Sudden unexpected death in infancy (SUDI).
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Child Abuse↗
Biomedical subjects
C M Loughrey
Publications and source records attributed to C M Loughrey.
Comparison of Ca2+ release and uptake characteristics of the sarcoplasmic reticulum in isolated horse and rabbit cardiomyocytes.
Both the cardiac action potential duration (APD) (0.6-1 s) and resting heart rate (30-40 beats/min) in the horse are significantly different from humans and smaller mammals, including the rabbit. This would be anticipated to have consequences for excitation-contraction (EC) coupling and require adaptation of the individual processes involved. The sarcoplasmic reticulum (SR) is one of the main components involved in EC coupling. This study examines and compares the activity of this organelle in the horse with that of the rabbit. In particular, the study focuses on SR Ca2+ release via the Ca2+ release channel/ryanodine receptor (RyR2) and Ca2+ uptake via the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) pump. Isolated cardiomyocytes from both horse and rabbit hearts were permeabilized, bathed in a mock intracellular solution, and exposed to a specified [Ca2+]. Rabbit cardiomyocytes exposed to 260 nM [Ca2+] produced spontaneous Ca2+ release and propagated Ca2+ waves. Horse cells failed to produce Ca2+ waves; instead, only local release in the form of Ca2+ sparks was evident. However, at 550 nM [Ca2+], Ca2+ waves were produced in both species. Ca2+ waves were four times less frequent yet approximately 1.5 times greater in amplitude in the horse compared with the rabbit. Ca2+ wave velocity was comparable between the species. The reason for this disparity in Ca2+ wave characteristics is unknown. Separate measurements of oxalate-supported Ca2+ uptake into the SR suggest that both horse and rabbit cardiomyocytes have comparable levels SERCA activity. The possible reasons for the observed differences in SR Ca2+ release between the horse and rabbit are discussed.
Animals↗
Over-expression of FK506-binding protein FKBP12.6 alters excitation-contraction coupling in adult rabbit cardiomyocytes.
This study investigated the function of FK506-binding protein (FKBP12.6) using adenoviral-mediated gene transfer to over-express FKBP12.6 (Ad-FKBP12.6) in adult rabbit ventricular cardiomyocytes. Infection with a beta-galactosidase-expressing adenovirus (Ad-LacZ) was used as a control. Peak-systolic intracellular [Ca(2+)] (measured with Fura-2) was higher in the Ad-FKBP12.6 group compared to Ad-LacZ (1 Hz field stimulation at 37 degrees C). The amplitude of caffeine-induced Ca(2+) release was also greater, indicating a higher SR Ca(2+) content in the Ad-FKBP12.6 group. Voltage clamp experiments indicated that FKBP12.6 over-expression did not change L-type Ca(2+) current amplitude or Ca(2+) efflux rates via the Na(+)-Ca(2+) exchanger. Ca(2+) transients comparable to those after Ad-FKBP12.6 transfection could be obtained by enhancing SR Ca(2+) content of Ad-LacZ infected cells with periods of high frequency stimulation. Line-scan confocal microscopy (Fluo-3 fluorescence) of intact cardiomyocytes stimulated at 0.5 Hz (20-21 degrees C) revealed a higher degree of synchronicity of SR Ca(2+) release and fewer non-responsive Ca(2+) release sites in the Ad-FKBP12.6 group compared to control. Ca(2+) spark morphology was measured in beta-escin-permeabilized cardiomyocytes at a free [Ca(2+)](i) of 150 nm. The average values of the spark parameters (amplitude, duration, width and frequency) were reduced in the Ad-FKBP12.6 group. Increasing [Ca(2+)](i) to 400 nm caused coherent propagating Ca(2+) waves in the Ad-FKBP12.6 group but only limited Ca(2+) release events were recorded in the control group. These data indicate that FKBP12.6 over-expression enhances Ca(2+) transient amplitude predominately by increasing SR Ca(2+) content. Moreover, there is also evidence that FKBP12.6 can enhance the coupling between SR Ca(2+) release sites independently of SR content.
Adenoviridae↗
Characterization of a range of fura dyes with two-photon excitation.
