Implications of FRA16A structure for the mechanism of chromosomal fragile site genesis.

Fragile sites are chemically induced nonstaining gaps in chromosomes. Different fragile sites vary in frequency in the population and in the chemistry of their induction. DNA sequences encompassing and including the rare, autosomal, folate-sensitive fragile site, FRA16A, were isolated by positional cloning. The molecular basis of FRA16A was found to be expansion of a normally polymorphic p(CCG)n repeat. This repeat was adjacent to a CpG island that was methylated in fragile site-expressing individuals. The FRA16A locus in individuals who do not express the fragile site is not a site of DNA methylation (imprinting), which suggests that the methylation associated with fragile sites may be a consequence and not a cause of their genesis.

Fragile X genotype characterized by an unstable region of DNA.

DNA sequences have been located at the fragile X site by in situ hybridization and by the mapping of breakpoints in two somatic cell hybrids that were constructed to break at the fragile site. These hybrids were found to have breakpoints in a common 5-kilobase Eco RI restriction fragment. When this fragment was used as a probe on the chromosomal DNA of normal and fragile X genotype individuals, alterations in the mobility of the sequences detected by the probe were found only in fragile X genotype DNA. These sequences were of an increased size in all fragile X individuals and varied within families, indicating that the region was unstable. This probe provides a means with which to analyze fragile X pedigrees and is a diagnostic reagent for the fragile X genotype.

Chromosomal fragile site FRA16D and DNA instability in cancer.

It has been proposed that common aphidicolin-inducible fragile sites, in general, predispose to specific chromosomal breakage associated with deletion, amplification, and/or translocation in certain forms of cancer. Although this appears to be the case for the fragile site FRA3B and may be the case for FRA7G, it is not yet clear whether this association is a general property of this class of fragile site. The major aim of the present study was to determine whether the FRA16D chromosomal fragile site locus has a role to play in predisposing DNA sequences within and adjacent to the fragile site to DNA instability (such as deletion or translocation), which could lead to or be associated with neoplasia. We report the localization of FRA16D within a contig of cloned DNA and demonstrate that this fragile site coincides with a region of homozygous deletion in a gastric adenocarcinoma cell line and is bracketed by translocation breakpoints in multiple myeloma, as reported previously (Chesi, M., et al., Blood, 91: 4457-4463, 1998). Therefore, given similar findings at the FRA3B and FRA7G fragile sites, it is likely that common aphidicolin-inducible fragile sites exhibit the general property of localized DNA instability in cancer cells.

A 500-kb region on chromosome 16p13.1 contains the pseudoxanthoma elasticum locus: high-resolution mapping and genomic structure.

We have recently mapped the genetic defect underlying pseudoxanthoma elasticum (PXE), an inherited disorder characterized by progressive calcification of elastic fibers in skin, eye, and cardiovascular system, to chromosome 16p 13.1. Here we report further data on the fine-mapping and genomic structure of this locus. Haplotype analysis of informative PXE families narrowed the locus to an interval of less than 500 kb located between markers D16B9621 and D16S764. Three overlapping YAC clones were found to cover this region through YAC-STS content mapping. An overlapping BAC contig was then constructed to cover this interval and the surrounding region. About 80% of this chromosomal region has been fully sequenced using the BAC shotgun technique. Gene content and sequence analysis predicted four genes (MRP1, MRP6, PM5, and a novel transcript) and two pseudogenes (ARA and PKDI) within this interval. By screening a somatic cell hybrid panel we were able to precision-map the breakpoint of Cy185 and the starting point of a chromosomal duplication within 20 kb of BAC A962B4. The present data further refine the localization of PXE, provide additional physical cloning resources, and will aid in the eventual identification of the genetic defect causing PXE.

The role of antibiotic prophylaxis in clean incised hand injuries: a prospective randomized placebo controlled double blind trial.

A prospective, randomized, double blind, placebo controlled trial was designed to investigate the effect of prophylactic flucloxacillin on the infection rate in clean incised hand injuries, which included trauma to skin, tendon and nerve in adults. Using strict exclusion criteria, a total of 170 patients were recruited into one of three trial groups; Group A - intravenous flucloxacillin on induction followed by an oral placebo; Group B - intravenous flucloxacillin on induction followed by an oral flucloxacillin course or Group C - oral placebo. Thirteen of the patients were subsequently withdrawn, leaving 92% available to complete the trial. Infection was diagnosed using clinical criteria. The infection rates in the three groups were Group A - 13%, Group B - 4% and Group C - 15%. Strictly, the results demonstrate no statistically significant difference in the infection rates between the groups.

Timolol kinetics in chronic renal insufficiency.

