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Biomedical subjects

R A King

Publications and source records attributed to R A King.

At least 19 recordsLinked to original sources
PubMed1992

The mouse pink-eyed dilution gene: association with human Prader-Willi and Angelman syndromes.

Complementary DNA clones from the pink-eyed dilution (p) locus of mouse chromosome 7 were isolated from murine melanoma and melanocyte libraries. The transcript from this gene is missing or altered in six independent mutant alleles of the p locus, suggesting that disruption of this gene results in the hypopigmentation phenotype that defines mutant p alleles. Characterization of the human homolog revealed that it is localized to human chromosome 15 at q11.2-q12, a region associated with Prader-Willi and Angelman syndromes, suggesting that altered expression of this gene may be responsible for the hypopigmentation phenotype exhibited by certain individuals with these disorders.

Amino Acid Sequence↗
PubMed1992

Risk factors for hypertension in Kimberley aborigines.

OBJECTIVE: To determine physical, biochemical and lifestyle factors associated with high blood pressure among Aborigines in the Kimberley region. DESIGN: Blood pressure and electrocardiographic (ECG) abnormalities in an age and sex stratified random sample of the Aboriginal population were related to other observations and measurements made at the same time specifically for the purpose of these comparisons. SETTING: A field study in which subjects were interviewed and measurements made mostly in community clinics. PARTICIPANTS: All 249 men and 241 women from the prevalence study were included although only complete data sets for the various comparisons were analysed. INTERVENTIONS: A sample of venous blood was obtained in addition to physical measurements and information at interview. MAIN OUTCOME MEASURES: Statistical analysis of the relationships between blood pressure or hypertension and alcohol consumption, plasma gamma-glutamyl transpeptidase (GGT) activity, use of tobacco, body mass index (BMI, kg/m2) and non-fasted plasma cholesterol level. Hypertension was defined as systolic blood pressure of 160 mmHg or greater or diastolic blood pressure of 95 mmHg or greater. RESULTS: High blood pressure in Aboriginal men below 30 years was associated both with current drinking status and with circulating GGT level. There was a positive association of diastolic hypertension with consumption of alcohol in middle aged men (30 to 49 years) and in older women. Drinking was highly prevalent among men, especially below 30 years, but was less prevalent among women. Both systolic and diastolic blood pressure were positively related to BMI across the population but obesity (BMI greater than or equal to 30 kg/m2) was highly prevalent only among middle-aged women. Both systolic and diastolic blood pressure were positively and strongly related to plasma cholesterol level independently of the latter's relationship to age and BMI. CONCLUSION: The high prevalence of drinking among Aboriginal men and of obesity among Aboriginal women involves a risk of hypertension. The association between plasma cholesterol and blood pressure in Aboriginal men and women may be relevant to the demonstrated link between systolic hypertension and ischaemic heart disease.

Adult↗
PubMed1992

Prevalence of hypertension in Kimberley aborigines and its relationship to ischaemic heart disease. An age-stratified random survey.

OBJECTIVE: To determine the age-specific prevalence of systolic and diastolic hypertension and of electrocardiographic abnormalities in the Aboriginal population of the Kimberley region of Western Australia. DESIGN AND SETTING: Age and sex stratified random samples of the Aboriginal population of the Kimberley region were selected and located. Measurements were made of systolic and diastolic blood pressure and electrocardiograms (ECG) were recorded. Hypertension was defined as a systolic blood pressure of 160 mmHg or greater or diastolic blood pressure of 95 mmHg or greater. ECG abnormalities were classified by the Minnesota system. PARTICIPANTS: Measurements were made on 249 men and 241 women distributed in seven age bands above 15 years and representing 78% of the selected men and 76% of the selected women. INTERVENTIONS: In addition to ECG and blood pressure, measurements were made of height and weight and information was obtained on medication, smoking, drinking and diet. A sample of venous blood was obtained. MAIN OUTCOME MEASURES: The data obtained on blood pressure, hypertension and ECG abnormalities were compared with existing data on Caucasian and Aboriginal Australians. RESULTS: Aboriginal men below the age of 30 years showed particularly high blood pressure compared with Caucasian men. The overall prevalence of hypertension in Aboriginal men 50 years of age and older was 45%. The prevalence of hypertension among Aboriginal women increased sharply from 35 years of age with a maximum between 55 and 65 years. The overall prevalence of hypertension in women 50 years of age and older was 50%. By regression, the average systolic/diastolic blood pressure at 40 years was 137/85 mmHg for men and 135/83 mmHg for women. ECG abnormalities indicating ischaemic heart disease (IHD) were more prevalent in both male and female Aborigines than had been found for Caucasians in 1966. In both sexes IHD and especially code 1.1 indicating myocardial infarct were associated with systolic hypertension. CONCLUSIONS: The prevalence of both systolic and diastolic hypertension and of probable IHD was two to three times higher in Kimberley Aborigines than in Caucasian Australians. ECG evidence of infarct was significantly related to systolic hypertension in both sexes.

