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Biomedical subjects

S K Hall

Publications and source records attributed to S K Hall.

At least 19 recordsLinked to original sources
PubMed2000

Conditional and unconditional inhibition of calcium-activated potassium channels by reversible protein phosphorylation.

Large conductance, calcium-activated potassium channels (BK(Ca) or maxi-K) are important determinants of membrane excitability in many cell types. We used patch clamp techniques to study the biochemical regulation of native BK(Ca) channel proteins by endogenous Ser/Thr-directed protein kinases and phosphatases in cell-free membrane patches from rat pituitary tumor cells (GH(4)C(1)). When protein kinase activity was blocked by removing ATP, endogenous protein phosphatases slowly increased BK(Ca) channel activity approximately 3-fold. Dephosphorylated channels could be activated fully by physiological increases in cytoplasmic calcium or membrane depolarization. In contrast, endogenous protein kinases inhibited BK(Ca) channel activity at two functionally distinct sites. A closely associated, cAMP-dependent protein kinase rapidly reduced channel activity in a conditional manner that could be overcome completely by increasing cytoplasmic free calcium 3-fold or 20 mV further depolarization. Phosphorylation at a pharmacologically distinct site inhibited channel activity unconditionally by reducing availability to approximately half that of maximum at all physiological calcium and voltages. Conditional versus unconditional inhibition of BK(Ca) channel activity through different protein kinases provides cells with a powerful computational mechanism for regulating membrane excitability.

Adenosine Triphosphate↗
PubMed1999

ATP inhibition of a mouse brain large-conductance K+ (mslo) channel variant by a mechanism independent of protein phosphorylation.

1. We investigated the effect of ATP in the regulation of two closely related cloned mouse brain large conductance calcium- and voltage-activated potassium (BK) channel alpha-subunit variants, expressed in human embryonic kidney (HEK 293) cells, using the excised inside-out configuration of the patch-clamp technique. 2. The mB2 BK channel alpha-subunit variant expressed alone was potently inhibited by application of ATP to the intracellular surface of the patch with an IC50 of 30 microM. The effect of ATP was largely independent of protein phosphorylation events as the effect of ATP was mimicked by the non-hydrolysable analogue 5'-adenylylimidodiphosphate (AMP-PNP) and the inhibitory effect of ATPgammaS was reversible. 3. In contrast, under identical conditions, direct nucleotide inhibition was not observed in the closely related mouse brain BK channel alpha-subunit variant mbr5. Furthermore, direct nucleotide regulation was not observed when mB2 was functionally coupled to regulatory beta-subunits. 4. These data suggest that the mB2 alpha-subunit splice variant could provide a dynamic link between cellular metabolism and cell excitability.

Adenosine Diphosphate↗
PubMed1999

Congenital hypothyroidism, seasonality and consanguinity in the West Midlands, England.

Seasonal variation in the incidence of congenital hypothyroidism (CHT) is reported by some centres. Also, the incidence of CHT varies with ethnic origin. We report our experience in the West Midlands, England. The overall incidence of CHT among 1128 632 neonates screened over 16 years in the West Midlands was 1:2924 live births, but was increased (1:2323; p<0.05) between October and December. In the city of Birmingham between 1981 and 1991, the incidence of CHT was 1:781, 1:5540 and 1:2257 in Pakistani, Indian and North-West European children, respectively; no cases were seen in those from other ethnic groups. Consanguinity among those of Pakistani descent could account for the increased incidence within this population. Identification of the cause of seasonal variation may aid development of preventative strategies.

Catchment Area, Health↗
PubMed1998

The origin of red blood cell biopterin.

Data are presented to support the hypothesis that the biopterin content of red blood cells arises during erythropoiesis. Only when the plasma concentration rises above the erythrocyte concentration of biopterin is there likely to be diffusion into the cell.

Adult↗
PubMed1998

Does a single plasma phenylalanine predict quality of control in phenylketonuria?

A 1993 MRC working group on phenylketonuria suggested standardising blood phenylalanine measurements by taking blood samples at the same time each day. Since it is not known how representative of a 24 hour period a single phenylalanine concentration is, the aim of this study was to investigate the 24 hour variability of plasma phenylalanine in well controlled children with phenylketonuria. Sixteen subjects, 12 girls and four boys aged 1 to 18 years, had hourly venous blood samples collected for 13 hours between 09.00 and 21.00 on one day. Serial skin puncture blood specimens were then collected at 24.00, 03.00, and 06.00 within the same 24 hour period. All food and drink was weighed. The median variation in plasma phenylalanine concentration was 155 mumol/l/day, with a minimum of 80 and a maximum of 280. The highest concentration occurred in the morning between 6.00 and 9.00 in 63% of subjects; the lowest occurred between midday and midnight in 94%. Concentrations < 100 mumol/l occurred in 46% of children below 11 years, three having concentrations < 30 mumol/l for two, six, and seven hours respectively. Three of five subjects had concentrations above the MRC guidelines for 24% of the period studied. Except in two subjects, the blood concentrations did not rise in response to phenylalanine consumption. However, the greater the quantity of protein substitute taken between waking and the 16.00 specimen, the larger the decrease in daytime phenylalanine concentration (r = -0.7030) (p < 0.005). There is therefore wide variability in phenylalanine concentrations in a 24 hour period in children with phenylketonuria which is not reflected in a single observation. Further study is needed to investigate the effects of timing of protein substitute on the stability of phenylalanine concentrations.

