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Biomedical subjects

John Ross

Publications and source records attributed to John Ross.

At least 37 records · Page 2Linked to original sources
PubMed2005

Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog.

The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release-inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses. These findings from studies on humans suggest a mechanism whereby diminished catestatin might increase the risk for hypertension. We generated Chga and humanized mice through transgenic insertion of a human CHGA haplotype in order to probe CHGA and catestatin in vivo. Chga mice displayed extreme phenotypic changes, including: (a) decreased chromaffin granule size and number; (b) elevated BP; (c) loss of diurnal BP variation; (d) increased left ventricular mass and cavity dimensions; (e) decreased adrenal catecholamine, neuropeptide Y (Npy), and ATP contents; (f) increased catecholamine/ATP ratio in the chromaffin granule; and (g) increased plasma catecholamine and Npy levels. Rescue of elevated BP to normalcy was achieved by either exogenous catestatin replacement or humanization of Chga mice. Loss of the physiological "brake" catestatin in Chga mice coupled with dysregulation of transmitter storage and release may act in concert to alter autonomic control of the circulation in vivo, eventuating in hypertension.

Animals↗
PubMed2005

'Goodbye and good luck': the mental health needs and treatment experiences of British ex-service personnel.

BACKGROUND: Little is known about the psychological health or treatment experiences of those who have left the British armed forces. AIMS: To describe the frequency and associations of common mental disorders and help-seeking behaviours in a representative sample of UK veterans at high risk of mental health problems. METHOD: A cross-sectional telephone survey of 496 'vulnerable' ex-service personnel selected from an existing epidemiological military cohort. RESULTS: The response rate was 64%; 44% of these had a psychiatric diagnosis, most commonly depression. Those with a diagnosis were more likely to be of lower rank and divorced or separated. Just over half of those with self-reported mental health problems were currently seeking help, most from their general practitioners. Most help-seekers received treatment, usually medication; 28% were in touch with a service charity and 4% were receiving cognitive-behavioural therapy. CONCLUSIONS: Depression is more common than post-traumatic stress disorder in UK ex-service personnel. Only about half of those who have a diagnosis are seeking help currently, and few see specialists.

Adult↗
PubMed2004

Usefulness of myocardial contrast echocardiographic quantification of risk area for predicting postprocedural complications in patients undergoing septal ethanol ablation for obstructive hypertrophic cardiomyopathy.

Septal ethanol ablation (SEA) is an alternative to surgical myectomy in patients who have drug-refractory obstructive hypertrophic cardiomyopathy. However, permanent atrioventricular conduction block is seen more frequently with SEA. To determine whether septal infarction risk area (SIRA) predicts outcome in patients who have obstructive hypertrophic cardiomyopathy and are undergoing SEA, we evaluated 51 patients (mean age 60 +/- 16, 53% women) who had a successful SEA at Toronto General Hospital (November 1998 to June 2003). Intracoronary myocardial contrast echocardiography that targeted the contact area between the septum and the anterior mitral leaflet was performed before ethanol injection. End-systolic myocardial contrast echocardiographic frames were color coded for better delineation of contrast borders, and myocardial contrast echocardiographic area was calculated by planimetry. Patients were assigned to 1 of 2 groups by median SIRA value (3.51 cm(2), range 0.4 to 7.8). The 2 groups did not differ significantly in age, medication before SEA, electrocardiographic characteristics, left ventricular function, left atrial diameter, volume of intracoronary ethanol injected, peak creatine kinase after ablation, and baseline and follow-up left ventricular outflow tract gradients at rest. Patients in the large SIRA group had greater hypertrophy and a larger septal artery than did patients in the small SIRA group. In the small SIRA group, 3 patients (11.5%) had pacemaker implantation; in the large SIRA group, 12 patients (48.0%) had complications after SEA (pacemaker in 5 patients, implantable defibrillator in 5 patients, death in 2 patients; p = 0.008). We conclude that patients who have hypertrophic cardiomyopathy with a small, well-localized SIRA benefit similarly from SEA as patients who have a larger SIRA but with significantly fewer serious complications.

Cardiomyopathy, Hypertrophic↗
PubMed2004

Extraction of kinetic information from single-molecule experiments.

