Biomedical subjects
Publications and source records attributed to J P Holland.
The authors report a rare case of thoracic intradural extramedullary capillary haemangioma, the clinical presentation of which was similar to any other intraspinal mass. Magnetic resonance imaging does not always distinguish this entity from others, but the presence of enlarged vasculature is often a useful clue. Complete resection is the treatment of choice of this hamartomatous lesion.
OBJECTIVE: The pathogenesis of human pituitary adenomas remains unclear, but we report a case of FSH-secreting pituitary adenoma whose monohormonal phenotype suggests it was of fetal origin. PATIENTS: A 28-year-old woman presented with abdominal discomfort and irregular menses, enlarged multicystic ovaries and elevated serum oestradiol, with sustained high-normal FSH and low LH levels. MEASUREMENTS: Endocrine studies were performed before and after curative surgery, with assessment of tumour hormone secretion in vitro, and immunostaining of tumour tissue for a series of gonadotrope proteins. RESULTS: Immunocytochemistry showed that tumour cells were monohormonal for FSH. Normal components of gonadotrope signalling pathways were expressed, including oestrogen receptor-alpha, activin receptors, secretogranin-II and chromogranin-A. beta-glycan, the putative inhibin coreceptor, was absent. Tumour culture in vitro confirmed secretion of FSH with minimal LH, that was unsuppressed by oestradiol or inhibin-A. Human fetal pituitary tissue contained FSH-only cells at 18 weeks gestation, whereas normal adult pituitary tissue contained only bihormonal gonadotropes. CONCLUSIONS: We propose that this pituitary adenoma represents an indolent tumour of monohormonal fetal gonadotrope cells that originated early in gestation. Pituitary tumours may therefore arise from abnormal persistence of fetal cell types, with extremely slow growth over many years until reaching a size threshold to generate an endocrine syndrome. Understanding fetal pituitary architecture and function may be more informative for new insights into pituitary tumour pathogenesis than classical theories of cancer biology that invoke unrestrained cell proliferation.
Resurfacing arthroplasty of the hip is being performed more frequently in the United Kingdom. The majority of these patients are younger than 55 years of age, and in this group the key benefits include conservation of femoral bone stock and the potential reduction in the rate of dislocation afforded by the larger resurfacing head. Early aseptic loosening is well recognised in patients younger than 55 years of age, and proponents of resurfacing believe that the improved wear characteristics of the metal-on-metal bearing may improve the long-term survival of this implant. There has been some concern, however, that resurfacing may not be conservative of acetabular bone. We compared a series of 33 consecutive patients who had a hybrid total hip arthroplasty with an uncemented acetabular component and a cemented femoral implant, with 35 patients undergoing a Birmingham hip resurfacing arthroplasty. We compared the diameter of the implanted acetabulum in both groups and, because they were not directly comparable, we corrected for patient size by measuring the diameter of the contralateral femoral head. The data were analysed using unpaired t-tests and analysis of covariance. There was a significantly larger acetabulum in the Birmingham arthroplasty group (mean diameter 56.6 mm vs 52.0 mm; p < 0.001). However, this group had a significantly larger femoral head diameter on the contralateral side (p = 0.03). Analysis of covariance revealed a significant difference between the mean size of the acetabular component implanted in the two operations. The greatest difference in the size of acetabulum was in those patients with a larger diameter of the femoral head. This study shows that more bone is removed from the acetabulum in hip resurfacing than during hybrid total hip arthroplasty, a difference which is most marked in larger patients.
The role of modular tibial implants in total knee replacement is not fully defined. We performed a prospective randomised controlled clinical trial using radiostereophotogrammetric analysis to compare the performance of an all-polyethylene tibia with a metal-backed cruciate-retaining condylar design, PFC-Sigma total knee replacement for up to 24 months. There were 51 patients who were randomised into two treatment groups. There were 10 subsequent withdrawals, leaving 21 all-polyethylene and 20 metal-backed tibial implants. No patient was lost to follow-up. There were no significant demographic differences between the groups. At two years one metal-backed implant showed migration > 1 mm, but no polyethylene implant reached this level. There was a significant increase in the SF-12 and Oxford knee scores after operation in both groups. In an uncomplicated primary total knee replacement the all-polyethylene PFC-Sigma tibial prosthesis showed no statistical difference in migration from that of the metal-backed counterpart. There was no difference in the clinical results as assessed by the SF-12, the Oxford knee score, alignment or range of movement at 24 months, although these assessment measures were not statistically powered in this study.