Two-photon excitation (TPE) spectra of Fura-2, -4F, -6F, -FF, and Furaptra were characterized using a tunable (750-850 nM) ultra-short pulse laser. Two-photon fluorescence of these dyes was studied in free solution and in the cytosol of isolated rabbit ventricular cardiomyocytes. The TPE spectra of the Ca(2+)-free and Ca(2+)-bound forms of the dyes were measured in free solution and expressed in terms of the two-photon fluorescence cross section (Goppert-Meyer units). The Fura dyes displayed the same Ca(2+)-free TPE spectrum in the intracellular volume of permeabilized and intact cardiomyocytes. Fluorescence measurements over a range of laser powers confirmed the TPE of both Ca(2+)-free and Ca(2+)-bound forms of the dyes. Single-wavelength excitation at 810 nM was used to determine the effective dissociation constants (K(eff)) and dynamic ranges (R(f)) of Fura-2, -4F, -6F, -FF, and Furaptra dyes (K(eff) = 181 +/- 52 nM, 1.16 +/- 0.016 micro M, 5.18 +/- 0.3 micro M, 19.2 +/- 1 micro M, and 58.5 +/- 2 micro M; and R(f) = 22.4 +/- 3.8, 12.2 +/- 0.34, 6.3 +/- 0.17, 16.1 +/- 2.8, and 25.4 +/- 4, respectively). Single-wavelength excitation of intracellular Fura-4F resolved diastolic and peak [Ca(2+)] in isolated stimulated cardiomyocytes after calibration of the intracellular signal using reversible exposure to low (100 micro M) extracellular [Ca(2+)]. Furthermore, TPE of Fura-4F allowed continuous, long-term (5-10 min) Ca(2+) imaging in ventricular cardiomyocytes using laser-scanning microscopy without significant cellular photodamage or photobleaching of the dye.
Animals↗
Fatal hepatic failure following accidental tramadol overdose.
A case of fatal overdose of tramadol is described, occurring in a 67-year-old man with painful rib fractures who accidentally ingested more than the recommended daily dose. The mode of death was acute liver failure due to fulminant hepatic necrosis. Post-mortem toxicology was negative apart from revealing a blood tramadol concentration well above the normal therapeutic range. This is the first report of fatal tramadol ingestion occurring in a therapeutic setting and also the first tramadol-related death where the mechanism was liver failure.
Accidents↗
Measurement of the dissociation constant of Fluo-3 for Ca2+ in isolated rabbit cardiomyocytes using Ca2+ wave characteristics.
The Ca(2+) dissociation constant (K(d)) of Fluo-3 was determined using confocal fluorescence microscopy in two different situations: (i) within the cytosol of a permeabilised cardiomyocyte; and (ii) in an intact cardiomyocyte after incubation with the acetoxymethyl ester form of Fluo-3 (AM). Measurements were made on isolated rabbit ventricular cardiomyocytes after permeabilisation by a brief treatment with beta-escin (0.1mg/ml) and equilibration with 10 microM Fluo-3. The K(d) of Fluo-3 within the cytosol was not significantly different from that in free solution (558 +/- 15 nM, n=6). Over a range of cytoplasmic [Ca(2+)], the minimum [Ca(2+)] values between Ca(2+) waves was relatively constant despite changes in wave frequency. After loading intact cardiomyocytes with Fluo-3 by incubation with the -AM, spontaneous Ca(2+) waves were produced by incubation with strophanthidin (10 microM). By assuming a common minimum [Ca(2+)] in permeabilised and intact cells, the intracellular K(d) of Fluo-3 in intact myocytes was estimated to be 898 +/-64 nM (n=6). Application of this K(d) to fluorescence records shows that Ca(2+) waves in intact cells have similar amplitudes to those in permeabilised cells. Stimulation of cardiac myocytes at 0.5 Hz in the absence of strophanthidin (room temperature) resulted in a Ca(2+) transient with a maximum and minimum [Ca(2+)] of 1190 +/- 200 and 158 +/- 30 nM (n=11), respectively.