A single-dose kinetic study of oral timolol, 20 mg, was undertaken in 3 groups of volunteers with varying degrees of renal function--(1) 10 normal subjects (N); (2) 9 patients with moderate chronic renal insufficiency (MCRI; C cr, 20 to 50 ml/min); (3) 4 patients with end-stage renal disease (ESRD)--to assess the need for dosage modification as renal function diminishes. There were borderline statistical differences in absorption between groups. The mean peak concentration (C max) was 84.3 +/- 44.8 ng/ml at 0.8 +/- 0.4 hr for N and 87.1 +/- 22.8 ng/ml at 1.7 +/- 1.2 hr (p, NS) for MCRI. N and MCRI mean half-lives (5.2 +/- 2.6 hr and 4.0 +/- 1.2 hr) were not statistically different. Salivary levels correlated with plasma levels in 3 N and 1 MCRI patient. Group differences in blood pressure and pulse response to timolol seems to reflect differences present at baseline with percent change from baseline identical for the two groups except at 12 to 24 hr. Administration of timolol on an interdialysis day revealed similar kinetic and physiologic response in the normal and the MCRI group. During dialysis, timolol, 20 mg, induced significant hypotension and bradycardia.

A rare case of severe bilateral ectropion from scleroderma.

A case of ectropion arising as a result of facial scleroderma is presented. This is the first such case reported. Problems and techniques of surgical management are discussed.

An improved nail-hook for Kleinert traction.

A new type of hook for Kleinert traction is described. It is made out of wire for the individual finger and glued to the nail, the actual hook projecting distally.

An accessory superficialis tendon involved by Dupuytren's contracture.

A 60-year-old Caucasian male presented with Dupuytren's contracture affecting his left little finger. On exploration he was found to have a band of Dupuytren's tissue attached to an accessory superficialis tendon.

Defining a normal finger web in children.

We calculated the interdigital web ratios for children between the ages of 5 and 6 and 10 and 11 years. We compared these ratios with those seen in adults and conclude that there is a change in finger web morphology with age. We found that a photocopier provided images of similar quality to conventional photography.

Quantifying interdigital web morphology.

A new method for the measurement of the interdigital webs of the hand is described and is shown to be reproducible. Measurements are taken from photographs and the method would be suitable for the comparison of post-operative appearances in the evaluation of "web creep" after surgery.

Dupuytren's disease in patients from the Indian sub-continent. Report of ten cases.

We report on ten patients from the Indian sub-continent operated on in our unit for Dupuytren's contracture. Their presentation, operative findings and subsequent course was indistinguishable from Caucasian patients. We believe that Dupuytren's disease among Indians is not so rare as previously thought.

Dupuytren's disease affecting the wrist.

A unusual example of Dupuytren's disease occurred in a black patient with a strong diathesis. The disease affected the insertion of flexor carpi ulnaris at the wrist as well as the palm.

A prospective, controlled, randomized trial comparing early active extension with passive extension using a dynamic splint in the rehabilitation of repaired extensor tendons.

This prospective, randomized, controlled trial compared two methods of rehabilitating extensor tendon repairs in zones IV-VIII. Group A patients followed an early active mobilization regimen and Group B patients followed a dynamic splintage regimen. Data on 19 patients in Group A and 17 patients in Group B were collected at 4 weeks and at final follow-up (3 months median follow-up for both groups). Extension lag, flexion deficit and total active motion (TAM) were measured. At 4 weeks, patients in Group B had a better TAM (median 87%, range 56-102%) compared to patients in Group A (median 77%, range 52-97%). At final follow-up, there were no significant differences in the results of the two groups. There were no ruptures in either group.

Dogs that bite.

OBJECTIVE: To study the circumstances of dog bites and identify risk factors. DESIGN: Postal questionnaire survey and case note review of victims of dog bites referred between 1982 and 1989. SETTING: One referral based regional plastic surgery unit. PATIENTS: 146 consecutive patients referred for primary treatment of dog bites, for whom current addresses were available for 133, 107 (81%) of whom returned the questionnaire. RESULTS: The male to female ratio was 74:72; 79 (54%) patients were aged below 15 years. The commonest dogs producing bites were Staffordshire bull terriers (15 cases), Jack Russell terriers (13), medium sized mongrels (10), and Alsatians (nine). 82 of 96 (85%) dogs were male. 29 of 47 (62%) adults were bitten at home and 45 of 60 (75%) children at a friend's, neighbour's, or relative's house. 91 of 107 (85%) bites occurred in the dog's home. Bites occurred during playing with 13 (12%), petting 14 (13%), or waking 16 (15%) dogs. 45 (42%) bites were judged as unprovoked. 32 bites were identified as severe and 11 attacks as sustained. CONCLUSIONS: Most victims are bitten by male dogs which they either own or have had frequent contact with, and the bite occurs in the dog's home.