Hip resurfacing is being performed more frequently in the United Kingdom. The possible benefits include more accurate restoration of leg length, femoral offset and femoral anteversion than occurs after total hip arthroplasty (THA). We compared anteroposterior radiographs from 26 patients who had undergone hybrid THA (uncemented cup/cemented stem), with 28 who had undergone Birmingham Hip Resurfacing arthroplasty (BHR). We measured the femoral offset, femoral length, acetabular offset and acetabular height with reference to the normal contralateral hip. The data were analysed by paired t-tests. There was a significant reduction in femoral offset (p = 0.0004) and increase in length (p = 0.001) in the BHR group. In the THA group, there was a significant reduction in acetabular offset (p = 0.0003), but femoral offset and overall hip length were restored accurately. We conclude that hip resurfacing does not restore hip mechanics as accurately as THA.
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We report a case of a 58-year-old woman who presented with an aneurysmal subarachnoid haemorrhage. Immediately following clipping of this aneurysm, she had a spontaneous hypertensive bleed in the contralateral hemisphere. Although very unusual, hypertensive episodes following aneurysmal subarachnoid haemorrhage must carry a risk of such an intracranial event.
Back problems are common, expensive, and the few patients who are the crux of the problem are uncomfortable but also an uncomfortable frustration for clinicians and employers alike. We now know that clinicians can greatly improve the patient's response to back symptoms by admitting our diagnostic limitations, demedicalizing the issue, providing assurance, and encouraging a more reasonable approach to improving comfortable activity tolerance.
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BACKGROUND AND PURPOSE: Calcitonin gene-related peptide is an endogenous vasodilating neuropeptide with a dense concentration in the trigeminocerebrovascular system. It is hypothesized that depletion of this peptide contributes to delayed cerebral ischemia after subarachnoid hemorrhage and that an exogenous supply of calcitonin gene-related peptide will augment ischemic cerebral blood flow and reduce neuronal injury. METHODS: In this study we have investigated the effect of an intravenous infusion of calcitonin gene-related peptide (100 ng/kg per minute), started 1 hour before and continued throughout 4 hours of focal cerebral ischemia, on cerebral blood flow and the volume of brain injury in a rat model of middle cerebral artery occlusion. RESULTS: Calcitonin gene-related peptide produces a significant improvement in ischemic cerebral blood flow (32 +/- 2 compared with 13 +/- 2 mL/100 g per minute in the controls; t = 6.92, P < .0001) with a concomitant reduction in the volume of ischemic brain injury (102 +/- 22 compared with 234 +/- 19 mm3; t = 4.47, P < .001). CONCLUSIONS: These findings lend support for the potential use of this peptide in the prophylactic treatment of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.
We describe two patients who underwent intracranial aneurysm surgery and developed postoperative subgaleal haematomas which, in the presence of an unfixed bone flap, resulted in significant extradural compression and a marked clinical deterioration. The application of a pressure dressing to tamponade a developing scalp haematoma is unwise unless the bone flap has been rigidly fixed in place.
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A retrospective analysis of 48 sportsmen and women from an original series of 76 consecutive patients who had undergone a modified McIntosh repair was carried out to establish whether or not the procedure could provide a satisfactory recovery and return to previous ability. The type and level of sport before injury was compared with that after operation. Symptoms of pain and giving way, and examination findings of pivot shift, and Lachman's test were compared before and after operation. Of the 48 patients assessed, 28 (58%) returned to full sporting capacity; 17 (35%) patients were participating in different sports or lower levels of their previous sports, and three patients did not participate in any sport. The more severely symptomatic knees did not perform so well after operation. The degree of preoperative anterior draw and Lachman's test did not influence the final result and the pivot shift, present in all before operation, was abolished in all but one case, which remained badly symptomatic. Concurrent meniscal injury or medial or lateral laxity did not influence return to sport once a full postoperative recovery was made. No deterioration was noticed in the level of sporting ability achieved thereafter. In this study it has been shown that the modified McIntosh repair is a swift extra-articular reconstruction for the anterior cruciate ligament deficient knee, which is less elaborate than previously described Ellison and McIntosh procedures, and which has produced a comparable result.
Four cases of limb shortening presenting in childhood are described. All four children had been managed in a neonatal intensive care unit and had developed complications following the insertion of intravascular cannulae. In two, lower limb shortening and deformity were secondary to direct epiphyseal damage following extravasation of calcium or dextrose from a peripheral venous line. In the other two, forearm shortening followed ischaemia, secondary to either radial artery thrombosis from a radial artery cannula or spasm of the brachial artery following extravasation from a venous cannula in a neonate who also had a radial artery cannula. These cases highlight an important complication of the use of vascular cannulae in neonates and the problems this may pose to the orthopaedic surgeon.
