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Biomedical subjects

J Ross

Publications and source records attributed to J Ross.

At least 163 records · Page 9Linked to original sources
PubMed1997

Ras-dependent pathways induce obstructive hypertrophy in echo-selected transgenic mice.

To overcome the genetic and interindividual variability frequently noted in complex phenotypes, we used echocardiographic selection to develop a substrain of myosin light chain (MLC)-Ras (RAS) transgenic mice with an enhanced ventricular hypertrophic phenotype. These echo-selected mice were then compared with wild-type (WT) animals and a pressure overload hypertrophy model (transverse aortic constriction; TAC). Echocardiography demonstrated increased wall thickness in RAS compared with the other groups. We developed novel miniaturized physiological technology to quantitatively identify in vivo intraventricular gradients; increased systolic Doppler velocity was seen in the left ventricle (LV) in 69% of RAS vs. none of WT or TAC. Intracavitary pressure gradients were present in 3 of 10 RAS vs. none of TAC or WT. Passive diastolic LV stiffness was not different among the three groups. Myofibrillar disarray was present in all RAS animals and was significantly more extensive (21.7% area fraction) than in TAC (1.5%) or WT (0.0%). RAS mice had selective induction of natriuretic peptide genes in the LV, a pattern distinct from that induced by pressure overload. Juvenile mortality was significantly increased in the offspring of echo-selected RAS parents. We conclude that adaptation of echocardiography to the mouse permits selection for cardiac phenotypes, and that selectively inbred MLC-Ras transgenic mice faithfully reproduce the molecular, physiological, and pathological features of human hypertrophic cardiomyopathy (HCM). Because previous studies support the concept that hypertrophy in human HCM is secondary to dysfunction created by sarcomeric protein mutations, the current studies suggest that Ras-dependent pathways might play a similar role in forms of human HCM.

Age Factors↗
PubMed1997

Caring for older people in the community.

This is a brief report of the aims and structure of a two-year project, which commenced in August 1996, researching the educational needs of nurses who care for older people in the community. The study involves the development and evaluation of an educational programme designed to help improve the efficiency of nurses working in this area.

Clinical Competence↗
PubMed1997

Compression of visual space before saccades.

Saccadic eye movements, in which the eye moves rapidly between two resting positions, shift the position of our retinal images. If our perception of the world is to remain stable, the visual directions associated with retinal sites, and others they report to, must be updated to compensate for changes in the point of gaze. It has long been suspected that this compensation is achieved by a uniform shift of coordinates driven by an extra-retinal position signal, although some consider this to be unnecessary. Considerable effort has been devoted to a search for such a signal and to measuring its time course and accuracy. Here, by using multiple as well as single targets under normal viewing conditions, we show that changes in apparent visual direction anticipate saccades and are not of the same size, or even in the same direction, for all parts of the visual field. We also show that there is a compression of visual space sufficient to reduce the spacing and even the apparent number of pattern elements. The results are in part consistent with electrophysiological findings of anticipatory shifts in the receptive fields of neurons in parietal cortex and superior colliculi.

Humans↗
PubMed1997

Developmental regulation of CRD-BP, an RNA-binding protein that stabilizes c-myc mRNA in vitro.

We previously isolated and characterized a coding region determinant-binding protein (CRD-BP) that might regulate c-myc mRNA post-transcriptionally. CRD-BP binds specifically to the coding region of c-myc mRNA and might stabilize c-myc mRNA in vitro by protecting it from endonucleolytic cleavage. Since c-myc abundance is regulated during embryonic development and cell replication, we investigated whether CRD-BP is also regulated in animal tissues. We focused on CRD-BP expression during rat liver development and liver regeneration, because c-myc mRNA is regulated post-transcriptionally in both cases. CRD-BP expression parallels c-myc expression during liver development; the protein is present in fetal and neonatal liver but is absent or in low abundance in adult liver. In contrast, the up-regulation of c-myc mRNA following partial hepatectomy is not accompanied by up-regulation of CRD-BP. To our knowledge, CRD-BP is the first example of a putative mammalian mRNA-binding protein that is abundant in a fetal tissue but either absent from or scarce in adult tissues. Its expression in fetal liver and in transformed cell lines suggests CRD-BP is an oncofetal protein.

Animals↗
PubMed1997

An endogenous calcium oscillator may control early embryonic division.

