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Biomedical subjects

J L Rees

Publications and source records attributed to J L Rees.

At least 19 recordsLinked to original sources
PubMed2002

Safety to drive after common limb fractures.

One hundred Orthopaedic Consultants in the UK were randomly selected and asked to complete a postal questionnaire indicating when they felt patients with treated, pain free, common limb fractures could return to driving. Seventy-two questionnaires were returned. Six were not completed leaving 66 completed questionnaires. Analysis revealed a clear mandate to allow or prevent driving in patients with certain treatment modalities and stages of union. In the lower limb there was majority agreement of suitability to drive in 61% of the 28 presented scenarios. Opinion was more divided for the upper limb, with only 43% of the scenarios having majority agreement. Our results show that while for some common limb fractures there is a clear body of opinion supporting safety to drive, for other common fractures opinion is less clear cut. This has important financial, medico-legal and legal implications that could be resolved by formal testing.

Arm Injuries↗
PubMed2002

Defining the femoral axis on lateral knee fluoroscopy.

The methodological detail about determining the femoral axis on lateral fluoroscopic images of the knee is lacking. This paper reports on the use of the posterior border of the lower femoral diaphysis to represent the axis. This method is accurate, simple, reliable and can be used by researchers studying knee joint kinematics using dynamic video fluoroscopy. It is also useful in the outpatient clinic to assess the flexion/extension position of femoral components after knee arthroplasty.

Arthroplasty, Replacement, Knee↗
PubMed2002

Accelerated recovery for unicompartmental knee replacement--a feasibility study.

A pilot study assessed the feasibility of discharging NHS patients undergoing knee replacement within a day of surgery. Seven patients with medial compartment osteoarthritis were recruited after fulfilling strict exclusion criteria. Pre-operative assessment revealed that all patients had significant dysfunction and pain before operation. They had medial unicompartmental replacement through a short incision without dislocation of the patella. Each patient underwent an accelerated recovery program that included pain control, physiotherapy and self-assessment. Patients were mobilised immediately after operation. Follow-up assessment was performed at 1, 2 and 6 weeks after surgery. All patients, except one (who failed to go home because of an administrative error), returned home the day after surgery. The average pain score for the first 2 weeks after surgery was 2/10. At 6 weeks, knee flexion averaged 125 degrees and all patients were walking independently and painfree. The new protocol allows for early, safe discharge of patients undergoing unicompartmental knee replacement.

Aged↗
PubMed2002

A kinematic study of lateral unicompartmental arthroplasty.

When the Oxford unicompartmental meniscal bearing arthroplasty (UCA) is used in the lateral compartment 10% of the bearings dislocate. A fluoroscopic study was performed to investigate if abnormal mid-sagittal plane kinematics was related to bearing dislocation. Video fluoroscopy is an accepted means of determining in-vivo knee kinematics in the sagittal plane. Video fluoroscopy was obtained of 5 Oxford lateral UCAs 10 years post-operatively and of five normal knees. Patellar tendon angle (PTA), derived from dynamic fluoroscopic images, was used to describe the joint kinematics. This in-vivo experiment demonstrated that the PTA/knee relationship for the Oxford lateral UCA is similar to the normal knee. Both the normal knee (r(2)=0.99) and the Oxford lateral UCA (r(2)=0.98) demonstrated a linear relationship between flexion angle and PTA. No significant difference in PTA was found between the normal knee and the Oxford lateral UCA. This study demonstrated normal kinematics, as indicated by PTA, ten years after implantation of the Oxford lateral UCA. It is therefore reasonable to suggest that abnormal kinematics is not a significant factor relating to meniscal bearing dislocation in the lateral compartment.

Adult↗
PubMed2002

What is the 'true' function of skin?

