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Biomedical subjects

Jonathan L Rees

Publications and source records attributed to Jonathan L Rees.

At least 19 recordsLinked to original sources
PubMed2004

The genetics of sun sensitivity in humans.

Humans vary >100-fold in their sensitivity to the harmful effects of ultraviolet radiation. The main determinants of sensitivity are melanin pigmentation and less-well-characterized differences in skin inflammation and repair processes. Pigmentation has a high heritability, but susceptibility to cancers of the skin, a key marker of sun sensitivity, is less heritable. Despite a large number of murine coat-color mutations, only one gene in humans, the melanocortin 1 receptor (MC1R), is known to account for substantial variation in skin and hair color and in skin cancer incidence. MC1R encodes a 317-amino acid G-coupled receptor that controls the relative amounts of the two major melanin classes, eumelanin and pheomelanin. Most persons with red hair are homozygous for alleles of the MC1R gene that show varying degrees of diminished function. More than 65 human MC1R alleles with nonsynonymous changes have been identified, and current evidence suggests that many of them vary in their physiological activity, such that a graded series of responses can be achieved on the basis of (i) dosage effects (of one or two alleles) and (ii) individual differences in the pharmacological profile in response to ligand. Thus, a single locus, identified within a Mendelian framework, can contribute significantly to human pigmentary variation.

Gene Dosage↗
PubMed2004

Sagittal plane kinematics of a mobile-bearing unicompartmental knee arthroplasty at 10 years: a comparative in vivo fluoroscopic analysis.

This study compares in vivo sagittal plane kinematics of the Oxford mobile-bearing unicompartmental knee arthroplasty (UKA) at 1 and 10 years' postsurgery (10 knees) with a fixed-bearing total knee arthroplasty (TKA) (5 knees) and the normal knee (5 knees), using dynamic fluoroscopic measurement of the patellar tendon angle. The Oxford UKA preserved normal changes in patellar tendon angle with flexion, and this was maintained at 10 years. In contrast, an abnormal pattern was seen with the TKA. The results suggest that a normal pattern of sagittal plane knee kinematics exists following Oxford medial UKA and imply that anterior cruciate ligament function is maintained in the long term.

Adult↗
PubMed2004

Measurement of itch using actigraphy in pediatric and adult populations.

We have studied nocturnal movements using wrist-worn accelerometers in 33 adults with a range of pruritic dermatoses, 30 adult control subjects, 25 children with atopic dermatitis, and 17 pediatric control subjects. In all, 26 adults and 20 children were studied on more than one occasion, up to a maximum of 6 occasions. Participants were examined and a range of subjective measures about the extent of skin disease, itch, and quality of sleep were recorded. We show clear differences between patients and control subjects for both age groups studied, with activity medians approximately twice as high in the patients as in the control subjects ( P < .001). Studies on the same person show a considerable night-to-night variation that is unlikely to relate to measurement error, but instead, we believe, reflect genuine differences in nocturnal activity (and perhaps disease severity). Movement through the night did not seem to follow any obvious pattern. The relation between subjective measures, Severity sCORing of Atopic Dermatitis (SCORAD) index scores, and objective recorded activity was imperfect, with much unaccounted for variation. In particular, in adults, but not in children, we found a negative correlation (-0.44, P < .02) between objective movement activity and self-reported quality of sleep. Our results support the use of objective measures of scratch in the assessment of disease activity, and suggest that the relation between subjective and objective measures of disease severity may not be straightforward.

Adolescent↗
PubMed2004

The development of an objective method for measuring scratch in children with atopic dermatitis suitable for clinical use.

Itch is a major symptom of skin disease and remains poorly studied. We have used limb-worn digital accelerometers, and infrared video of patients as a gold standard, on children with atopic dermatitis and control subjects in their own homes at night. Video analysis shows that nocturnal scratching and restlessness are more complex than we first thought, with many movements that potentially damage the skin not conforming to stereotypical scratch movements. Children with atopic dermatitis spent a mean of 46 minutes less time motionless or sleeping at night than control subjects (468 +/- 3 [SEM] vs 422 +/- 37 [SEM], P<.001). Children with atopic dermatitis showed 2 to 3 times as much scratching or restlessness activity as control subjects, with little overlap between groups (P<.01). Scratching and restlessness were highly correlated with each other (0.94, P<.01). Accelerometer scores were highly correlated with video results (rho>0.02, P<.01, for scratching, restlessness, and sleeping time). Individual limb scores were highly correlated with each other (rho approximately 0.87-0.98), suggesting that little information would be lost if only 1 limb was measured. There was little relation between parental assessment of scratch and objective measured scratch. Accelerometers provide a useful and practical way of assessing scratching at night in the patient's own home and could be used as an objective measure of disease activity both in clinical trials and in everyday clinical practice.

Behavior↗
PubMed2004

Quantitative measures of the effect of the melanocortin 1 receptor on human pigmentary status.