Transient elevations in the concentration of free cytosolic calcium ion ([Ca2+]i) promote cell phase transitions in early embryonic division and persist even if these transitions are blocked. These observations suggest that a [Ca2+]i oscillator is an essential timing element of the early embryonic "master clock." We explore this possibility by coupling a [Ca2+]i oscillator model to an early embryonic cell cycle model based on the protein interactions that govern the activity of the M-phase-promoting factor (MPF). We hypothesize three dynamical states of the MPF system and choose parameter sets to represent each. We then investigate how [Ca2+]i dynamics may control early embryonic division in both sea urchin and Xenopus embryos. To investigate both systems, distinct [Ca2+]i profiles matching those observed in sea urchin embryos (in which [Ca2+]i exhibits sharp transients) and Xenopus embryos (in which [Ca2+]i is elevated and oscillates sinusoidally) are imposed on each of the hypothesized dynamical states of MPF. In the first hypothesis, [Ca2+]i oscillations entrain the autonomous MPF oscillator. In the second and third hypotheses, where the MPF system rests in excitatory and bistable states, respectively, [Ca2+]i oscillations drive MPF activation cycles. Simulation results show that hypotheses two and three, in which a [Ca2+]i oscillator is a fundamental timing element of the master clock, best account for key experimental observations and the questions that they raise. Finally, we propose experiments to elucidate further [Ca2+]i regulation and the fundamental components of the early embryonic master clock.

Animals↗
PubMed1997

MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure.

MLP is a LIM-only protein of terminally differentiated striated muscle cells, where it accumulates at actin-based structures involved in cytoarchitecture organization. To assess its role in muscle differentiation, we disrupted the MLP gene in mice. MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth. Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture. At birth, these hearts were not hypertrophic, but already abnormally soft, with cell-autonomous and MLP-sensitive alterations in cytoarchitecture. Thus, MLP promotes proper cardiomyocyte cytoarchitecture, whose perturbation can lead to dilated cardiomyopathy. In vivo analysis revealed that MLP-deficient mice reproduce the morphological and clinical picture of dilated cardiomyopathy and heart failure in humans, providing the first model for this condition in a genetically manipulatable organism.

Animals↗
PubMed1997

A hypothesis to explain why translation inhibitors stabilize mRNAs in mammalian cells: mRNA stability and mitosis.

Protein synthesis inhibitors prolong the half-lives of most mRNAs at least fourfold in the somatic cells of higher eukaryotes and in yeast cells. Some mRNAs are stabilized because the inhibitors affect mRNA-specific regulatory factors; however, hundreds or thousands of other mRNAs are probably stabilized by a common mechanism. We propose that mRNA stabilization in cells treated with a translation inhibitor reflects a physiological process that occurs during each mitosis and is important for cell survival. Transcription and translation rates decline drastically during a 1-2 hour interval of mitosis. We hypothesize that translational repression during this interval somehow inactivates a critical component of the mRNA degradation machinery. As a result, mRNA half-lives are prolonged during the interval when transcription is repressed. If labile mRNAs were not stabilized during mitosis they, and perhaps also the labile proteins they encode, would be depleted as the cell entered G1 phase, with deleterious consequences. Stabilization during mitosis, or in response to translation inhibitors, thus preserves the capacity of the cell to synthesize essential proteins as it enters G1 or recovers from inhibitor treatment. mRNA stabilization might serve a similar purpose during starvation or any stress negatively affecting translation.

Animals↗
PubMed1997

Prepubertal varicoceles.

OBJECTIVES: Varicoceles are rarely detected in prepubertal boys. In an effort to further determine the natural history of prepubertal varicoceles, we have reviewed our experience with prepubertal boys who had varicoceles. METHODS: Eleven patients with prepubertal varicoceles were seen. The majority of patients (9 of 11) were asymptomatic. The mean age was 10.8 years (range 6 to 12). Ten of 11 patients had left-sided varicoceles. All varicoceles were grade III except for one that was grade II. Four patients underwent varicocele ligation, 3 via the Ivanessevich approach and 1 via the Palomo approach. RESULTS: The 4 patients who underwent varicocele ligation (operative group) had a follow-up that ranged from 6 to 72 months (mean 27.2) and the 7 patients who were observed (nonoperative group) had follow-up that ranged from 17 to 84 months (mean 40.8). All patients in the operative group exhibited "catch-up" growth of the affected testicle (mean relative testicular size 47% to 84% at follow-up). The relative left testicular size in the nonoperative group had decreased by a mean of 16.8% from the time of presentation (100% to 83.2% on follow-up). CONCLUSIONS: We conclude that prepubertal boys should be screened in the standing position for the presence of varicoceles. Secondary causes should be excluded. Patients may ultimately require intervention as our initial experience suggests improved testicular growth with early surgical repair.

Age Factors↗
PubMed1997

Syndromes and arthritis.

There are many questions and no clear answers raised by these children. These syndromes, however, seem to be biologic experiments of nature and present unique opportunities to study the various elements involved in the pathogenesis of arthritis. Pediatric rheumatologists are in a unique position to study these syndromes.