Adolescent↗
PubMed1992

Molecular analysis of type I-A (tyrosinase negative) oculocutaneous albinism.

Type I oculocutaneous albinism (OCA) is caused by the reduction in or absence of activity of tyrosinase in melanocytes in skin, hair, and the eyes, the result of mutations of the tyrosinase gene. To date, a total of 22 unique mutations in the coding region of tyrosinase have been described in the literature. In this report we present 5 additional mutations of the tyrosinase gene associated with type I-A OCA in four individuals, including 2 missense, 1 frameshift and 2 nonsense mutations, and review the relevant literature on all published mutations. Analysis of the distribution of all identified missense mutations (n = 17) shows that most cluster in three areas of the gene and involve amino acids conserved between humans and the mouse. Two clusters involve the copper A and copper B binding sites and may disrupt the metal ion-protein interaction necessary for enzyme function. The third cluster in exon I could represent a functional domain important in enzyme function such as the tyrosine or the dihydroxyphenylalanine (DOPA) binding site of the enzyme. Small deletions or insertions resulting in frameshift mutations and nonsense mutations are distributed throughout the coding region and do not appear to cluster.

Albinism, Oculocutaneous↗
PubMed1992

Behavioral treatment of children and adolescents with trichotillomania.

Trichotillomania is a behavior disorder with onset generally in childhood, characterized by repetitive, compulsive pulling out of hair from the scalp, eyebrows, or other parts of the body, often leading to disfigurement. Trichotillomania tends to be persistent and is often resistant to counselling and standard psychiatric care. A systematic behavioral treatment program for children and adolescents and pilot findings with three patients are described. Methodological issues in relation to compliance and assessment are discussed. The relative safety and potential effectiveness of behavioral techniques suggest a useful role for this approach, perhaps in conjunction with pharmacological, family, and other treatment modalities.

Adolescent↗
PubMed1992

Double-blind, crossover trial of fluoxetine and placebo in children and adolescents with obsessive-compulsive disorder.

Rigorously designed clinical trials have demonstrated the efficacy and safety of fluoxetine in adults with major depressive disorder and obsessive-compulsive disorder (OCD) but not in patients below 18 years old. This report describes a randomized, double-blind, placebo-controlled, fixed-dose (20 mg qd) trial of fluoxetine in 14 children and adolescents with OCD, ages 8 to 15 years old; the study was 20 weeks long with crossover at 8 weeks. Obsessive-compulsive symptom severity was measured on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinician's Global Impression-Obsessive Compulsive Disorder scale (CGI-OCD). The CY-BOCS total score decreased 44% (N = 7, p = .003) after the initial 8 weeks of fluoxetine treatment, compared with a 27% decrease (N = 6, p = .13) after placebo. During the initial 8 weeks, the magnitude of improvement for the fluoxetine group significantly exceeded that for the placebo group as measured by the CGI-OCD (p = .01) but not by the CY-BOCS (p = .17). The most common drug side effects were generally well tolerated. The results suggest that fluoxetine is a generally safe and effective short-term treatment for children with OCD.

Adolescent↗
PubMed1992

Site-directed mutagenesis of an amino acid residue in the bacteriophage P2 ogr protein implicated in interaction with Escherichia coli RNA polymerase.

