Prevalence of superficial fungal infections among sports-active individuals: results from the Achilles survey, a review of the literature.

OBJECTIVE: To examine the effect of sport activities on the prevalence of foot disease in the Achilles survey, conducted during the spring of 1997 and 1998 in several European countries. SUBJECT: Foot diseases, especially fungal infections (tinea pedis and onychomycosis). METHODS: A questionnaire and a clinical examination regarding individuals presenting to a general practitioner for disorders irrespective of possible foot problems. RESULTS: More than 50% of subjects visiting a general practitioner had clinical evidence of foot disease, and approximately two-thirds of these had clinical evidence of a superficial fungal infection. The survey evidenced a significant age-dependent association between sporting activities and the prevalence of foot diseases and superficial fungal infection, especially in children. CONCLUSIONS: The results of this pan-European survey indicate that sporting activities can have an unfavourable effect on the individual regarding the occurrence of foot disease and superficial fungal infection. The results indicate a need to pay more attention to foot disease, to predict and prevent future diseases and further complications.

Melanoma screening: results of the first one-day campaign in Belgium ('melanoma Monday').

BACKGROUND: Although the incidence of melanoma is increasing and many informative campaigns have been organized. The general population is still little informed about this tumour. AIMS: To organize a media campaign, with more relevant information and the opportunity for free skin inspections. METHODS: A 'Task Force' organized a media campaign in April 1999 and convinced 65% of the Belgian dermatologists to give up 4 h of their time to do free skin examinations for skin cancer on Monday 26 April 1999; it was called 'Melanoma Monday'. RESULTS: A total 2767 patients were screened. We found 25 melanomas and suspected 59 basal cell carcinomas. In the following 4 weeks another 141 melanomas were found. These 166 melanomas found in one month represent 15-20% of the total number of melanomas per year in Belgium. SUMMARY: A media campaign with relevant information combined with screening opportunities can lead to the early detection of melanomas in a large number of patients and can continue to alert people at risk in the following weeks.

Refined physical mapping and genomic structure of the EXTL1 gene.

Recently, the EXTL1 gene, a member of the EXT tumor suppressor gene family, has been mapped to 1p36, a chromosome region which is frequently implicated in a wide variety of malignancies, including breast carcinoma, colorectal cancer and neuroblastoma. In this study, we show that the EXTL1 gene is located between the genetic markers D1S511 and D1S234 within 200 kb of the LAP18 gene on chromosome 1p36. 1, a region which has been proposed to harbor a tumor suppressor gene implicated in MYCN-amplified neuroblastomas. In addition, we determined the genomic structure of the EXTL1 gene, revealing that the EXTL1 coding sequence spans 11 exons within a 50-kb region.

Oral treatment schedules for onychomycosis: a study of patient preference.

BACKGROUND: An improved understanding of patients' attitudes to medication may help promote compliance with oral medications for onychomycosis. This study was performed to assess patients' preference between continuous and intermittent oral treatment schedules for onychomycosis and to determine the reasons underlying the selections made. METHODS: Patients were eligible for inclusion if they had current onychomycosis and were willing to take oral medication for this condition. In a 30-min, face-to-face interview, each patient answered questions about four possible treatment schedules for onychomycosis; regimen 1--continuous (daily regular intake) for 12 weeks; regimen 2--intermittent 1 week/month for 3 months (last week of therapy is week 9); regimen 3--intermittent once weekly for 21 weeks; regimen 4--intermittent 1 week/month for 4 months (last week of therapy is week 13). RESULTS: A total of 102 patients from Germany and Spain participated in the study. When asked to choose between regimens 1, 2, and 3, 46% of patients favored the 9-week intermittent schedule, 42% selected the 12-week continuous schedule, and 12% preferred the 21-week intermittent schedule. The preference for the 9-week intermittent schedule was more notable among younger patients (< 45 years), possibly because they are less used to taking regular medication, and among Spanish patients, an effect that could not be attributed to age because the average age of patients was similar in the participating countries (Germany 47.2 years; Spain 48.0 years). When the patients who preferred regimen 2 were asked to choose between regimens 1, 3, and 4 (both intermittent schedules longer than the continuous schedule), most (57%) favored the shortest treatment schedule (regimen 2). CONCLUSIONS: Overall, patients favored an intermittent schedule lasting 9 weeks. Treatment duration is the critical factor in determining patients' preference for treatment schedules for onychomycosis.

Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.

Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function.

Identification of a third EXT-like gene (EXTL3) belonging to the EXT gene family.