Transcription of the yeast enolase gene ENO2 is reduced 20- to 50-fold in strains carrying a null mutation in the positive regulatory gene GCR1. A small deletion mutation within one of two upstream activation sites (UAS elements) in the 5'-flanking region of ENO2 permitted wild-type levels of ENO2 gene expression in a strain carrying the gcr1 null mutation. These data show that sequences required for UAS element activity in GCR1 strains were required to repress ENO2 expression in a gcr1 strain. Protein factors that specifically bound to this UAS/repression site were identified. We show that the DNA-binding protein ABFI (autonomously replicating sequence-binding factor) is the major protein which binds the UAS/repression site. Minor DNA-binding activities that interact specifically with the UAS/repression site were also identified and may correspond to proteolytic breakdown products of ABFI. None of the observed binding activities were encoded by the GCR1 structural gene. A double-stranded oligonucleotide that included the UAS/repression site activated transcription of UAS-less ENO1 and ENO2 gene cassettes in vivo to wild-type levels in strains carrying the GCR1 allele as well as the gcr1 null mutation. These latter data show that the UAS/repression site is sufficient for transcriptional activation but is not sufficient to repress transcription of the enolase genes in a gcr1 genetic background.
Binding sites for three distinct proteins were mapped within the upstream activation sites (UAS) of the yeast enolase genes ENO1 and ENO2. Sequences that overlapped the UAS1 elements of both enolase genes bound a protein which was identified as the product of the RAP1 regulatory gene. Sequences within the UAS2 element of the ENO2 gene bound a second protein which corresponded to the ABFI (autonomously replicating sequence-binding factor) protein. A protein designated EBF1 (enolase-binding factor) bound to sequences which overlapped the UAS2 element in ENO1. There was a good correlation among all of the factor-binding sites and the location of sequences required for UAS activity identified by deletion mapping analysis. This observation suggested that the three factors play a role in transcriptional activation of the enolase genes. UAS elements which bound the RAP1 protein or the ABFI protein modulated glucose-dependent induction of ENO1 and ENO2 expression. The ABFI-binding site in ENO2 overlapped sequences required for UAS2 activity in wild-type strains and for repression of ENO2 expression in strains carrying a null mutation in the positive regulatory gene GCR1. These latter results showed that the ABFI protein, like the RAP1 protein, bound sequences required for positive as well as negative regulation of gene expression. These observations strongly suggest that the biological functions of the RAP1 and ABFI proteins are similar.
Sequences within the spacer region of yeast rRNA cistrons stimulate synthesis of the major 35S rRNA precursor in vivo 10- to 30-fold (E. A. Elion and J. R. Warner, Cell 39:663-673, 1984). Spacer sequences that mediate this stimulatory activity are located approximately 2.2 kilobases upstream from sequences that encode the 5' terminus of the 35S rRNA precursor. By utilizing a centromere-containing plasmid carrying a 35S rRNA minigene, a 160-base-pair region of spacer rDNA was identified by deletion mapping that is required for efficient stimulation of 35S rRNA synthesis in vivo. A 22-base-pair sequence, previously shown to support RNA polymerase I-dependent selective initiation of transcription in vitro, was located 15 base pairs upstream from the 3' boundary of the stimulatory region. A 77-base pair region of spacer DNA that mediates transcriptional terminator activity in vivo was identified immediately downstream from the 5' boundary of the stimulatory region. Deletion mutations extending downstream from the 5' boundary of the 160-base-pair stimulatory region simultaneously interfere with terminator activity and stimulation of 35S rRNA synthesis from the minigene. The terminator region supported termination of transcripts initiated by RNA polymerase I in vivo. The organization of sequences that support terminator and promoter activities within the 160-base-pair stimulatory region is similar to the organization of rDNA gene promoters in higher organisms. Possible mechanisms for spacer-sequence-dependent stimulation of yeast 35S rRNA synthesis in vivo are discussed.
The intracellular concentrations of the polypeptides encoded by the two enolase (ENO1 and ENO2) and three glyceraldehyde-3-phosphate dehydrogenase (TDH1, TDH2, and TDH3) genes were coordinately reduced more than 20-fold in a Saccharomyces cerevisiae strain carrying the gcr1-1 mutation. The steady-state concentration of glyceraldehyde-3-phosphate dehydrogenase mRNA was shown to be approximately 50-fold reduced in the mutant strain. Overexpression of enolase and glyceraldehyde-3-phosphate dehydrogenase in strains carrying multiple copies of either ENO1 or TDH3 was reduced more than 50-fold in strains carrying the gcr1-1 mutation. These results demonstrated that the GCR1 gene encodes a trans-acting factor which is required for efficient and coordinate expression of these glycolytic gene families. The GCR1 gene and the gcr1-1 mutant allele were cloned and sequenced. GCR1 encodes a predicted 844-amino-acid polypeptide; the gcr1-1 allele contains a 1-base-pair insertion mutation at codon 304. A null mutant carrying a deletion of 90% of the GCR1 coding sequence and a URA3 gene insertion was constructed by gene replacement. The phenotype of a strain carrying this null mutation was identical to that of the gcr1-1 mutant strain.