We discuss two possible approaches for extracting kinetic information from single-molecule experiments. The first approach is based on computing correlation functions from measured fluorescence signals, and the second on studying the statistics of on and off times of the same fluorescence signal. We show that in both cases it is possible to extract kinetic information about the nature of intramolecular fluctuations of the single molecule. We show that for single-molecule kinetics the intramolecular fluctuations produce stochastic memory effects which lead to new dynamic features that do not exist in traditional chemical kinetics. In particular, we investigate a new type of chemical oscillations in correlation functions observed experimentally by Edman and Rigler (Proc. Natl. Acad. Sci. USA 2000, 97, 8266).

Fluorescence↗
PubMed2004

Small proline-rich protein 1A is a gp130 pathway- and stress-inducible cardioprotective protein.

The interleukin-6 cytokines, acting via gp130 receptor pathways, play a pivotal role in the reduction of cardiac injury induced by mechanical stress or ischemia and in promoting subsequent adaptive remodeling of the heart. We have now identified the small proline-rich repeat proteins (SPRR) 1A and 2A as downstream targets of gp130 signaling that are strongly induced in cardiomyocytes responding to biomechanical/ischemic stress. Upregulation of SPRR1A and 2A was markedly reduced in the gp130 cardiomyocyte-restricted knockout mice. In cardiomyocytes, MEK1/2 inhibitors prevented SPRR1A upregulation by gp130 cytokines. Furthermore, binding of NF-IL6 (C/EBPbeta) and c-Jun to the SPRR1A promoter was observed after CT-1 stimulation. Histological analysis revealed that SPRR1A induction after mechanical stress of pressure overload was restricted to myocytes surrounding piecemeal necrotic lesions. A similar expression pattern was found in postinfarcted rat hearts. Both in vitro and in vivo ectopic overexpression of SPRR1A protected cardiomyocytes against ischemic injury. Thus, this study identifies SPRR1A as a novel stress-inducible downstream mediator of gp130 cytokines in cardiomyocytes and documents its cardioprotective effect against ischemic stress.

Adenoviridae↗
PubMed2004

Asymmetric septal hypertrophy in heterozygous cMyBP-C null mice.

OBJECTIVE: Cardiac myosin-binding protein C (cMyBP-C) gene mutations are involved in familial hypertrophic cardiomyopathy (FHC). Many of these mutations produce truncated proteins, which are unstable in the cardiac tissue of patients, suggesting that haploinsufficiency could account for the development of the phenotype. However, existing mouse models of cMyBP-C gene mutations have represented hypomorphic alleles without evidence of asymmetric septal hypertrophy, a key FHC phenotypic feature. In the present study, we generated a new model of cMyBP-C null mice and characterized the phenotype in both homozygotes and heterozygotes at different ages. METHODS: The mouse model was based upon the targeted deletion of exons 1 and 2, which contain the transcription initiation site, and the phenotype was determined by molecular, functional and morphological analyses. RESULTS: Herein, we demonstrate that inactivation of one or two mouse cMyBP-C alleles leads to different cardiac disorders at different post-natal time windows. The homozygous cMyBP-C null mice do not express the cMyBP-C gene, develop eccentric left ventricular hypertrophy with decreased fractional shortening at 3-4 months of age and a markedly impaired relaxation after 9 months. This is associated with myocardial disarray and an increase of interstitial fibrosis. The heterozygous cMyBP-C null mice present a slight but significant decrease of cMyBP-C amount and develop asymmetric septal hypertrophy associated with fibrosis at 10-11 months of age. CONCLUSION: These data provide evidence that heterozygous cMyBP-C null mice represent the first model with a key feature of human FHC that is asymmetric septal hypertrophy.

Animals↗
PubMed2004

Enhanced (hydrodynamic) transport induced by population growth in reaction-diffusion systems with application to population genetics.

