the promoter alone. Removal of FIRE abolished reporter gene expression, revealing a suppressive activity in the remaining intronic sequences. Hence, FIRE is shown to be a key regulatory element in the fms gene.

3T3 Cells↗
PubMed2000

Emergent mechanical properties of self-assembled polymeric capsules.

Synthetic self-assembled systems combine responsiveness and reversibility with the ability to perform chemical tasks such as molecular recognition and catalysis. An unmet challenge is the construction of polymeric materials that, like nature's tubulin, are simultaneously reversible and capable of useful physical tasks. We report here a class of reversibly formed polymers that show covalent-polymer mechanical integrity in solution and in the solid state. Non-Newtonian, polymeric behavior is observed despite the low molecular weight of the individual subunits and the seemingly weak forces holding the assemblies together. These polymers assemble through self-complementary hydrogen bonding and by physical encapsulation of small molecules; accordingly, the emergent macroscopic structure and function can be controlled by appropriate chemical signals.

Calixarenes↗
PubMed2000

From genes to proteins: high-throughput expression and purification of the human proteome.

The development of high-throughput methods for gene discovery has paved the way for the design of new strategies for genome-scale protein analysis. Lawrence Livermore National Laboratory and Onyx Pharmaceuticals, Inc., have produced an automatable system for the expression and purification of large numbers of proteins encoded by cDNA clones from the IMAGE (Integrated Molecular Analysis of Genomes and Their Expression) collection. This high-throughput protein expression system has been developed for the analysis of the human proteome, the protein equivalent of the human genome, comprising the translated products of all expressed genes. Functional and structural analysis of novel genes identified by EST (Expressed Sequence Tag) sequencing and the Human Genome Project will be greatly advanced by the application of this high-throughput expression system for protein production. A prototype was designed to demonstrate the feasibility of our approach. Using a PCR-based strategy, 72 unique IMAGE cDNA clones have been used to create an array of recombinant baculoviruses in a 96-well microtiter plate format. Forty-two percent of these cDNAs successfully produced soluble, recombinant protein. All of the steps in this process, from PCR to protein production, were performed in 96-well microtiter plates, and are thus amenable to automation. Each recombinant protein was engineered to incorporate an epitope tag at the amino terminal end to allow for immunoaffinity purification. Proteins expressed from this system are currently being analyzed for functional and biochemical properties.

Cloning, Molecular↗
PubMed2000

A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection: selection of thymidine analog regimen therapy (START I).

BACKGROUND: No clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. OBJECTIVE: To compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DESIGN: Randomized, open-label, multi-center. SETTING: Fifteen HIV clinical research centers. PATIENTS: Two-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts > or = 200 x 10(6)/l and HIV-1 RNA > or = 10,000 copies/ml (bDNA assay), modified to 5000 copies/ml. INTERVENTION: d4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MEASUREMENTS: Primary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA < or = 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. RESULTS: For HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, -0.204 to 0.036; P= 0.213], with 49% and 47% respectively achieving < or = 50 copies/ml at 48 weeks (90% CI, -0.134 to 0.096; P = 0.834). Median change in CD4 cell counts at 48 weeks was +227 x 10(6)/l and +198 x 10(6)/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 x 10(6)/l versus 110 x 10(6)/l; P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. CONCLUSIONS: These results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

Anti-HIV Agents↗
PubMed2000

Intracerebellar conditioning--Brogden and Gantt revisited.

In 1942, Brogden and Gantt reported that electrical stimulation of cerebellar white matter elicited specific behavioral responses (limb flexion, eyeblink, etc.) and that these movements so elicited could easily be conditioned to a neural tone CS, using standard Pavlovian procedures. This early evidence for the key role of the cerebellum in learning of discrete movements has in recent years been replicated and much extended. It is now clear that the cerebellum is the essential structure for associative learning of discrete movements elicited by peripheral aversive or intracerebellar stimuli and that the memory traces so formed are stored in the cerebellum.

Animals↗