The P2 ogr gene encodes a 72-amino-acid protein required for P2 late gene expression. This gene was defined originally by a class of compensatory mutations which overcome the block to P2 late transcription imposed by a host mutation, rpoA109, in the gene encoding the alpha subunit of Escherichia coli RNA polymerase. Spontaneous compensatory ogr mutations substitute a Cys for a Tyr residue at amino acid 42 in the Ogr polypeptide. Using suppression of an ogr amber mutation and site-directed oligonucleotide mutagenesis, we have studied the effect of amino acid substitutions at this position in Ogr. Substitution of charged residues at this site renders Ogr protein inactive, in rpoA+ and rpoA109 strains. While 11 different amino acids are capable of replacing the wild-type Tyr-42 to allow P2 growth to varying degrees in a wild-type E. coli strain, only three of these allow phage growth in strains carrying the rpoA109 mutation. Phages carrying Cys or Ala in place of Tyr-42 gave burst sizes at least as high as P2 ogr+ in a rpoA+ strain; a Gly substitution also allowed P2 to grow in either a rpoA+ or rpoA109 background, but markedly reduced the burst size. These results are consistent with a direct interaction between Ogr and the alpha subunit of E. coli RNA polymerase in positive control of P2 late transcription, and indicate that the block imposed by the rpoA109 mutation is due to steric hindrance.

Amino Acid Sequence↗
PubMed1992

Molecular basis of type IA (tyrosinase negative) oculocutaneous albinism.

Type IA (Tyrosinase negative) oculocutaneous albinism (OCA) is produced by mutations of the tyrosinase gene. We have found a total of 13 different mutations associated with type IA OCA. Analysis of the distribution of the 9 missense mutations shows that most of these mutations cluster in three areas of the gene. All but one of these mutations involve amino acids that are conserved between the mouse and human. Two clusters involve the copper A and copper B binding sites, and could disrupt the metal ion-protein interaction necessary for enzyme function. The third cluster is in exon I and could represent an important functional domain of the enzyme such as the tyrosine binding site. The deletion or insertion frameshift mutations are distributed throughout the coding region and do not appear to cluster. We conclude that a diverse number of mutations are responsible for type IA OCA and many individuals are compound heterozygotes for mutations responsible for this genetic disease (Table 3).

Albinism, Oculocutaneous↗
PubMed1992

Analysis of mutations in the copper B binding region associated with type I (tyrosinase-related) oculocutaneous albinism.

Mutations of the tyrosinase gene are responsible for type I (tyrosinase-related) oculocutaneous albinism (OCA), an autosomal recessive genetic syndrome with a broad phenotypic spectrum. Mutant tyrosinase alleles can be associated with no melanin synthesis (I-A, tyrosinase-negative OCA), small to moderate amounts of melanin (I-B, yellow OCA) or unusual pigment patterns (I-TS, temperature-sensitive OCA). A total of 26 mutations of this gene have been described in type I OCA. Analysis of all known mis-sense mutations (n = 17) shows that most cluster in three areas of the coding region. Two clusters involve the copper A or copper B binding sites and may disrupt the metal ion-protein interaction necessary for enzyme function and the third cluster is located in exon I. Computer modeling of the secondary structure of the copper binding regions based on homology with the known crystal structure of hemocyanin show that they both consist of two alpha helices containing three histidine ligands that complex to a single copper atom. Mutations in the copper B binding region lie in the region between the two alpha helices that consists of a loop structure. These mutations may affect tyrosinase activity by either altering the position of the alpha helical domains and thus preventing proper copper binding to the histidine ligands, or affecting a catalytic or substrate binding site located between the two alpha helical domains.

Albinism, Oculocutaneous↗
PubMed1992

Effects of enalapril and hydralazine treatment and withdrawal upon cardiovascular hypertrophy in stroke-prone spontaneously hypertensive rats.