Variation in human hair and skin color is the most striking visible aspect of human genetic variation. The only gene known to exert an effect on pigmentary within the normal population is the melanocortin-1 receptor (MC1R). Previous studies have used a Mendelian framework to relate MC1R genotype to phenotype, by measuring pigmentary status using categorical scales. Such approaches are inadequate. We report results using direct measures of hair color using objective colorimetric dimensions and HPLC determined hair melanins. We have linked MC1R genotype with chemical measures of melanin quantity and type and objective phenotype measures of color. MC1R genotype was predictive of hair melanin expressed as the ratio of the loge of eumelanin to pheomelanin ratio, with a dosage effect evident: MC1R homozygote mean, 1.46; heterozygote, 4.44; and wild type, 5.81 (p<0.001). Approximately 67% of the variance in this model could be accounted for in terms of MC1R genotype. There was also a relation between MC1R status and hair color, most prominently for the b* axis (p<0.001), but also for the a* and L* scales (L*a*b*, CIE). We show for one of the most polymorphic human traits that it is possible to demonstrate meaningful relations between various physical characteristics: DNA sequence diversity, hair-wavelength-specific reflectance patterns, and chemical melanin assays.

Female↗
PubMed2004

Physiological variation in the erythemal response to ultraviolet radiation and photoadaptation.

We have studied the cutaneous response to ultraviolet radiation, measured objectively as erythema in a sample of 12 body sites on 15 Northern European subjects with multiple doses of ultraviolet B (UVB). Skin pigmentation and the development of photoadaptation in response to five repeated doses of irradiation at three body sites was also measured. We report striking differences of up to 5-fold at different body sites to the same challenge dose (p < 0.001) and demonstrate that for this population, site variation is just as important as between-person variation. Skin color at each body site is a strong predictor of response (p < 0.001) and that this cannot be attributed to vascular differences, but instead we believe it reflects site-specific variations in melanin pigmentation. We also observed similar but smaller within-person effects for responses to another inflammatory agent, dithranol (p < 0.01). Despite this, we did not find evidence for differences in the development of photoadaptation by body site. These results have clear clinical implications for the practice of phototesting prior to commencing phototherapy, for therapeutic failure in sites such as the legs in patients with psoriasis, and perhaps for melanoma body-site distribution.

Adaptation, Physiological↗
PubMed2004

Pharmacological characterization of loss of function mutations of the human melanocortin 1 receptor that are associated with red hair.

Variation in skin color is the major host risk factor for melanoma and other forms of skin cancer. Individuals with red hair show an increased ratio of phaeomelanin to eumelanin in both hair and skin. This ratio is regulated by the melanocortin (MC) 1 receptor. There are several common point mutations in the human MC1 receptor that are overrepresented in North European red-heads, and in individuals with pale skin. In order to determine the functional significance of these mutations, we expressed the Asp84Glu, Val92Met, Arg163Gln, and Asp294His variants of the human MC1 receptors in eukaryotic cells and determined their ability to bind alpha-melanocyte stimulating hormone (MSH) peptides and increase intracellular cAMP. The mutants Asp84Glu and Asp294His showed a much lower response to alpha-MSH in cAMP and a slightly impaired ability to bind alpha-MSH, and the Val92Met mutant bound alpha-MSH with 100-fold lower affinity as compared with the wild-type. The Arg163Gln variant, widely found in some Asian populations, reached normal level of cAMP response but had just slightly lower potency for alpha-MSH in binding and second messenger studies. The results provide important pharmacological characterization of common MC1 receptor variants in various world populations.

Amino Acid Sequence↗
PubMed2004

The time course of photoadaptation and pigmentation studied using a novel method to distinguish pigmentation from erythema.

The dynamics of human pigmentation in response to ultraviolet radiation (UVR) remain poorly characterized. In part, this is attributable to methodological issues relating to the overlap in spectra of hemoglobin and melanin. We describe a new method, based on the recording of reflectance properties following iontophoresis of a potent vasoconstrictor, noradrenaline. This removes the influence of blood, allowing measurement of pigmentation, represented as L* on the L*a*b* scale. Blood flow was separately assessed using laser Doppler flowmetry. We show that there is a clear dose response with the dose of UVR administered, that pigmentation peaks at 1 wk and declines over the following 10 wk, but does not return to baseline within this period. We show clear differences in the degree, but not the temporal pattern of pigmentation between different pigmentary groups. We also report that the relation between facultative pigment and constitutive pigment is incomplete, with a wide scatter of responses for the development of pigmentation irrespective of constitutive levels. For comparison we also document overall photoadaptation and relate changes in pigmentation to the overall changes in photoadaptation.

Adaptation, Physiological↗
PubMed2003

Time course of ultraviolet B-induced erythema in people with red hair harbouring homozygous melanocortin 1 receptor mutations.

