A longitudinal study of MARS MRI scanning of soft-tissue lesions around metal-on-metal total hip arthroplasties and disease progression.

We investigated the changes seen on serial metal artefact reduction magnetic resonance imaging scans (MARS-MRI) of metal-on-metal total hip arthroplasties (MoM THAs). In total 155 THAs, in 35 male and 100 female patients (mean age 70.4 years, 42 to 91), underwent at least two MRI scans at a mean interval of 14.6 months (2.6 to 57.1), at a mean of 48.2 months (3.5 to 93.3) after primary hip surgery. Scans were graded using a modification of the Oxford classification. Progression of disease was defined as an increase in grade or a minimum 10% increase in fluid lesion volume at second scan. A total of 16 hips (30%) initially classified as 'normal' developed an abnormality on the second scan. Of those with 'isolated trochanteric fluid' 9 (47%) underwent disease progression, as did 7 (58%) of 'effusions'. A total of 54 (77%) of hips initially classified as showing adverse reactions to metal debris (ARMD) progressed, with higher rates of progression in higher grades. Disease progression was associated with high blood cobalt levels or an irregular pseudocapsule lining at the initial scan. There was no association with changes in functional scores. Adverse reactions to metal debris in MoM THAs may not be as benign as previous reports have suggested. Close radiological follow-up is recommended, particularly in high-risk groups.

Posterior mini-incision total hip arthroplasty controls the extent of post-operative formation of heterotopic ossification.

Heterotopic ossification (HO) is the formation of bone at extra-skeletal sites. Reported rates of HO after hip arthroplasty range from 8 to 90 %; however, it is only severe cases that cause problems clinically, such as joint stiffness. The effects of surgical-related controllable intra-operative risk factors for the formation of HO were investigated. Data examined included gender, age of patient, fat depth, length of operation, incision length, prosthetic fixation method, the use of pulsed lavage and canal brush, and component size and material. All cases were performed by the same surgeon using the posterior approach. A total of 510 cases of hip arthroplasty were included, with an overall rate of HO of 10.2 %. Longer-lasting operations resulted in higher grades of HO (p = 0.047). Incisions >10 cm resulted in more widespread HO formation (p = 0.021). No further correlations were seen between HO formation and fat depth, blood loss, instrumentation, fixation methods or prosthesis material. The mini-incision approach is comparable to the standard approach in the aetiology of HO formation, and whilst the rate of HO may not be controllable, a posterior mini-incision approach can limit its extent.

Growth and skeletal development in families with NOGGIN gene mutations.

INTRODUCTION: There is a scarcity of data on height as well as bone densitometry in humans with NOGGIN mutations. METHODS: In 2 families with symphalangism, anthropometry, bone densitometry and genetic analysis of the NOGGIN gene were performed. RESULTS: In family A, the height standard deviation scores of the affected father and son were -0.4 and 3.5, respectively. In family B, the height standard deviation scores of the affected father, twin daughters and another daughter were 1.7, 1.8, 2.4 and 1.8, respectively. In the children, percentage predicted bone mineral content (BMC) for height at the appendicular sites (total femur, femoral neck) was lower than at an axial site lumbar spine. In the 2 fathers, median bone mineral density at total femur and femoral neck was -0.3 standard deviation scores (-0.7, 0.2) and at lumbar spine the scores were -0.4 and 0.9. The children had median tibial and radial speed of sound velocities of -2.1 (-0.9 to -6.4) and -1.4 (-0.2 to -4.9), respectively. DNA analysis revealed a novel missense mutation in family A and family B, resulting in a Met190Val substitution and a Pro42Arg substitution, respectively. CONCLUSION: Heterozygous gene mutations in NOGGIN are associated with tall stature in children but not necessarily in adults. The appendicular BMC and speed of sound may be low in affected children but normalises by adulthood. However, axial BMC seems normal in childhood and is high in adulthood.

Potential role for concurrent abnormalities of the cyclin D1, p16CDKN2 and p15CDKN2B genes in certain B cell non-Hodgkin's lymphomas. Functional studies in a cell line (Granta 519).