We consider a system made up of different physical, chemical, or biological species undergoing replication, transformation, and disappearance processes, as well as slow diffusive motion. We show that for systems with net growth the balance between kinetics and the diffusion process may lead to fast, enhanced hydrodynamic transport. Solitary waves in the system, if they exist, stabilize the enhanced transport, leading to constant transport speeds. We apply our theory to the problem of determining the original mutation position from the current geographic distribution of a given mutation. We show that our theory is in good agreement with a simulation study of the mutation problem presented in the literature. It is possible to evaluate migratory trajectories from measured data related to the current distribution of mutations in human populations.

Diffusion↗
PubMed2004

Vision: the world through picket fences.

Our visual system must allow us to see the form of objects in motion. Tracking objects of interest stabilises their images on the retina, but is not sufficient, as untracked images move on the retina. This problem is solved by cells tuned in both space and time, combining information about form with information about motion.

Form Perception↗
PubMed2004

Response experiments for nonlinear systems with application to reaction kinetics and genetics.

A unified type of response experiment is suggested for complex systems made up of individual species (atoms, molecules, quasi-particles, biological organisms, etc.). We make the following assumptions: (i) some of the species may exist in two forms, labeled and unlabeled, respectively; (ii) the kinetic and transport properties of the labeled and unlabeled species are the same, respectively (neutrality assumption); (iii) the experiment preserves the total input and output fluxes; only the fractions of the labeled compounds in the input and output fluxes are varied. Under these circumstances a linear integral superposition law connects the fractions of labeled species in the input and output fluxes. This linear superposition law is valid for homogeneous and inhomogeneous systems and for systems with intrinsic (hidden) state variables; it arises from the neutrality condition and holds even though the underlying dynamics of the process may be highly nonlinear. Because this response law does not involve the linearization of the evolution equations it has great potential for the analysis of complex physical, chemical, and biological systems. We compare our approach with the linearization techniques used in biochemistry and genetics. We consider a simple reaction network involving replication, transformation, and disappearance steps and study the influence of experimental (measurement) and linearization errors on the evaluated values of rate coefficients. We show that the method involving the linearization of the kinetic equations leads to unpredictable results; because of the interference between measurement and linearization errors, either error compensation or error amplification occurs. Although our approach does not eliminate the effects of measurement errors, it leads to more consistent results. For a broad range of input fractions no error amplification or compensation occurs, and the error range for the rate coefficients is about the same as the error range of the measurements.

Genetics, Medical↗
PubMed2004

Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart.

Many genetic diseases are caused by mutations in cis-acting splicing signals, but few are triggered by defective trans-acting splicing factors. Here we report that tissue-specific ablation of the splicing factor SC35 in the heart causes dilated cardiomyopathy (DCM). Although SC35 was deleted early in cardiogenesis by using the MLC-2v-Cre transgenic mouse, heart development appeared largely unaffected, with the DCM phenotype developing 3-5 weeks after birth and the mutant animals having a normal life span. This nonlethal phenotype allowed the identification of downregulated genes by microarray, one of which was the cardiac-specific ryanodine receptor 2. We showed that downregulation of this critical Ca2+ release channel preceded disease symptoms and that the mutant cardiomyocytes exhibited frequency-dependent excitation-contraction coupling defects. The implication of SC35 in heart disease agrees with a recently documented link of SC35 expression to heart failure and interference of splicing regulation during infection by myocarditis-causing viruses. These studies raise a new paradigm for the etiology of certain human heart diseases of genetic or environmental origin that may be triggered by dysfunction in RNA processing.

Animals↗
PubMed2004

A nitric oxide-releasing derivative of enalapril, NCX 899, prevents progressive cardiac dysfunction and remodeling in hamsters with heart failure.