Two homologous genes, EXT1 and EXT2, responsible for the development of benign multiple cartilagenous bone tumors (exostoses) on the long bones, have been identified in the past 2 years. Several arguments have been provided to support the hypothesis that these genes have tumor suppressor activity and that loss of function of these genes may contribute to the development of bone tumors. The recent identification of two EXT-like genes, EXTL1 and EXTL2, homologous to the EXT genes and to each other, revealed the existence of a larger family of genes. We now report the identification of a homologous EST (EST01365), not derived from the known EXT and EXTL genes, indicating the existence of one additional member of this gene family. We characterized this third EXT-like gene, EXTL3, and compared it with the other four members of the EXT-EXTL family. In view of its putative tumor suppressor function, the EXTL3 gene can be considered a candidate gene for the breast cancer locus on chromosome 8p12-p22.

Identification and characterization of a novel member of the EXT gene family, EXTL2.

Recently, two homologous genes, EXT1 and EXT2, with a putative tumor suppressor function have been described. Mutations in both genes are responsible for multiple exostosis syndrome (EXT), an autosomal dominant condition characterized by the presence of multiple osteochondromas, bony excrescences that sometimes undergo malignant transformation to chondrosarcoma. This family of EXT genes has been extended by the identification of an EXT-like (EXTL) gene showing a high degree of homology with the EXT genes. We report here a second EXT-like gene (EXTL2) which is homologous to the EXT and EXTL genes. EXTL2 consists of 5 exons encoding an ubiquitously expressed protein of 330 amino acids. In addition, a putative pseudogene, EXTL2P was also identified. The EXTL2 gene was assigned to chromosome 1p11-p12, whereas EXTL2P was mapped on chromosome 2q24-q31.

n-Docosanol 10% cream in the treatment of recurrent herpes labialis: a randomised, double-blind, placebo-controlled study.

n-Docosanol has been shown to have antiviral activity. To demonstrate the efficacy of n-docosanol 10% cream in the treatment of recurrent herpes labialis, a randomised, double-blind, parallel group, placebo-controlled study was undertaken in 63 patients. In a crossover extension, 22 of the patients used the alternative treatment for a further episode. A total of 98 episodes were evaluated. Application of n-docosanol 10% cream early in the prodromal or erythema stage of a recurrent episode of herpes labialis shortened mean healing time by approximately 3 days, as compared to late treatment with n-docosanol 10% cream and early or late treatment with the placebo. The crossover study revealed that late treatment with n-docosanol 10% cream significantly reduced mean healing time compared to placebo. Treatments were well tolerated.

Positional cloning of a gene involved in hereditary multiple exostoses.

Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.

Long-term potentiation in the hippocampus of fragile X knockout mice.

To gain more insight in the physiological function of the fragile X gene (FMR1) and the mechanisms leading to fragile X syndrome, the Fmr1 gene has been inactivated in mice by gene targeting techniques. In the Morris water maze test, the Fmr1 knockout mice learn to find the hidden platform nearly as well as the control animals, but show impaired performance after the position of the platform has been modified. As malperformance in the Morris water maze test has been associated with impaired long-term potentiation (LTP), electrophysiological studies were performed in hippocampal slices of Fmr1 knockout mice to check for the presence of LTP. Judged by field extracellular excitatory postsynaptic potential recordings in the CA1 hippocampal area, Fmr1 knockout mice express LTP to a similar extent as their wild type littermates during the first 1-2 hr after high frequency stimulation. Also, short-term potentiation (STP) was similar in both types of mice. To investigate whether Fmr1 is involved in the latter stages of LTP as an immediate early gene, we compared Fmr1 mRNA quantities on northern blots after chemical induction of seizures. A transient increase in the transcription of immediate early genes is thought to be essential for the maintenance of LTP. As no increase in Fmr1 mRNA could be detected, neither in cortex nor in total brain, during the first 2 1/2 hr after pentylenetetrazol-induced seizures, it is unlikely that Fmr1 is an immediate early gene in mice. In conclusion, we found no evidence for a function of FMR1 in STP or LTP.

Transgenic mouse model for the fragile X syndrome.

Transgenic fragile X knockout mice have been constructed to provide an animal model to study the physiologic function of the fragile X gene (FMR1) and to gain more insight into the clinical phenotype caused by the absence of the fragile X protein. Initial experiments suggested that the knockout mice show macroorchidism and cognitive and behavioral deficits, abnormalities comparable to those of human fragile X patients. In the present study, we have extended our experiments, and conclude that the Fmr1 knockout mouse is a reliable transgenic model to study the fragile X syndrome.

Severe mental retardation and macroorchidism without mutation in the FMR1 gene.