Conventional textbook wisdom portrays the skin as an organ that literally enwraps whatever each of us stands for as a more or less functional, individual member of the mammalian species, and has it that the skin primarily establishes, controls and transmits contacts with the external world. In addition, the skin has long been recognized to protect the organism from deleterious environmental impacts (physical, chemical,microbiological), and is well-known as crucial for the maintenance of temperature, electrolyte and fluid balance. Now, ever more studies are being published that show the skin to also operate as a huge and highly active biofactory for the synthesis,processing and/or metabolism of an astounding range of e.g. structural proteins, glycans, lipids and signaling molecules. Increasingly, it becomes appreciated that the skin, furthermore, is an integral component of the immune, nervous and endocrine systems, with numerous lines of cross-talk between these systems established intracutaneously (e.g. Ann NY Acad Sci Vol 885, 1999; Endocrine Rev 21:457-487, 2000; Physiol Rev 80:980-1020, 2001; Exp Dermatol 10: 349-367, 2001). All these emerging cutaneous functions beyond the classical image of the skin as a barrier and sensory organ are immediately relevant for many of the quandaries that clinical dermatology, dermatopathology, and dermatopharmacology are still struggling with to-date, and offer the practising dermatologist attractive new targets for therapeutic intervention. Yet, many of these skin functions are not even mentioned in dermatology textbooks and await systematic therapeutic targeting. Following a suggestion by Enno Christophers, the current 'Controversies' feature brings together an unusually diverse council of biologists and clinicians, who share their thought-provoking views with the readers and allow us to peek into the future of research in cutaneous biology, not the least by reminding us of the -- often ignored -- evolutionary and embryonal origins of our favorite organ. Hopefully, this unique discussion feature will foster an understanding of the 'true' skin functions that is both more comprehensive and more profound than conventional teaching on this topic, and will stimulate more than 'skin-deep' reflections on the full range of skin functions.

Aging↗
PubMed2002

Dislocation of the bearing of the Oxford lateral unicompartmental arthroplasty. A radiological assessment.

When the Oxford unicompartmental meniscal bearing arthroplasty is used in the lateral compartment of the knee, 10% of the bearings dislocate. A radiological review was carried out to establish if dislocation was related to surgical technique. The postoperative radiographs of 46 lateral unicompartmental arthroplasties were analysed. Five variables which related to the position and alignment of the components were measured. Dislocations occurred in six knees. Only one of the five variables, the proximal tibial varus angle, had a statistically significant relationship to dislocation. This variable quantifies the height of the lateral joint line. The mean proximal tibial varus angle for knees the bearings of which had dislocated was 9 degrees and for those which had not it was 5 degrees. In both groups it was greater than would be expected in the normal knee (3 degrees). Our study suggests that a high proximal tibial varus angle is associated with dislocation. The surgical technique should be modified to account for this, with care being taken to avoid damage to or overdistraction of the lateral soft tissues.

Aged↗
PubMed2001

Functional variation of MC1R alleles from red-haired individuals.

Red hair in humans is associated with variant alleles of the alphaMSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of alphaMSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.

Alleles↗
PubMed2001

Expression, candidate gene, and population studies of the melanocortin 5 receptor.

In mouse the melanocortin 5 receptor is known to regulate sebaceous gland function. To clarify its role in man, we have studied melanocortin 5 receptor expression in skin, and allelic variation at the melanocortin 5 receptor locus in diverse human populations and candidate disease groups. Melanocortin 5 receptor protein and mRNA expression were studied by immunohistochemistry and reverse transcriptase polymerase chain reaction. Melanocortin 5 receptor mRNA was detected in normal skin and cultured keratinocytes but not in cultured fibroblasts or melanocytes. Immunohistochemistry revealed melanocortin 5 receptor immunoreactivity in the epithelium and appendages, including the sebaceous gland, eccrine glands, and apocrine glands, as well as low level expression in the interfollciular epidermis. In order to screen for genetic diversity in the melanocortin 5 receptor that might be useful for allelic association studies we sequenced the entire melanocortin 5 receptor coding region in a range of human populations. One nonsynonymous change (Phe209Leu) and four synonymous changes (Ala81Ala, Asp108Asp, Ser125Ser, and Thr248Thr) were identified. Similar results were found in each of the populations except for the Inuit in which only the Asp108Asp variant was seen. The apparent "global distribution" of melanocortin 5 receptor variants may indicate that they are old in evolutionary terms. Variation of melanocortin 5 receptor was examined in patients with acne (n = 21), hidradenitis supprativa (n = 4), and sebaceous gland lesions comprising sebaceous nevi, adenomas, and hyperplasia (n = 13). No additional mutations were found. In order to determine the functional status of the Phe209Leu change, increase in cAMP in response to stimulation with alpha-melanocyte-stimulating hormone was measured in HEK-293 cells transfected with either wild-type or the Phe209Leu variant. The variant melanocortin 5 receptor was shown to act in a concentration-dependent manner, which did not differ from that of wild type. We have therefore found no evidence of a causative role for melanocortin 5 receptor in sebaceous gland dysfunction, and in the absence of any association between variation at the locus and disease group, the pathophysiologic role of the melanocortin 5 receptor in man requires further study.