Abnormalities of several cell-cycle regulatory genes including cyclin D1, p16CDKN2 and p15CDKN2B have been described in B cell non-Hodgkin's lymphoma (B-NHL). We describe a new B-NHL cell line (Granta 519), with concurrent abnormalities of the cyclin D1, pl6CDKN2 and pl5CDKN2B genes. An independent clinical case of mantle cell NHL (Mc-NHL) with concomitant overexpression of cyclin D1, and deletion of the p16CDKN2 gene was also identified, suggesting that this combination of oncogenic aberration is a pathophysiologic contribution to a subset of NHL cases. More in-depth functional studies of this concept were facilitated by the availability of the cell line Granta 519 which was derived from a case of high-grade NHL and has a mature B cell immunophenotype. Cytogenetic analysis identified translocation t(11;14)(q13;q32) and complex rearrangements involving chromosomes 9p22, 13p21, 17pl1, and 18q21. Molecular analysis identified overexpression of cyclin D1 mRNA and biallelic deletion of the p16CDKN2 and p15CDKN2B genes. To elucidate the effect of these genetic abnormalities on the G1 control of Granta 519 cells, the level and function of the major components of the cyclinD/retinoblastoma (RB) pathway were investigated. Cyclin D1 was dominant among the D-type cyclins, formed abundant complexes with cyclin-dependent kinase (Cdk) Cdk4 rather than Cdk6, and the immunoprecipitated cyclin D1/Cdk4 holoenzyme was active as a pRB kinase. Electroporation of wild-type pl6CDKN2 arrested the Granta 519 cells in G1, consistent with the p16CDKN2 loss as a biologically relevant event during multistep evolution of the tumor, and with the expression of functional pRB. Direct cooperation of these distinct abnormalities to cell-cycle, deregulation in NHL cells was suggested by G1 acceleration upon inducible overexpression of cyclin D1 in a control breast cancer cell line lacking p16CDKN2, an effect which could be prevented by ectopic expression of p16CDKN2. Taken together, these data suggest that concurrent overexpression of cyclin D1 and functional elimination of p16CDKN2 and p15CDKN2B may characterize certain cases of mantle cell NHL, and that cooperation of the abnormalities is likely to provide a growth advantage of the tumour cells through more efficient inactivation of the RB tumor suppressor. Further clinicopathologic studies of this possibility are warranted.

Concurrent activation of MYC and BCL2 in B cell non-Hodgkin lymphoma cell lines by translocation of both oncogenes to the same immunoglobulin heavy chain locus.

Concurrent activation of BCL2 and MYC usually occurs in B cell non-Hodgkin lymphoma (B-NHL) by translocation of both oncogenes to both immunoglobulin heavy chain (IGH) alleles: this abrogates immunoglobulin synthesis. We have studied three B-NHL cell lines (DoHH2, VAL and ROS 50) and show that concurrent activation of BCL2 and MYC may follow translocation of both oncogenes to the same IGH allele. Conventional cytogenetics of DoHH2 suggested the presence of a t(14;18)(q32;q21) translocation. However, fluorescent in situ hybridization (FISH) studies using whole chromosome paints, alpha satellite probes and flow-sorted chromosomes as probes revealed an unexpected complexity of rearrangements involving chromosomes 8, 14 and 18, namely t(8;14;18)(q24;q32;q21). DNA blot and previous PCR analysis confirmed the juxtaposition of BCL2 major breakpoint region (mbr) with IGJH6, but also demonstrated a rearrangement within the first exon of MYC. The centromeric (5') MYC rearranged fragment comigrated with the BCL2-JH6 rearranged fragment in BamHI, EcoRI and Bg/II restriction digests. The der(8)t(8;14;18) therefore comprised 5' MYC (exon I)-Sgamma4-JH6-BCL2 mbr. Similar rearrangements were observed in both ROS 50 and VAL cell lines which contained two and three copies of the der(8)t(8;14;18) respectively. Quantitative flow cytometry for BCL2 and MYC expression showed abundant expression of both proteins in all three lines. These data indicate the der(14)t(14;18)(q32;q21) may itself be the target for any second translocation. The presence of the intact BCL2-JH fusion gene on the der(8)t(8;14;18) allowed concurrent activation of both BCL2 and MYC with no loss of immunoglobulin expression.