Aniline Compounds↗
The relationship between intracellular [Ca(2+)] and Ca(2+) wave characteristics in permeabilised cardiomyocytes from the rabbit.
Spontaneous sarcoplasmic reticulum (SR) Ca(2+) release and propagated intracellular Ca(2+) waves are a consequence of cellular Ca(2+) overload in cardiomyocytes. We examined the relationship between average intracellular [Ca(2+)] and Ca(2+) wave characteristics. The amplitude, time course and propagation velocity of Ca(2+) waves were measured using line-scan confocal imaging of beta-escin-permeabilised cardiomyocytes perfused with 10 microM Fluo-3 or Fluo-5F. Spontaneous Ca(2+) waves were evident at cellular [Ca(2+)] > 200 nM. Peak [Ca(2+)] during a wave was 2.0-2.2 microM; the minimum [Ca(2+)] between waves was 120-160 nM; wave frequency was approximately 0.1 Hz. Raising mean cellular [Ca(2+)] caused increases in all three parameters, particularly Ca(2+) wave frequency. Increases in the rate of SR Ca(2+) release and Ca(2+) uptake were observed at higher cellular [Ca(2+)], indicating calcium-sensitive regulation of these processes. At extracellular [Ca(2+)] > 2 microM, the mean [Ca(2+)] inside the permeabilised cell did not increase above 2 microM. This extracellular-intracellular Ca(2+) gradient could be maintained for periods of up to 5 min before the cardiomyocyte developed a sustained and irreversible hypercontraction. Inclusion of mitochondrial inhibitors (2 microM carbonyl cyanide m-chlorophenylhydrazone and 2 microM oligomycin) while perfusing with > 2 microM Ca(2+) abolished the extracellular-intracellular Ca(2+) gradient through the generation of Ca(2+) waves with a higher peak [Ca(2+)] compared to control conditions. Under these conditions, cardiomyocytes rapidly (< 2 min) developed a sustained and irreversible contraction. These results suggest that mitochondrial Ca(2+) uptake acts to delay an increase in [Ca(2+)] by blunting the peak of the Ca(2+) wave.
Animals↗
Pearson's syndrome: a multisystem disorder.
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Anemia, Sideroblastic↗
Race and gender differences in cord blood lipoproteins.
Race and gender differences in lipoproteins and apolipoproteins have repeatedly been demonstrated in adults. The same disparities have been observed in children of different race and gender, implying that these differences may be influenced by genetic factors. To further explore this hypothesis, cord blood concentrations of both lipoproteins and apolipoproteins were examined in black and white neonates of both sexes. Results were controlled for the observed effects of gestational age and growth parameters. Similar patterns of lipoprotein differences to those observed in adults and children were also detected between black and white, and between male and female neonates. These findings support the concept that the aetiology of the difference in lipoprotein concentration observed between race and gender groups includes a significant genetic component.
Apolipoproteins↗
Homocysteine and B-group vitamins in renal transplant patients.
Increased plasma homocysteine is an independent risk factor for cardiovascular disease. We have investigated homocysteine and B-group vitamin levels in renal transplant patients. Fasting blood was collected from 55 renal transplant recipients with good renal function and 32 age/sex matched control subjects. Total homocysteine was increased in transplant recipients in comparison to controls (10.9+/-1.5 vs. 6.7+/-1.3 micromol/l, P < 0.001). There was no difference in homocysteine between patients receiving cyclosporin (n = 39, homocysteine 11.0+/-1.5 micromol/l) and patients receiving prednisolone + azathioprine (n = 16, 10.8+/-1.6 micromol/l, mean+/-S.D.), although there was a significant correlation between homocysteine and serum cyclosporin concentration in the sub-group of patients receiving that immunosuppressive regimen (r = 0.42, P < 0.05). Levels of B-group vitamins were similar in patients and controls. Plasma homocysteine is increased in renal transplant recipients even in the presence of minor degrees of renal impairment and normal levels of B-group vitamins.
Adolescent↗
Paraoxonase polymorphisms are not associated with cardiovascular risk in renal transplant recipients.