Acne Vulgaris↗
PubMed2001

The relation between melanocortin 1 receptor genotype and experimentally assessed ultraviolet radiation sensitivity.

Pigmentary phenotype is a key determinant of an individual's response to ultraviolet radiation with the presence of phaeomelanin thought to be of particular importance. Reports of minimal erythema testing, however, have failed to show a consistent difference between skin type I and other skin types. The melanocortin 1 receptor is a key genetic determinant of the cutaneous response to ultraviolet radiation. In this study we investigate the relation between experimentally induced erythemal response to ultraviolet radiation and the melanocortin 1 receptor genotype. Phototesting was performed in 20 redheads and 20 nonredheaded subjects, the majority of whom were also screened for the presence of melanocortin 1 receptor variants. The majority of redheads sequenced (89%) had two melanocortin 1 receptor variants previously found to be associated with red hair compared to none of the controls. There was no significant difference between the groups in minimal erythema dose: the median minimal erythema dose in redheads was 44 mJ per cm2 (interquartile range 34-56) and in the nonredheaded group was 40 mJ per cm2 (interquartile range 40-56). Objective measurements of ultraviolet-B-induced erythema were performed using reflectance instrument measurements of erythema intensity and dose-response curves constructed for each subject. The slope of the dose-response curve in the redheaded group was statistically greater than in the nonredheaded group (median in redheads 4.08 vs 3.56 for controls, 95% confidence interval for the difference between the medians being 0.01-1.23, p = 0.043). In addition the ratio D0.05:D0.025 was significantly lower for the redheaded group (median in redheads 1.22, interquartile range 1.18-1.26; median in nonreds 1.28, interquartile range 1.23-1.32; p < 0.05). Thus, although the minimal erythema dose values were not different, subjects with red hair develop greater intensity of erythema than nonredheaded individuals when doses greater than the minimal erythema dose are given. Importantly, when analyzed by genotype alone rather than phenotype, the slope of the erythema dose-response differed between those persons who were homozygous or heterozygous mutants and wildtype/pseudo-wildtype (p = 0.026).

Adult↗
PubMed2001

Medial unicompartmental arthroplasty after failed high tibial osteotomy.

Satisfactory selection criteria are essential for the successful outcome of unicompartmental knee arthroplasty (UCA). We report the frequency of revision of the Oxford medial unicompartmental arthroplasty in knees previously treated for anteromedial osteoarthritis by high tibial osteotomy (HTO). The combined results from three sources were used to allow statistical analysis of this uncommon subgroup. In the combined series of 631 knees (507 patients) which had medial unicompartmental replacement, 613 were primary procedures and 18 were for a failed HTO. The mean follow-up times of the two groups were similar (5.8 years and 5.4 years, respectively). At review, 19 (3.1%) of the primary procedures and five (27.8%) of those undertaken for a failed HTO had been revised to total knee replacement. Survival analysis revealed the ten-year cumulative survivals to be 96% and 66%, respectively. The log-rank comparison of these survivals revealed a highly significant difference (p < 0.0001). We recommend that the Oxford UCA should not be used in knees which have previously undergone an HTO.

Adult↗
PubMed2001

Reconstruction does not reduce tibial translation in the cruciate-deficient knee an in vivo study.

We have assessed the effectiveness of reconstruction of the anterior cruciate ligament (ACL) in reducing functional tibial translation (TT). The gait of 11 ACL-deficient patients was studied using Vicon equipment before and after surgery. Measurements of the angle between the patellar tendon and the long axis of the tibia were obtained in order to calculate TT in the sagittal plane relative to the uninjured limb during standing and walking. Before surgery, patients did not show abnormal TT on the injured side, but after surgery significant anterior TT was found in the operated limb for every parameter of gait. Abnormal anterior TT occurring during activity does not seem to be reduced by reconstruction; rather, it increases. It may be that the increased translation results from relaxation of excess contraction of the hamstring muscles, since compensatory muscle activity no longer is required in a reconstructed knee. The reduction of TT may not be an appropriate objective in surgery on the ACL.

Adult↗
PubMed2000

Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation.

Variants of the melanocortin 1 receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.

Alleles↗
PubMed2000

Melanocortin-1-receptor gene and sun sensitivity in individuals without red hair.

