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Biomedical subjects

J P Osborne

Publications and source records attributed to J P Osborne.

At least 19 recordsLinked to original sources
PubMed1998

Tuberous sclerosis complex and Wolff-Parkinson-White syndrome.

This report highlights the association between tuberous sclerosis and Wolff-Parkinson-White syndrome. Ten patients with concurrent diagnoses of Wolff-Parkinson-White syndrome and tuberous sclerosis were identified. Wolff-Parkinson-White syndrome presented early in life, nine cases being diagnosed in the first year. Eight of the 10 cases were male. In eight cases, the syndrome was associated with supraventricular tachycardias, and in nine with cardiac rhabdomyomata. One child died from cardiac failure secondary to obstruction of the left ventricular outflow tract by a rhabdomyoma. Five of nine survivors showed resolution of Wolff-Parkinson-White syndrome on follow up. The accessory pathway was localised in nine patients from surface electrocardiograms: six children had left sided pathways and three had right sided pathways.

Electrocardiography↗
PubMed1997

A conserved glutamic acid in helix VI of cytochrome bo3 influences a key step in oxygen reduction.

We have compared the reactions with dioxygen of wild-type cytochrome bo3 and a mutant in which a conserved glutamic acid at position-286 of subunit I has been changed to an alanine. Flow-flash experiments reveal that oxygen binding and the rate of heme-heme electron transfer are unaffected by the mutation. Reaction of the fully (3-electron) reduced mutant cytochrome bo3 with dioxygen yields a binuclear center which is substantially in the P (peroxy) state, not the well-characterized F (oxyferryl) state which is the product of the reaction of the fully reduced wild-type enzyme with dioxygen [Puustinen, A., et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 1545-1548]. These results confirm that proton uptake is important in controlling the later stages of dioxygen reduction in heme-copper oxidases and show that E286 is an important component of the channel that delivers these protons to the active site.

Amino Acid Sequence↗
PubMed1996

Resonance Raman spectroscopic identification of a histidine ligand of b595 and the nature of the ligation of chlorin d in the fully reduced Escherichia coli cytochrome bd oxidase.

Cytochrome bd oxidase is a bacterial terminal oxidase that contains three cofactors: a low-spin heme (b558), a high-spin heme (b595), and a chlorin d. The center of dioxygen reduction has been proposed to be a binuclear b595/d site, whereas b558 is mainly involved in transferring electrons from ubiquinol to the oxidase. Information on the nature of the axial ligands of the three heme centers has come from site-directed mutagenesis and spectroscopy, which have implicated a His/Met coordination for b558 (Spinner, F., Cheesman, M. R., Thomson, A. J., Kaysser, T., Gennis, R. B., Peng, Q., & Peterson, J. (1995) Biochem. J. 308, 641-644; Kaysser, T. M., Ghaim, J. B., Georgiou, C., & Gennis, R. B. (1995) Biochemistry 34, 13491-13501), but the ligands to b595 and d are not known with certainty. In this work, the three heme chromophores of the fully reduced cytochrome bd oxidase are studied individually by selective enhancement of their resonance Raman (rR) spectra at particular excitation wavelengths. The rR spectrum obtained with 413.1-nm excitation is dominated by the bands of the 5cHS b595(2+) cofactor. Excitation close to 560 nm yields a rR spectrum dominated by the 6cLS b558(2+) heme. Wavelengths between these values enhance contributions from both b595(2+) and b558(2+) chromophores. The rR bands of the ferrous chlorin become the major features with red laser excitation (595-650 nm). The rR data indicate that d2+ is a 5cHS system whose axial ligand is either a weakly coordinating protein donor or a water molecule. In the low-frequency region of the 441.6-nm spectrum, we assign a rR band at 225 cm-1 to the (b595)Fe(II)-N(His) stretching vibration, based on its 1.2-cm(-1) upshift in the 54Fe-labeled enzyme. This observation provides the first physical evidence that the proximal ligand of b595 is a histidine. Site-directed mutagenesis had suggested that His 19 is associated with either b595 or d (Fang, H., Lin, R. -J., & Gennis, R. B. (1989) J. Biol. Chem. 264, 8026-8032). On the basis of the present study, we propose that the proximal ligand of b595 is His 19. We have also studied the reaction of cyanide with the fully reduced cytochrome bd oxidase. In approximately 700-fold excess cyanide (approximately 35 mM), the 629-nm UV/vis band of d2+ is blue-shifted to 625 nm and diminished in intensity. However, the rR spectra at each of three different gamma(0) (413.1, 514.5, and 647.1 nm) are identical with or without cyanide, thus indicating that both b595 and d remain as 5cHS species in the presence of CN-. This observation leads to the proposal that a native ligand of ferrous chlorin d is replaced by CN- to form the 5cHS d2+ cyano adduct. These findings corroborate our companion study of the "as-isolated" enzyme in which we proposed a 5cHS d3+ cyano adduct (Sun, J., Osborne, J. P., Kahlow, M. A., Kaysser, T. M., Hill, J. J., Gennis, R. B., & Loehr, T. M. (1995) Biochemistry 34, 12144-12151). To further characterize the unusual and unexpected nature of these proposed high-spin cyanide adducts, we have obtained EPR spectral evidence that binding of cyanide to fully oxidized cytochrome bd oxidase perturbs a spin-state equilibrium in the chlorin d3+ to yield entirely the high-spin form of the cofactor.