Nitric oxide (NO) production is known to be impaired in heart failure. A new compound (NCX 899), a NO-releasing derivative of enalapril was characterized, and its actions were evaluated in Bio 14.6 cardiomyopathic (CM) hamsters with heart failure. The hamsters were randomized to oral treatment for 4 weeks with vehicle (n=11), NCX 899 (NCX, 25 mg/kg, n=10), or enalapril (25 mg/kg, n=10). In the vehicle group, fractional shortening by echocardiography decreased (-23.6+/-2.0%) and LV end-diastolic dimension) increased (+10.9+/-1.0%), whereas fractional shortening increased (+17.5+/-4.4%) in NCX and was unchanged in the enalapril group (both P<0.01 vs. vehicle). End-diastolic dimension decreased only in NCX. LV contractility (LVdP/dt max and Emax) was significantly greater in NCX than in enalapril or vehicle, while relaxation (Tau) was shortened in both NCX and enalapril vs. vehicle. ACE activity was inhibited equally by NCX and enalapril in the CM hamster, and plasma nitrate levels were increased only in NCX (P<0.05 vs. enalapril and vehicle). In aortic strips endothelium-independent relaxation occurred only with NCX. The superior effects of NO-releasing enalapril (NCX) vs. enalapril alone to enhance vascular effects, increase LV contractility and prevent unfavorable remodeling and are consistent with vascular delivery of exogenous NO. NCX 899 may hold promise for the future treatment of heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Acute airway management in the emergency department by non-anesthesiologists.

PURPOSE: The responsibility of acute airway management often falls into the hands of non-anesthesiologists. Emergency physicians now routinely use neuromuscular blockade to facilitate intubation. The literature in support of this practice has almost exclusively been published in emergency medicine (EM) journals. This body of literature is presented and issues of educational support are discussed. SOURCE: A narrative review of the literature on the practice of airway management by non-anesthesiologists. PRINCIPAL FINDINGS: A significant proportion of acute airway management occurring outside the operating room is being performed by non-anesthesiologists. Rapid sequence intubation (RSI) is recognized as a core procedure within the domain of EM. RSI is being performed routinely by emergency physicians practicing in larger centres. Anesthesiologist support for the practice of RSI by non-anesthesiologists has been weak. Formal educational support outside of postgraduate training in the form of dedicated programs for advanced airway management are now being offered. The majority of the literature on the use of RSI by non-anesthesiologists represents retrospective case series, observational studies and registry data published in EM journals. The reported success rates for RSI performed by non-anesthesiologists is high. Complication rates are significant, however reporting consistency has been poor. CONCLUSIONS: The role of non-anesthesiologists in acute airway management is significant. Despite shortcomings in methodology, current evidence and practice supports the use of RSI by trained emergency physicians. Constructive collaborative efforts between anesthesiology and EM need to occur to ensure that educational needs are met and that competent airway management is provided.

Anesthesiology↗
PubMed2004

N-acetylcysteine reduces contrast-associated nephropathy but not clinical events during long-term follow-up.

BACKGROUND: Contrast-associated nephropathy (CAN) is associated with increased morbidity and mortality following percutaneous coronary intervention (PCI). N-acetylcysteine (NAC) has been shown to reduce the risk of nephropathy; however, the impact of NAC on long-term clinical outcomes has not been assessed. METHODS: This randomized, double-blind, placebo-controlled trial enrolled 180 patients with moderate renal dysfunction undergoing PCI or coronary angiography with a high likelihood of ad hoc PCI; 171 patients completed the clinical follow-up. Patients received oral NAC (2000 mg/dose, n = 95) or placebo (n = 85) twice a day for 3 doses if randomized the night prior to the procedure, and 2 doses if randomized the day of the procedure. The primary end point was the incidence of a > or =25% increase in serum creatinine level 48 to 72 hours after PCI. Secondary end points were the inhospital incidence of death, nonfatal myocardial infarction, or urgent dialysis, and the 9-month incidence of death, nonfatal myocardial infarction, need for dialysis, or repeat hospitalization for cardiac reasons. RESULTS: CAN occurred in 9.6% of patients assigned to NAC and 22.2% of patients assigned to placebo (P =.04); 1 patient receiving NAC required urgent dialysis. The inhospital composite end point occurred in 7 (7.4%) NAC-treated and 3 (3.5%) placebo-treated patients, P = NS. At 9 months, the composite end point occurred in 23 (24.2%) NAC-treated patients and 18 (21.2%) placebo-treated, P = NS. CONCLUSION: Although high-dose NAC prevented periprocedural CAN, this benefit did not translate into a decrease in adverse outcomes over 9 months. Further studies to determine the clinical utility of this drug are required.

Acetylcysteine↗
PubMed2004

The perceived direction and speed of global motion in Glass pattern sequences.