Adolescent↗
PubMed1997

Force-frequency relations in the failing rabbit heart and responses to adrenergic stimulation.

BACKGROUND: Recent experiments have documented the importance of beta-adrenergic regulation of the force-frequency relation (FFR) in the normal and failing heart. As in isolated human cardiac muscle, a descending limb of the FFR occurs at high frequencies in the intact rabbit heart, and therefore a new model of atrial pacing-induced heart failure was developed in the rabbit. Responses of the FFR to beta-adrenergic stimulation were then assessed in the conscious state before and after the induction of heart failure. METHODS AND RESULTS: Rapid atrial pacing for an average of 19.5 days in instrumented rabbits produced severe left ventricular dilation with reduced cardiac output (echocardiography) and depressed myocardial contractility and relaxation rate (left ventricular dP/dt, catheter-tip micromanometer), associated with reductions in beta-adrenergic receptor density and adenylyl cyclase activity. Before heart failure, heart rate was slowed in the conscious animal from 280 +/- 30 (SD) to about 225 beats/min using a sinus node inhibitor (zatebradine), and heart rate was then increased in steps by atrial pacing from 250 to 450 beats/min; the heart rate-versus-left ventricular dP/dtmax (FFR) response showed an ascending response (increasing contractility), with a descending limb at rates greater than 375 beats/min, and dobutamine infusion amplified the ascending limb of the FFR (increased slope) and attenuated the descending limb. In heart failure the basal FFR was severely depressed with a descending limb over 350 beats/min; dobutamine shifted the FFR upward somewhat without change in the slope of the ascending limb, whereas dobutamine prevented the descending limb of the FFR. Similar responses were observed in the relations between heart rate and cardiac output. CONCLUSIONS: A new model of heart failure in the conscious rabbit was developed using rapid atrial pacing and applied to study force-frequency effects. In heart failure, normal beta-adrenergic amplification of the ascending limb of the FFR by dobutamine was absent, but a marked descending limb of the FFR at higher heart rates was prevented by dobutamine. Observed reductions in components of the beta-adrenergic receptor system likely were responsible for impaired beta-adrenergic FFR amplification, but the mechanism(s) for the descending limb and its correction by dobutamine are not yet established. These responses of the FFR may influence importantly the ability of the failing heart to respond to exercise and stress.

Adrenergic beta-Agonists↗
PubMed1997

Inducible nitric oxide synthase in pancreatic islets of the non-obese diabetic mouse: a light and confocal microscopical study of its ontogeny, co-localization and up-regulation following cytokine administration.

Nitric oxide has been shown to mediate beta-cell destruction in rodent islets exposed to interleukin 1 beta in culture. The inhibitory effect is potentiated by tumour necrosis factor-alpha and interferon-gamma. Cytokine stimulation leads to gene transcription and translation of inducible nitric oxide synthase, the biosynthetic enzyme of nitric oxide. In the non-obese diabetic mouse, progressive invasion of pancreatic islets by immune cells may lead to local production of inflammatory cytokines, resulting in inducible nitric oxide synthase expression within the islets. In this study, the ontogeny of this enzyme and its cellular expression were examined in pancreatic sections of female non-obese diabetic mice by double-label immunofluorescence. Light and confocal microscopy were employed to study the up-regulation, co-localization and immunocytoplasmic distribution of the enzyme in female non-obese, diabetic and Swiss mice following cytokine treatment. From day 40 to day 220 a small number of beta-cells and a proportion of macrophages, usually in peri-islet and exocrine areas, expressed the enzyme. At onset of diabetes, an increasing number of macrophages within and surrounding the islets were positive for the enzyme. Treatment of day 60 female non-obese diabetic mice with interleukin 1 beta alone and in combination with tumour necrosis factor-alpha and/or interferon-gamma resulted in a significant influx of macrophages into the pancreas, while this was lower in female Swiss mice treated similarly. Cytokine administration led to intense but sometimes eccentric immunocytoplasmic labelling for the enzyme in a considerable proportion of macrophages and beta-cells. Macrophages positive for inducible nitric oxide synthase were located in peri- and intra-islet areas, being distal and adjacent to enzyme-positive and negative beta-cells. Treatment with tumour necrosis factor-alpha and/or interferon-gamma did not lead to enzyme up-regulation. These results show that in the non-obese diabetic mouse there is low and sustained expression of islet inducible nitric oxide synthase in the prediabetic period, which is followed by an increase around onset. However, treatment of female non-obese diabetic and Swiss mice with interleukin-1 beta, alone or together with tumour necrosis factor-alpha and/or interferon-gamma leads to a marked expression of this enzyme within macrophages and beta-cells.

Animals↗
PubMed1997

Merkel cell carcinoma arising after therapeutic immunosuppression.