Cytochrome a Group↗
PubMed1996

Cranial computed tomographic findings in tuberous sclerosis are not affected by sex.

Males with the tuberous sclerosis complex (TSC) have been shown to be more at risk of learning disorder than females. A retrospective population based study was undertaken to see if males with TSC have more cerebral lesions than females. 47 of 131 individuals with TSC identified in a prevalence study had a cranial CT scan available for review. No significant difference between the sexes was found in the number of subependymal nodules or the number, site or size of parenchymal lesions. However, males with five or fewer parenchymal lesions were at greater risk of learning disorder than females. The increased risk of learning disorder in males with tuberous sclerosis is not accounted for by an increase in number, site or size of cranial lesions as seen on CT scans. Therefore there must be an alternative mechanism to account for this difference between the sexes.

Adult↗
PubMed1996

Morbidity associated with tuberous sclerosis: a population study.

Neurological complications and other causes of morbidity were studied in 122 of 131 individuals (64 males, 67 females) with tuberous sclerosis, in a popululation in which its prevalence was 1/26,500. Seizures occurred in 78 per cent, beginning at less that one year of age in 69 per cent (in more males than females in both cases) and after age 16 in 4 per cent. More males than females also had infantile spasms and persistent seizures. Learning disorder occured in 53 per cent (also in more males), all with a history of seizures, and was strongly correlated with age at onset of seizures, type of seizure and outcome for seizure control. Of subjects with learning disorder, 85 per cent required supervision for daily living and 65 per cent had little or no language; 97 per cent were fully mobile. Hemiparesis had occurred in eight of the 131, giant cell astrocytomas in nine bilateral polycystic kidney disease in two, and haemorrhagic complication relating to renal angiomyolipomas in six.

Adolescent↗
PubMed1996

The cutaneous features of tuberous sclerosis: a population study.

We report the cross-sectional age-related prevalence of cutaneous features of the tuberous sclerosis complex in a defined population. Of 131 affected individuals, 126 (96%) exhibited skin signs. Although there is considerable variation in the age of expression of all the skin lesions, there is a trend towards the earlier expression of hypomelanic macules and forehead fibrous plaques compared with facial angiofibromas and ungual fibromas. Shagreen patches are usually present by puberty. Ungual fibromas appeared for the first time as late as the fifth decade and were the only clinical feature in three individuals. Gum fibromas were present in 36%. Ten individuals (8%) presented because of the skin manifestations and 21% received treatment for symptomatic skin lesions. Two individuals had large hamartomas at unusual sites (occiput and forearm).

Adolescent↗
PubMed1995

Resonance Raman studies of Escherichia coli cytochrome bd oxidase. Selective enhancement of the three heme chromophores of the "as-isolated" enzyme and characterization of the cyanide adduct.