Susceptibility to sunburn, photoageing, and skin cancer is inversely related to an individual's ability to tan after sun exposure. We examined variants in the melanocortin-1-receptor (MC1R) gene in individuals from Ireland and the UK. We found evidence of an association between the degree of tanning after repeated sun exposure, and the number of variant alleles present. Heterozygotes were intermediate between wild-type individuals and those with two variant alleles. We suggest that MC1R gene status therefore determines sun sensitivity in people without red hair.

Adult↗
PubMed2000

Evidence for variable selective pressures at MC1R.

It is widely assumed that genes that influence variation in skin and hair pigmentation are under selection. To date, the melanocortin 1 receptor (MC1R) is the only gene identified that explains substantial phenotypic variance in human pigmentation. Here we investigate MC1R polymorphism in several populations, for evidence of selection. We conclude that MC1R is under strong functional constraint in Africa, where any diversion from eumelanin production (black pigmentation) appears to be evolutionarily deleterious. Although many of the MC1R amino acid variants observed in non-African populations do affect MC1R function and contribute to high levels of MC1R diversity in Europeans, we found no evidence, in either the magnitude or the patterns of diversity, for its enhancement by selection; rather, our analyses show that levels of MC1R polymorphism simply reflect neutral expectations under relaxation of strong functional constraint outside Africa.

Africa↗
PubMed2000

Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma.

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin 16 (K16) cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. Here, we report 2 novel mutations in K16 causing distinct phenotypes. A heterozygous missense mutation (L124R) was detected in a kindred with PC-1. In a family where mild FNEPPK was the only phenotype, a 23 bp deletion and a separate 1 bp deletion downstream were found in exon 6: [1244-1266del; 1270delG]. At the protein level, these mutations remove 8 residues and substitute 2 residues in the helix termination motif (HTM) of the K16 polypeptide. The HTM sequence is conserved in all known intermediate filament proteins and for convenience, this complex mutation was designated deltaHTM. Transient expression of K16 cDNAs carrying either the L124R or the deltaHTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the deltaHTM mutation were morphologically different and appeared to be less disruptive to the endogenous cytoskeleton. Therefore, loss of the HTM sequence may render this mutant K16 less capable of contributing to filament assembly and decrease its dominant-negative effect, resulting in the milder FNEPPK phenotype.

Base Sequence↗
PubMed2000

The melanocortin 1 receptor (MC1R): more than just red hair.

The melanocortin 1 receptor, a seven pass transmembrane G protein coupled receptor, is a key control point in melanogenesis. Loss-of-function mutations at the MC1R are associated with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, in animals at least, lead to enhanced eumelanin synthesis. In man, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired persons) are compound heterozygotes or homozygotes for up to five frequent loss-of-function mutations. A minority of redheads are, however, only heterozygote. The MC1R is, therefore, a major determinant of sun sensitivity and a genetic risk factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote effect on skin type, with up to 30% of the population harbouring loss-of-function mutations. Activating mutations of the MC1R in man have not been described. The MC1R is particularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of MC1R diversity is compatible with functional constraint operating in Africa, whereas the greater allelic diversity seen in non-African populations is consistent with neutral predictions rather than selection. Whether this conclusion is as a result of weakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great interest for studies of human skin colour evolution.

Alleles↗
PubMed2000

The temporal and spatial distribution of p21WAF expression in skin appendages.

p21WAF is a cyclin-dependent kinase inhibitor which is widely expressed in epidermal structures. Using a combination of double immunocytochemical staining and combined in situ hybridization, we show that there is a striking exclusivity between the expression of Ki67 and p21WAF in the hair matrix. Some cells that are Ki67-positive also express p53, but as they exit the cell cycle they assume p21WAF-positive/p53-negative status. By contrast, cells in the interfollicular epidermis of psoriatic lesions, in the sebaceous gland, and in the outer root sheath are p21WAF-positive/p53-positive but Ki67-negative. These results suggest that in some anatomical parts of the epidermis, p21WAF expression can accompany p53 expression, whereas in other parts, the expression of these markers is reciprocal, suggesting that other pathways may be controlling p21WAF expression. In order to define, functionally, the presence of p53-independent p21WAF expression in skin, we examined lesions of Bowen's disease in which both alleles of p53 were inactivated. p21WAF expression was still observed, confirming a role for p53-independent expression of p21WAF in human skin in vivo.

Bowen's Disease↗