BACKGROUND: Paraoxonase (PON1) gene variants have been identified as risk factors for cardiovascular disease (CVD). There are two common PON1 polymorphisms at position 55 (Leu-Met change) and 192 (Gln-Arg change) of the amino acid chain. Leucine at position 55 and arginine at position 192 have been associated with increased cardiovascular risk. The increased prevalence of CVD in renal transplant recipients can be only partly explained by the increased prevalence of conventional risk factors. METHODS: We therefore investigated PON1 polymorphisms in renal transplant recipients (N = 491) with (N = 103) and without CVD (N = 388) using polymerase chain reaction-restriction fragment length analysis. PON1 polymorphisms and their associated PON1/arylesterase activities were also assessed in a subgroup of patients (N = 165). RESULTS: The genotype distribution and allele frequencies for both polymorphisms were similar in both groups. The frequencies for LL, LM, and MM genotypes for the 55 position in patients with CVD were 0.39, 0.51, and 0.10, respectively, compared with 0.43, 0.43, and 0.14 in patients without CVD (P = 0.31). The distribution for the QQ, QR, and RR genotypes at the 192 position were 0.48, 0.43, and 0.09, respectively, in patients with CVD compared with 0.46, 0.46, and 0.08 in patients without CVD (P = 0.8). There were highly significant differences in serum activities of PON1/arylesterase between genotypes defined by 55 and 192 polymorphisms. Leucine at position 55 and arginine at position 192 were associated with higher activities. CONCLUSION: These data indicate that there is no association between the PON1 gene variants, conferring higher enzyme activity, and the increased cardiovascular risk in renal transplant recipients.
Adult↗
Susceptibility of VLDL to oxidation in patients on regular haemodialysis.
Oxidation of VLDL in vitro increases macrophage uptake and promotes foam cell formation, and the dyslipidaemia of chronic renal failure is characterised by an increase in VLDL. However, little information is available with regard to the susceptibility of VLDL to oxidation in patients at increased risk of atherosclerosis. We have therefore assessed the composition and susceptibility to oxidation of VLDL from haemodialysis patients and control subjects. VLDL from haemodialysis patients contained increased lipid hydroperoxides (81.6 +/- 12.6 versus 16.1 +/- 3.4 nmol/mg protein, P < 0.001) and malondialdehyde (35.9 +/- 7.3 versus 16.0 +/- 4.1 nmol/mg protein, P < 0.05). Susceptibility to oxidation was increased as shown by an increased rate of propagation of the copper induced lipid peroxidation chain-reaction (11.6 +/- 1.5 x 10(-5) versus 7.6 +/- 1.1 x 10(-5)abs. U/min, P < 0.05) and a greater increase in conjugated diene formation during peroxidation (0.47 +/- 0.04 versus 0.25 +/- 0.03 abs. U, P < 0.001). Increased VLDL peroxidation in dialysis patients may contribute to the increased risk of cardiovascular disease observed in this group of patients.
Adult↗
Tuberculosis in health service employees in Northern Ireland.
Tuberculosis can be transmitted from patients to health care workers. However, where the incidence of tuberculosis is low, and good infection control practices exist, the risk of health care workers acquiring the disease is likely to be small. The objective of this study was to determine the rate of notification of tuberculosis in health care workers in Northern Ireland compared with the general population. Information from the statutory tuberculosis notification forms for the period 1982-1991 was entered on to a computer database. Those patients involved in health care occupations were identified and age and sex standardized incidence rates were calculated. The overall notification rate for tuberculosis was 7.4 cases per 100,000 of general population. There was no significant increase in notification of tuberculosis among health care workers [standardized incidence ratio: 126% (95% CI 91-170)]. No cases were diagnosed as a result of screening methods performed during employment. It was concluded that health care workers in Northern Ireland did not have a significantly increased incidence of tuberculosis compared with the general population over the 10-year period studied. This suggests that the risk of transmission from patients to health care workers is negligible in the setting of a low general incidence of tuberculosis and good infection control practice. Under these circumstances, the present findings support the cessation of routine screening of health care workers.
Contact Tracing↗
Effect of hemodialysis on total antioxidant capacity and serum antioxidants in patients with chronic renal failure.