Cytochrome bd oxidase is a terminal bacterial oxidase containing three cofactors: a low-spin heme (b558), a high-spin heme (b595), and a chlorin d. The center of dioxygen reduction has been proposed to be at a dinuclear b595/d site, whereas b558 is mainly involved in transferring electrons from ubiquinone. One of the unique functional features of this enzyme is its resistance to high concentrations of cyanide (Ki in the millimolar range). With the appropriate selection of laser lines, the ligation and spin states of the b558, b595, and d hemes can be probed selectively by resonance Raman (rR) spectroscopy. Wavelengths between 400 and 500 nm predominantly excite the rR spectra of the b558 and b595 chromophores. Spectra obtained within this interval show a mixed population of spin and ligation states arising from b558 and b595, with the former more strongly enhanced at higher energy. Red excitation wavelengths (590-650 nm) generate rR spectra characteristic of chlorins, indicating the selective enhancement of the d heme. These rR results reveal that cytochrome bd oxidase "as isolated" contains the b558 heme in a six-coordinate low-spin ferric state, the b595 heme in a five-coordinate high-spin (5cHS) ferric state, and the d heme in a mixture of oxygenated (FeIIO2 <--> FeIIIO2-; d650) and ferryl-oxo (FeIV = O; d680) states. However, the rR spectra of these two chlorin species indicate that they are both in the 5cHS state, suggesting that the d heme is lacking a strongly coordinated sixth ligand.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyanides↗
PubMed1994

A population study of renal disease in patients with tuberous sclerosis.

OBJECTIVE: To establish the prevalence of renal disease, asymptomatic renal lesions and possible renal symptoms in a geographically defined population of individuals with tuberous sclerosis. PATIENTS AND METHODS: The study involved 131 patients (64 men, 67 women) with tuberous sclerosis who were resident in nine of the districts within the Wessex Region and three Bristol Health Districts and who had been identified by a prevalence study [1]. The patients' mean age was 22 years (range 6 months-74 years). Established renal disease was identified by history. Where possible individuals were seen and were examined. Specific enquiry was made for flank pain and macroscopic haematuria. Renal ultrasound, blood pressure measurement and urine analysis was offered to all individuals with tuberous sclerosis who were resident in the Bath Health District. RESULTS: Eight patients (6%) had a history of either renal polycystic kidney disease (two patients) or haemorrhage from renal angiomyolipomas (five female patients, one male patient). A further 21% of female and 3% of male patients had a history of severe flank pain or haematuria. Renal ultrasound screening revealed abnormalities in 10 of 21 individuals; angiomyolipomas > 1 cm were found in seven and were twice as common in female patients. CONCLUSIONS: Regular clinical review of individuals with tuberous sclerosis should include enquiry for renal symptoms and abdominal examination. Lesions > 4 cm are most likely to be symptomatic but longitudinal studies are needed before renal ultrasound screening of adolescents or adults can be recommended.

Adolescent↗
PubMed1994

Tuberous sclerosis: how to recognise this challenging disorder.

Tuberous sclerosis is a multi-system genetic disorder affecting up to one in 6000 newborn infants. It is about one third as common as cystic fibrosis, and half as common as Duchennes muscular dystrophy, yet many doctors and health professionals are ill-acquainted with the condition. Parents who turn to medical text books for information find only a brief mention of a few, frequently out-dated facts. Antonia Clarke and John Osborne describe the symptoms of the disorder and the special needs of affected children and their families.

Child↗
PubMed1993

Cardiac rhabdomyomas and their association with tuberous sclerosis.

A search for children presenting with signs or symptoms of cardiac rhabdomyomas was made through members of the paediatric section of the British Cardiac Society in order to establish their birth incidence, presenting features, clinical course, and the frequency of a concurrent diagnosis of tuberous sclerosis. Fifteen children were identified and 12 had tuberous sclerosis (80%). Heart failure was the presentation in six, five of whom died; six presented because of a murmur and three because of arrhythmias. The prevalence of echocardiographic evidence of cardiac rhabdomyomas in a population of patients with tuberous sclerosis was established. Twenty individuals had echocardiography and eight had echodensities consistent with cardiac rhabdomyomas. It is concluded that the minimum birth incidence for children presenting because of the effects of cardiac rhabdomyomas is 1/326,000 and a minimum of 80% have tuberous sclerosis. In a population of patients with tuberous sclerosis a minimum of 60% under 18 years have cardiac rhabdomyomas.

Echocardiography↗