OBJECTIVE: To test the hypothesis that effects of angiotensin converting enzyme (ACE) inhibitors upon resistance vessel structure are responsible for their ability to cause long-term reduction in blood pressure. DESIGN: Stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rats were treated with enalapril or hydralazine from 4 to 15 weeks of age. Effects upon tail-cuff blood pressure, left ventricular hypertrophy and structural indices of the superior mesenteric artery (SMA) and its resistance vessels were assessed at 11 weeks of treatment and up to 11 weeks post-treatment. METHODS: Left ventricular hypertrophy was assessed by left ventricular weight:body weight ratios. Evidence of vascular structural change was obtained from tissue weight:body weight ratios, levels of RNA, DNA and expression of alpha-actin and elastin messenger (m)RNA. RESULTS: The effects of enalapril and hydralazine upon left ventricular hypertrophy in SHRSP were consistent with their respective effects upon blood pressure. Both drugs prevented the development of medial hypertrophy in SMA and resistance vessels. This was accompanied by substantial reductions in RNA:DNA ratios. Alpha-actin mRNA levels were not affected by either drug but elastin mRNA levels were reduced by both drugs. During the first 12 days post-treatment there was evidence of structural change in SMA accompanying the increases in blood pressure but importantly not in the resistance vessels. CONCLUSION: The effects of enalapril upon left ventricular hypertrophy and mesenteric arterial hypertrophy are totally consistent with responses to blood pressure and the persistence of structural changes post-treatment does not underlie the ability of the ACE inhibitors to persistently suppress hypertension.

Animals↗
PubMed1991

Variable expression of vision in sibs with albinism.

Oculocutaneous albinism is defined by the presence of cutaneous and ocular hypopigmentation, the latter associated with nystagmus, iris transillumination, reduced retinal pigment, foveal hypoplasia, and misrouting of the optic fibers at the chiasm. The visual acuity is variable but almost always reduced. We report on two brothers with oculocutaneous albinism and markedly different visual acuity. One brother has a visual acuity of 20/100, while the second has similar cutaneous pigmentation and visual acuity of 20/20 and had not previously been recognized as having oculocutaneous albinism. Both brothers have foveal hypoplasia and misrouting of the optic fibers at the chiasm. Biochemical analysis suggests that this is a tyrosinase-related type of oculocutaneous albinism. This study demonstrates that careful observation of foveal development in relatives with normal vision is necessary to detect all individuals with albinism in a family. A suspected diagnosis of albinism may be confirmed when the visual-evoked potentials show excessive decussation of the optic fibers at the chiasm.

Adolescent↗
PubMed1991

Thromboxane responsiveness of dog platelets is inherited as an autosomal recessive trait.

Most mongrel dogs have platelets that form thromboxane A2 (TXA2) from exogenous arachidonate, but they fail to aggregate or secrete in response to it. In contrast to these TXA2 insensitive (TXA2-) platelets, some dogs have TXA2 sensitive (TXA2+) platelets that aggregate and secrete when stirred with arachidonate. To evaluate the possible genetic basis for this difference, we carried out seven matings of mongrel dogs that yielded 48 viable offspring. Four matings of dogs with TXA2- platelets (presumed genotype TT) including 2 back-crosses, produced 32 pups with TXA2- (TT) platelets and 0 pups with TXA2+ platelets. A cross between a male with TXA2+ platelets (presumed genotype tt) and a female with TXA2+ (tt) platelets yielded 9 offspring with TXA2+ (tt) platelets and 0 with TXA2- platelets. Crossing a male presumed homozygous (TT) for TXA2- platelets with a female with TXA2+ (tt) platelets produced 2 pups with TXA2- (Tt) platelets and 0 pups with TXA2+ (tt) platelets. The same female with TXA2+ platelets crossed with a male presumed to be heterozygous (Tt) for TXA2- platelets yielded 2 pups with TXA2+ (tt) platelets and 3 pups with TXA2- (Tt) platelets. Segregation analysis of these data supports the hypothesis that the ability of dog platelets to aggregate and secrete in response to TXA2 is inherited as an autosomal recessive trait.

Aging↗
PubMed1991

Sudden death in children receiving Norpramin: a review of three reported cases and commentary.

The 1990 "package insert" for Norpramin, the Merrell Dow Pharmaceuticals Inc., brand of desipramine, was changed to include the following statement in the Adverse Reactions section, "There has been a report of an 'acute collapse' and 'sudden death' in an eight-year-old (18 kg) male, treated for two years for hyperactivity. There have been additional reports of sudden death in children." The purpose of this commentary is to review what is known about the three reported cases of sudden death and to discuss the implications of these tragedies for children receiving treatment with tricyclic drugs.

Attention Deficit Disorder with Hyperactivity↗