Cardiovascular disease is the major cause of mortality in patients receiving hemodialysis for chronic renal failure. Increased lipid peroxidation and depletion of chain-breaking antioxidants may contribute to increased risk of atherosclerosis. We have therefore assessed the effect of a single episode of hemodialysis on antioxidant status in 22 patients and control subjects. Overall, total antioxidant capacity of serum was increased in dialysis patients, but there was a marked reduction after hemodialysis [571 +/- 31 vs 342 +/- 22 mumol/L Trolox (water-soluble vitamin E analog) equivalents, P < 0.001]. The increase in total antioxidant capacity before hemodialysis was almost entirely due to relatively high serum urate. Among individual chain-breaking antioxidants, dialysis led to a decrease in urate (398 +/- 15 vs 136 +/- 12 mumol/L, P < 0.001), ascorbate (10.5 +/- 1.7 vs 5.9 +/- 1.0 mumol/L, P < 0.01), and lipid-corrected tocopherol (4.70 +/- 0.56 vs 4.26 +/- 0.39 mumol/mmol cholesterol, P < 0.05). Protein thiol groups increased after dialysis (328 +/- 16 vs 422 +/- 22 mumol/L, P < 0.001), whereas albumin remained unchanged (40.1 +/- 1.1 vs 41.0 +/- 1.6 g/L, not significant). Although total antioxidant capacity of serum is increased in hemodialysis patients, depletion of key chain-breaking antioxidants may lead to accelerated atherogenesis.
Adult↗
Oxidation of low density lipoprotein in patients on regular haemodialysis.
Patients undergoing chronic haemodialysis are known to have a high incidence of premature atherosclerosis for reasons which have not been fully elucidated. The susceptibility of low density lipoprotein (LDL) to oxidation by copper ions in vitro is widely used as a measure of its atherogenicity in vivo. We measured the susceptibility of LDL to oxidation using copper ions in haemodialysis patients and found, surprisingly, a markedly increased resistance to oxidation. The experiment was therefore repeated using an alternative free radical generator, AAPH [2,2'-azobis-(2-amidinopropane hydrochloride)], to promote LDL oxidation; using AAPH, the susceptibility to oxidation was similar in the dialysis group compared to controls. Abnormal LDL composition in the dialysis patients was also demonstrated. We suggest that, in such situations, susceptibility of LDL to oxidation in vitro may be highly dependent on the biochemical method employed and therefore may not accurately reflect atherogenic risk.
Amidines↗
Oxidative stress in haemodialysis.
Patients with chronic renal failure, including those receiving regular long-term haemodialysis, have a high incidence of premature cardiovascular disease. Oxidative stress, which occurs when there is excessive free-radical production or low antioxidant levels, has recently been implicated as a causative factor in atherogenesis. The aim of this study was to determine if chronic renal failure and haemodialysis were associated with increased oxidative stress. Serum malondialdehyde was measured as a marker of lipid peroxidation in 15 patients with conservatively managed chronic renal failure (CRF), 15 patients with CRF undergoing regular haemodialysis and 15 healthy controls. Selenium, glutathione peroxidase and antioxidant vitamins were also measured. Malondialdehyde was elevated in dialysis patients in comparison to CRF and control groups (dialysis 1.16 +/- 0.08 mumol/l, CRF 0.94 +/- 0.07, controls 0.66 +/- 0.10). Antioxidants, including vitamin C, selenium and glutathione peroxidase, were decreased in dialysis patients and to a lesser extent in the CRF group (vitamin C-dialysis 16.43 +/- 3.76 mumol/l, CRF 34.5 +/- 8.6, controls 56.11 +/- 7.41; selenium-dialysis 0.77 +/- 0.07 mumol/l, CRF 0.69 +/- 0.06, controls 1.09 +/- 0.06: glutathione peroxidase-dialysis 101 +/- 5 U/l, CRF 160 +/- 11, controls 290 +/- 10). These findings indicate oxidative stress in patients with CRF which is further exacerbated by haemodialysis, as evidenced by increased lipid peroxidation and low antioxidant levels. This stress may play a role in the development of atherosclerosis in these groups.
Adult↗