It has previously been reported that the time course of erythema may be delayed in those with sun-sensitive skin types and those with skin cancer. One molecular explanation for this putative phenotype would be that it is caused by mutations of the melanocortin 1 receptor (MC1R). In the present study of 20 persons, 10 of whom were MC1R homozygous, we measured erythema over a 21-day period in response to a range of ultraviolet B doses using methods that improved on previous studies. We could detect no consistent differences in ultraviolet radiation-induced erythema between the groups studied. The pharmacological mechanisms underpinning such prolonged inflammatory responses merit further investigation.

Case-Control Studies↗
PubMed2003

The relationship between constitutive pigmentation and sensitivity to ultraviolet radiation induced erythema is dose-dependent.

The relationship between skin colour and experimental exposure to ultraviolet radiation (UVR) B, with response measured as erythema was studied. Two reflectance methods were used to measure skin colour--tristimulus colorimetry using a Minolta instrument (summarized as the alpha characteristic angle) and the melanin index based on the Diastron reflectance instrument. As expected both measures are highly correlated (0.91). A dose-dependent relationship between skin colour measured as the alpha characteristic angle and UVR was established, with the gradient increasing from 0.99 at 119 mJ to 2.7 at 300 mJ, with the relevant standard errors being 0.39 and 0.47, respectively. Similarly, for the melanin index (where the scale goes in the opposite direction) the gradient differs between -0.49 for 119 mJ and -0.91 for 300 mJ, with the standard errors being 0.14 and 0.17 respectively. The proportion of variation explained is also greater at higher UVR challenge doses. Studies relating UVR sensitivity and pigmentation need to take account of the dose of UVR administered.

Dose-Response Relationship, Radiation↗
PubMed2003

Genetics of hair and skin color.

Differences in skin and hair color are principally genetically determined and are due to variation in the amount, type, and packaging of melanin polymers produced by melanocytes secreted into keratinocytes. Pigmentary phenotype is genetically complex and at a physiological level complicated. Genes determining a number of rare Mendelian disorders of pigmentation such as albinism have been identified, but only one gene, the melanocortin 1 receptor (MCR1), has so far been identified to explain variation in the normal population such as that leading to red hair, freckling, and sun-sensitivity. Genotype-phenotype relations of the MC1R are reviewed, as well as methods to improve the phenotypic assessment of human pigmentary status. It is argued that given advances in model systems, increases in technical facility, and the lower cost of genotype assessment, the lack of standardized phenotype assessment is now a major limit on advance.

Agouti Signaling Protein↗
PubMed2002

Production of acute and chronic itch with histamine and contact sensitizers in the mouse and guinea pig.

Itch is a major symptom of skin disease and is poorly understood, in part due to the lack of adequate small animal models. We show, using iontophoresis of histamine and capsaicin, that it is possible to induce scratching behaviour in both guinea pig and mouse. Use of iontophoresis may obviate the problems of induction of pain as well as itch when injection is used. The behavioural response to capsaicin, however, differs from that seen with histamine, raising the possibility that the use of scratch counts as a method of measuring itch severity needs to be set in the context of other responses. Naloxone partly inhibits scratching in mouse and guinea pig due to histamine. We also show that contact sensitization with 2-4 dinitrochlorobenzene (DNCB) can be used as a simple assay for chronic itch allowing study of scratching over at least a 15-h period. The characteristics of scratching (but not the time course) induced with DNCB are similar to those seen with histamine.

Acute Disease↗
PubMed2002

The usefulness of 4-amino-3-hydroxyphenylalanine as a specific marker of pheomelanin.

Reductive hydrolysis of pheomelanin with hydriodic acid (HI) gives two aminohydroxyphenylalanine isomers, 4-amino-3-hydroxyphenylalanine ('specific AHP') and 3-amino-4-hydroxyphenylalanine (3-aminotyrosine, AT), which derive from the oxidative polymerization of 5-S-cysteinyldopa, and 2-S-cysteinyldopa, respectively. Since we first introduced this analytical method, the combined amount of AHP and AT ('total AHP') has been extensively used as a marker of pheomelanin. However, one problem with using total AHP as a marker is that background levels originate from precursors other than pheomelanin. Considerable and variable amounts of background AT are produced from other sources, most likely nitrotyrosine residues in proteins. In order to overcome this problem, we developed HPLC conditions which enable the direct injection of the HI reduction products into the HPLC system allowing good separation of AHP and AT. In this way we could study the importance of both degradation products separately and their specificity as markers for pheomelanin. The usefulness of the present method is validated using human hair samples of various colours which were divided into dark, fair or red colours. The combined amount of specific AHP and AT shows an excellent correlation with total AHP, and the amount of specific AHP also correlates with the amount of total AHP. We also examined total AHP and specific AHP values against pyrrole-2,3,5-tricarboxylic acid (PTCA) values in the human hair samples. These results show that specific AHP measurement gives a more prominent segregation for the ratio of specific AHP to PTCA among hairs of various colours than the ratio of total AHP to PTCA. Thus, we conclude that 'specific AHP' is a more specific marker of pheomelanin than is 'total AHP'.

Animals↗