Only one missense mutation, an Ile304Asn, has been reported in the fragile X gene (FMR1). This mutation is located in the second KH domain of FMR1, and has led to the discovery of the function of the FMR1 gene product as an RNA-binding protein. The patient carrying this mutation has profound mental retardation, macroorchidism, and an "acromegalic" face with prominent supraorbital ridges, enlarged jaw, heavy brow ridges, thick lips, and a broad nose. We have studied the possible involvement of FMR1 in two maternal half-brothers with a phenotype similar to that of the patient with the Ile304Asn mutation. Both brothers had an identical number of CGG repeats in the normal size-range, and shared the same maternal Xq27 haplotype. Southern blot analysis with two overlapping FMR1 cDNA clones, spanning the total FMR1 open reading frame, showed no major deletions, insertions, or gross rearrangements. Single-strand conformation pattern (SSCP) analysis of the KH domains showed no aberrant patterns. The total open reading frame of the FMR1 gene was cloned and sequenced, but no mutation was found. Northern blot analysis showed mRNA in the normal size-range, and immunocytochemistry on individual lymphocytes indicated that FMRP, the protein product of FMR1, was present. In conclusion, it is unlikely that FMR1 plays a role in the phenotype of this patient. Other genes may be responsible for the combination of mental retardation and macroorchidism.

Mean corpuscular hemoglobin is not increased in Fmr1 knockout mice.

A slight increase in mean corpuscular hemoglobin (MCH) has been reported in erythrocytes from human fragile X patients. As it is difficult to perform case-controlled studies in patients with fragile X syndrome, we studied MCH in erythrocytes from transgenic mice with an Fmr1 knockout. None of the knockout mice showed increased MCH levels when compared with normal littermates. We conclude that it is unlikely that the FMR1 gene product has an effect on MCH.

Gene conversion between red and defective green opsin gene in blue cone monochromacy.

Blue cone monochromacy is an X-linked condition in which the function of both the red pigment gene (RCP) and the green pigment gene (GCP) is impaired. Blue cone monochromacy can be due to a red/green gene array rearrangement existing of a single red/green hybrid gene and an inactivating C203R point mutation in GCP. We describe here a family with blue cone monochromacy due to the presence of the C203R mutation in both RCP and GCP. The flanking sequences of the C203R mutation in exon 4 of RCP were characteristic for GCP, indicating that this mutation was transferred from GCP into RCP by gene conversion.

Apparent regression of the CGG repeat in FMR1 to an allele of normal size.

The fragile X syndrome is the result of amplification of a CGG trinucleotide repeat in the FMR1 gene and anticipation in this disease is caused by an intergenerational expansion of this repeat. Although regression of a CGG repeat in the premutation range is not uncommon, regression from a full premutation (> 200 repeats) or premutation range (50-200 repeats) to a repeat of normal size (< 50 repeats) has not yet been documented. We present here a family in which the number of repeats apparently regressed from approximately 110 in the mother to 44 in her daughter. Although the CGG repeat of the daughter is in the normal range, she is a carrier of the fragile X mutation based upon the segregation pattern of Xq27 markers flanking FMR1. It is unclear, however, whether this allele of 44 repeats will be stably transmitted, as the daughter has as yet no progeny. Nevertheless, the size range between normal alleles and premutation alleles overlap, a factor that complicates genetic counseling.

Variable regions of chromosome 11 loss in different pathological tissues of a patient with the multiple endocrine neoplasia type I syndrome.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder characterized by nodular proliferation of the parathyroid glands and tumors of the anterior pituitary gland, the endocrine pancreas, and the neuroendocrine cell system of the gut. Loss of the putative tumor suppressor effect of the MEN1 gene is probably responsible for the development of MEN1-associated tumors. We report here a genetic study of a female MEN1 patient with the association of nodular hyperplasia of two parathyroid glands, an insulinoma, multiple duodenal gastrinomas, a prolactinoma, and a gastric carcinoid. We performed loss of heterozygosity (LOH) studies of chromosome 11 on all affected tissues except the insulinoma. Allelic losses of chromosome 11 were detected in several tumors, but the chromosomal regions of LOH were different, suggesting that different somatic mutational events are involved in the pathogenesis of these tumors. LOH of chromosome 11 was also detected in the prolactinoma of this patient, which indicates that the MEN1 gene has a tumor suppressor effect in the pituitary.

MASA syndrome is due to mutations in the neural cell adhesion gene L1CAM.

MASA syndrome is a recessive X-linked disorder characterized by mental retardation, adducted thumbs, shuffling gait, aphasia and, in some cases, hydrocephalus. Since it has been shown that X-linked hydrocephalus can be caused by mutations in L1CAM, a neuronal cell adhesion molecule, we performed an L1CAM mutation analysis in eight unrelated patients with MASA syndrome. Three different L1CAM mutations were identified: a deletion removing part of the open reading frame and two point mutations resulting in amino acid substitutions. L1CAM, therefore, harbours mutations leading to either MASA syndrome or HSAS, and might be frequently implicated in X-linked mental retardation with or without hydrocephalus.