Azathioprine and cyclosporin have been used as immunosuppressants for many years, but long-term use has also been associated with neoplasia. We report three cases of rapidly fatal Merkel cell carcinoma in patients who had been treated with azathioprine for many years either for rheumatoid arthritis or following organ transplantation. Two of these patients had also received cyclosporin. We suggest that Merkel cell carcinoma may be seen more commonly in immunosuppressed patients than in the normal population and that the oncogenic potential of azathioprine and cyclosporin should be borne in mind when prescribing these drugs.

Aged↗
PubMed1997

Human La protein: a stabilizer of histone mRNA.

Histone mRNA is destabilized at the end of S phase and in cell-free mRNA decay reaction mixtures supplemented with histone proteins, indicating that histones might autoregulate the histone mRNA half-life. Histone mRNA destabilization in vitro requires three components: polysomes, histones, and postpolysomal supernatant (S130). Polysomes are the source of the mRNA and mRNA-degrading enzymes. To investigate the role of the S130 in autoregulation, crude S130 was fractionated by histone-agarose affinity chromatography. Two separate activities affecting the histone mRNA half-life were detected. The histone-agarose-bound fraction contained a histone mRNA destabilizer that was activated by histone proteins; the unbound fraction contained a histone mRNA stabilizer. Further chromatographic fractionation of unbound material revealed only a single protein stabilizer, which was purified to homogeneity, partially sequenced, and found to be La, a well-characterized RNA-binding protein. When purified La was added to reaction mixtures containing polysomes, a histone mRNA decay intermediate was stabilized. This intermediate corresponded to histone mRNA lacking 12 nucleotides from its 3' end and containing an intact coding region. Anti-La antibody blocked the stabilization effect. La had little or no effect on several other cell cycle-regulated mRNAs. We suggest that La prolongs the histone mRNA half-life during S phase and thereby increases histone protein production.

Adenosine Triphosphatases↗
PubMed1997

Force-frequency effect is a powerful determinant of myocardial contractility in the mouse.

The effects of heart rate (HR) on myocardial contractility in the mouse heart in situ were first investigated in open-chest mice (n = 7) by left ventricular (LV) catheter-tip micromanometry. HR was first slowed with a sinus node inhibitor (zatebradine), and atrial pacing to progressively increase the HR caused a positive inotropic response (assessed by maximum positive first derivative of LV pressure, LV dP/dtmax) up to a HR of 282 beats/min with the onset of a descending limb of the force-frequency relation (FFR) at 332 beats/min. beta-Adrenergic receptor stimulation (dobutamine) shifted upward and significantly steepened the positive FFR and increased HR at the onset of the descending limb to 402 beats/min. HR and LV dP/dtmax were then studied in closed-chest mice without pacing during recovery from anesthesia (n = 7), and during rest and intermittent physical activity the FFR was linear and positive up to 600 beats/min. HR was then progressively slowed with zatebradine, and the points at rest and during activity fell on the same linear relation. Thus we conclude the following: 1) in the open-chest anesthetized mouse, a positive FFR was amplified by beta-adrenergic receptor stimulation, and 20 in the mouse recovering from anesthesia the sinus node rate remained a critical determinant of myocardial contractility, without a descending limb of the FFR.

Anesthesia, General↗
PubMed1997

Left ventricular volumes and function in the embryonic mouse heart.

This study describes miniaturized technology for the in vivo analysis of the volume and function of the embryonic mouse heart and the application of this technology to study the normal embryonic left ventricle (LV) at two stages of development. With the use of microsurgical techniques, embryos from embryonic day (ED) 10.5 (ED10.5) to ED16 were delivered individually from litters of normal dams, and cardiac visualization was achieved with the use of intravital microscopy by transillumination, with the umbilical circulation intact. At ED10.5-11, the heart could be imaged in color in the intact embryo, whereas at ED12.5 it was necessary to open the chest; at ED13.5-14.5, fluorescent imaging with the use of microinjection of fluorescein-conjugated albumin was necessary to visualize the LV chamber. At ED10.5-11, the LV end-diastolic volumes averaged 0.16 microliter (n = 14), and at ED13.5-14.5, they averaged 0.57 microliter (n = 16). At both ages there was a positive linear relationship between the LV end-diastolic volume and the stroke volume despite substantial variations in individual heart rates, reflecting the relative uniformity of the LV ejection fractions within each age group. The average of the individual ejection fractions was 27.4% at ED10.5-11 and 58.4% at ED13.5-14.5, the latter being within the normal range for the adult rodent heart. These methods will be useful for assessing in vivo cardiac function at ED10.5 and older murine embryos in litters of transgenic or gene-targeted mice when the mutation leads to later embryonic lethality.

Animals↗