Observers indicated the perceived direction of global motion in sequences of noisy Glass patterns containing real motion signals in directions that conflicted with the orientation of signal dipoles in the Glass patterns. Dipole orientation influenced the perceived direction of motion. Observers also judged the apparent speed of sequences of independent noiseless Glass and Glass Line patterns (dipoles replaced by lines). Speed was high and increased with the length of lines in Glass Line patterns but not with dipole separation in Glass patterns. When real motion signals were added to sequences of noisy Glass patterns they exerted an influence on apparent speed that increased with motion signal strength but was independent of pattern signal strength. The results suggest that pattern exerts a global influence on the computation of motion direction and, possibly, on speed.

Humans↗
PubMed2004

Molecular determinants of the physiological adaptation to stress in the cardiomyocyte: a focus on AKT.

Cardiomyocytes (CMCs) adapt to physiological or pathological stimuli by undergoing molecular changes which differentiate according to the specificity of the stimulus and eventually generate a phenotype with peculiar molecular characteristics. Here, we review the literature on the molecular mechanisms activated in the CMC during physiologic adaptation to stress, as opposed to maladaptation. The critical role of the IGF-1 receptor/PI3K/Akt signaling pathway during this process is described, including effector targets regulating inotropism and cell size.

Adaptation, Physiological↗
PubMed2004

Same-day discharge after coronary stenting: a feasibility study using a hemostatic femoral puncture closure device.

A major limiting factor for percutaneous coronary interventions carried out via the femoral route is the time it takes to achieve femoral artery hemostasis and subsequent mobilization. Discharge from hospital usually occurs the following day. In this pilot study, we assessed the feasibility of mobilization at 4 hours and same-day discharge from hospital of selected elective patients undergoing intracoronary stenting using the Angio-Seal Vascular Closure device. Seventy-five patients (56 +/- 10 years) with stable single-vessel coronary disease scheduled for elective coronary stenting were enrolled. All patients were mobilized at 4 hours and assessed at 10 hours postprocedure as to their suitability for hospital discharge. The first 50 patients remained in hospital overnight. The next 25 patients followed the same procedures but were discharged at 10 hours. The subjects were followed up at 48 hours and 30 days. Hemostasis was achieved in all patients following sheath removal and deployment of the Angio-Seal device. Twenty patients (27%) had minor groin oozing and two developed small hematoma. There were no major bleeding complications, pseudoaneurysm, vascular surgery, or groin infection. Groin oozing resulted in the delay of ambulation for 13 subjects but discharge was not delayed in any patient. All patients were reported to be suitable for hospital discharge at 10 hours postprocedure. There were no further complications at 30 days. The present study demonstrated that early mobilization and same-day discharge after coronary stenting using the Angio-Seal device is feasible in selected patients. Further studies are needed to determine the patient selection criteria and the potential cost-saving implications of this strategy.

Adolescent↗
PubMed2004

Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats.

Ablation or inhibition of phospholamban (PLN) has favorable effects in several genetic murine dilated cardiomyopathies, and we showed previously that a pseudophosphorylated form of PLN mutant (S16EPLN) successfully prevented progressive heart failure in cardiomyopathic hamsters. In this study, the effects of PLN inhibition were examined in rats with heart failure after myocardial infarction (MI), a model of acquired disease. S16EPLN was delivered into failing hearts 5 weeks after MI by transcoronary gene transfer using a recombinant adeno-associated virus (rAAV) vector. In treated (MI-S16EPLN, n = 16) and control (MI-saline, n = 18) groups, infarct sizes were closely matched and the left ventricle was similarly depressed and dilated before gene transfer. At 2 and 6 months after gene transfer, MI-S16EPLN rats showed an increase in left ventricular (LV) ejection fraction and a much smaller rise in LV end-diastolic volume, compared with progressive deterioration of LV size and function in MI-saline rats. Hemodynamic measurements at 6 months showed lower LV end-diastolic pressures, with enhanced LV function (contractility and relaxation), lowered LV mass and myocyte size, and less fibrosis in MI-S16EPLN rats. Thus, PLN inhibition by in vivo rAAV gene transfer is an effective strategy for the chronic treatment of an acquired form of established heart failure.

Animals↗