Adolescent↗
PubMed1998

A comparison of disease and gene frequencies of inborn errors of metabolism among different ethnic groups in the West Midlands, UK.

OBJECTIVE: To assess birth and gene frequencies of specific autosomal recessively inborn errors of metabolism (IEM) within different ethnic groups. DESIGN: Retrospective study in a regional centre for investigation and treatment of IEM. SUBJECTS: All children born within the West Midlands NHS Region, UK, during the decade immediately preceding the 1991 National Census. METHODS: Birth frequencies for individual IEM were calculated separately for the main ethnic groups in the West Midlands using data from the West Midlands Neonatal Screening Programme, the regional register of IEM patients, and population frequencies from the National Census. Gene frequencies were calculated using previously documented observations on parental consanguinity rates and inbreeding coefficients. RESULTS: The overall incidence of recorded IEM was tenfold higher among Pakistanis compared to white children (1:318 v 1:3760), whereas only one AfroCaribbean child was identified (incidence 1:16 887). Tyrosinaemia type 1, cystinosis, mucopolysaccharidosis type 1, non-ketotic hyperglycinaemia, and hyperchylomicronaemia all occurred more frequently among Pakistanis. An increased gene frequency was only confirmed for tyrosinaemia. The incidence of phenylketonuria was similar in Pakistani and white children (1:14 452 v 1:12 611), but the gene frequency was significantly lower in Pakistanis (1:713 v 1:112). These results illustrate the interplay between gene frequency and parental consanguinity in determining disease frequencies in different populations, and indicate anticipated disease frequencies in the absence of consanguineous marriage. These figures have implications for the organisation of services for management of inborn errors, for genetic counselling, and for the assessment of gene flow in world populations.

Ethnicity↗
PubMed1997

An early transient current is associated with hyposmotic swelling and volume regulation in embryonic chick cardiac myocytes.

Hyposmotically induced changes in membrane conductance were measured in embryonic chick cardiac myocytes using conventional and perforated patch-clamp recording techniques; simultaneous measurements of cell volume were made from the video image of the voltage-clamped cell. Hyposmotic challenge was associated with a rapid, transient current coincident with the onset of cell swelling; cell volume subsequently recovered towards control values (regulatory volume decrease; RVD). The transient swelling-induced current (I(swell)) reversed at +15 mV, and was not found to be carried exclusively by any single ion in the physiological solutions. I(swell) was abolished by gadolinium (Gd3+), a blocker of stretch-activated ion channels, and was absent when the cytoskeleton was disrupted by treatment with cytochalasin B. I(swell) was also prevented when intracellular [Ca2+] was buffered with BAPTA AM. Under those experimental conditions which prevented the generation of I(swell), cell volume regulation failed so that the cells remained swollen in hyposmotic solution. Our data reveal a functional relationship between I(swell) and RVD, whereby I(swell) is a necessary prerequisite, although not exclusively sufficient, for volume recovery following cell swelling. We propose that I(swell) is an important early signalling event which activates subsequent mechanisms to regulate cell volume.

Animals↗
PubMed1996

Factors affecting the variation in plasma phenylalanine in patients with phenylketonuria on diet.

The optimal dietary management of children with phenylketonuria (PKU) has rarely been rigorously explored. The aim of this study was to assess longitudinally the effects of three factors thought to influence plasma phenylalanine concentrations in PKU: total energy intake; protein intake from natural foods allowed freely in addition to allocated phenylalanine exchanges; and the distribution of protein substitute throughout the day. Nineteen subjects, 15 girls and four boys aged 1-16 years, were enrolled. Food intake was weighed, and twice daily plasma phenylalanine concentrations measured during either 3-day or 4-day periods, for a total of 21 days throughout six months. There was a negative correlation between the percentage of protein substitute eaten by the time of the evening meal and the fall in plasma phenylalanine concentration during the day (r = -0.941; p < 0.0001). On average, 49% of pre-evening meal plasma phenylalanine concentrations were less than 100 mumol/l in children who had taken at least 65% of their protein substitute by the time of their evening meal. There was no correlation between excess natural protein intake from freely allowed foods and (a) pre-breakfast or pre-evening meal plasma phenylalanine concentrations or (b) the daily change between pre-breakfast and pre-evening meal concentrations. Nor was there any correlation between excess natural protein intake on the previous day and plasma phenylalanine concentration on the following morning. Energy intake was not correlated with plasma phenylalanine concentrations. It is therefore preferable to distribute the protein substitute evenly through the day in order to achieve stable phenylalanine concentrations, rather than to carry out further fine manipulation of the phenylalanine intake, which would make management of the diet even more difficult.

Adolescent↗
PubMed1996

Screening for tyrosinaemia type I.

AIMS: To assess the incidence of tyrosinaemia type I in the West Midlands Region, and the value of current neonatal screening programmes for phenylketonuria (PKU) for its detection. METHODS: Retrospective study of results from the PKU neonatal screening programmes in Birmingham (using plasma amino acid chromatography) and in the rest of the West Midlands (using the Guthrie microbiological assay for blood spot phenylalanine) was carried out between January 1985 and March 1994. Patients with tyrosinaemia I born in the region during the same period were identified from a regional database of patients with confirmed inherited metabolic disease. The study was carried out in a specialist children's hospital; the regional centre in the West Midlands for neonatal screening and investigation of inborn errors, and a supraregional centre for liver transplantation and management of paediatric liver disease. RESULTS: Amino acid chromatography showed increased tyrosine in 447 of 145,444 neonates born in Birmingham; this was still increased at 6 weeks of age in six cases. Five had tyrosinaemia I; the sixth had tyrosinaemia type III. Two others in whom amino acid chromatography was considered normal have since presented with tyrosinaemia I. Outside Birmingham, 525,151 children were screened using the Guthrie test. Five have presented clinically with tyrosinaemia I; screening did not contribute to diagnosis in any case. The incidence of tyrosinaemia I was 1 in 20,791 live births within Birmingham and 1 in 105,037 outside. Of the total 12 patients in the West Midlands with tyrosinaemia I, 10 (83%) were of non-oriental Asian ethnicity; the incidence of tyrosinaemia I was 3.7/10(6) head of population in this group and 0.04/10(6) in the rest of the population. CONCLUSIONS: Asians in the West Midlands have a high incidence of tyrosinaemia I. Neonatal PKU screening using amino acid chromatography may contribute to diagnosis and early treatment.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Cyclic AMP prevents activation of a swelling-induced chloride-sensitive conductance in chick heart cells.

1. Changes in myocardial cell volume and whole-cell currents were measured simultaneously during hyposmotically induced cell swelling. In the conventional patch clamp configuration, hyposmotic challenge caused myocytes to swell continuously and was associated with the development of a sustained, swelling-induced chloride conductance (ICl). In contrast, perforated patch-clamped myocytes demonstrated regulatory volume decreases (RVD) during hyposmotic challenge, and ICl was not generated. 2. The swelling-induced ICl in conventionally patch-clamped myocytes was inhibited by application of forskolin (15 microM) and was prevented when the pipette filling solution contained cAMP (10 microM) and isobutylmethylxanthine (IBMX, 1 mM). ICl could also be prevented by inhibition of protein phosphatase activity, using okadaic acid (100 nM). Conversely, a swelling-induced current could be generated in myocytes under perforated patch clamp by inhibition of protein kinase A, using the antagonist Rp-cAMPS (10 microM). These data demonstrate that cAMP-dependent protein phosphorylation is both necessary and sufficient to prevent development of ICl during cell swelling. 3. Unlike other chloride currents described previously in heart muscle, generation of the novel swelling-induced ICl requires dephosphorylation of a cAMP-dependent protein phosphorylation site; hence it can be prevented by stimulation of cAMP-dependent protein phosphorylation or by inhibition of protein phosphatase activity.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Management of chemical disaster victims.

Following a hazardous chemical accident, early critical care life support is crucial to minimizing potential morbidity and mortality (1). Providing effective care to victims, however, depends on the nature of the incident, the number of victims affected, the availability of medical care, the coordination of rescue efforts, the available modes of evacuation, and the availability of post-evacuation tertiary care. The goal in mass casualty scenarios is to minimize mortality and morbidity. Consequently, the most basic emergency response must include a method for assessing the incident, the extent of injury to victims, methods for determining which victims will receive treatment first, and what types of treatment will be given during the various stages of the incident. The basic need to handle hazardous chemical incident victims exists regardless of the environment in which the incident occurs, or whether small or large numbers of victims are involved.

Critical Care↗
PubMed1994

Acute angle-closure glaucoma as a complication of combined beta-agonist and ipratropium bromide therapy in the emergency department.

Acute angle-closure glaucoma is an uncommon complication of inhaled ipratropium bromide therapy for asthma. All previously reported cases have occurred in hospitalized patients receiving continuing nebulized therapy. A 66-year-old woman with asthma returned to the emergency department with bilateral acute angle-closure glaucoma less than 48 hours after successful treatment with nebulized albuterol sulfate and ipratropium bromide given by metered-dose inhaler. Acute angle-closure glaucoma occurring after ipratropium bromide use is believed to result from local ophthalmic effects attributable to topical absorption instead of systemic action. Greater awareness of this complication and suggested preventive measures may lessen morbidity.

Acute Disease↗
PubMed1993

A microtitre plate method for measuring biopterin with cryopreserved Crithidia fasciculata.

The assay of biopterin derivatives in dried blood spots is used by us in initial screening for inherited defects in tetrahydrobiopterin synthesis. The previously described method (1) required aseptic technique and microbiological facilities. The modification detailed here has the advantages of antibiotic cover, which overcomes these needs and microtitre plate technology allowing the incubation time to be halved with precision and accuracy retained. Data reduction facilities may be applied.

Adult↗