Deletions and rearrangement of CDKN2 in lymphoid malignancy.

Recurrent abnormalities of the short arm of chromosome 9, including translocations and interstitial deletions, have been reported in both leukemia and lymphoma. The pathologic consequences of these abnormalities remain unknown. The cyclin-dependent kinase 4 inhibitor (CDKN2) gene, which maps to 9p21, has been implicated by the finding of a high frequency of biallelic deletions in leukemic cell lines. We have determined the incidence of structural abnormalities affecting CDKN2 by DNA blot in a panel of 231 cases of leukemia and lymphoma and 66 cell lines derived from patients with lymphoid malignancies with defined cytogenetic abnormalities. Structural alterations of CDKN2 were seen in 20 (8.3%) of all fresh cases and 10 (15.1%) of all cell lines. Biallelic CDKN2 deletions were seen in 11 of 53 (21%) cases of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There was no association with any particular cytogenetic abnormality. Biallelic deletions were also found in high-grade and transformed non-Hodgkin's lymphoma (NHL) of both B- and T-cell lineages. In two cases of transformed NHL, analysis of sequential samples showed loss of CDKN2 with transformation. Neither deletions nor rearrangements of the CDKN2 gene were seen in any of the 119 leukemias of mature B or T cells analyzed. Biallelic deletions of CDKN2 were observed in 6 of 13 NHL cell lines. Three of the 6 cases had undergone transformation from low- to high-grade disease: in 2 of these cases it was possible to show that the CDKN2 deletions were present in fresh material from the patient and were therefore not an artifact of in vitro culture. Rearrangements of CDKN2 were seen in 2 cases (4%) of BCP-ALL, in 1 case of B-NHL, and in 1 Burkitt's lymphoma cell line and suggest the presence of a "hot spot" for recombination in the vicinity of the CDKN2 gene. These data indicate that the loss of CDKN2 expression may be involved in the pathogenesis of a subset of BCP-ALL, some high-grade NHL, and in the transformation of NHL from low- to high-grade disease. CDKN2 deletions and rearrangements occurred in the absence of detectable cytogenetic changes of chromosome 9p in 25 of 30 (83%) cases. Finally, of 10 cases of BCP-ALL that produced overt, transplantable leukemia in mice with severe combined immunodeficiency (SCID), seven showed biallelic CDKN2 deletions. In contrast, none of 11 cases that failed to engraft showed biallelic CDKN2 deletions. BCP-ALL cases that lack CDKN2 expression may have a particular propensity to grow in SCID mice.

Anterior ankle arthrodesis with cross-screw fixation. A dowel graft method used in 20 cases.

We report a new method of ankle arthrodesis which combines an anterior approach with a dowel technique of bone grafting and screw fixation. In 20 ankles of 20 patients, ten with osteoarthritis, eight with rheumatoid arthritis and two others, we achieved 19 solid bony fusions and one painless fibrous ankylosis. The average time to union was 12.5 weeks. Patient satisfaction was high and the functional results were as good as for other reported methods, with fewer complications.

B-cell non-Hodgkin's lymphoma cell line (Karpas 1106) with complex translocation involving 18q21.3 but lacking BCL2 rearrangement and expression.

A B-cell non-Hodgkin's lymphoma (B-NHL) cell line (Karpas 1106) with an unusual three-way translocation involving 18q21.3 has been derived from a patient with mediastinal lymphoblastic B-NHL. Although conventional cytogenetics showed a derivative 18q-identical to that seen in cases with t(14;18)(q32.3;q21.3), no translocations of either chromosome 14 could be detected. Instead fluorescent in situ hybridization analysis using a chromosome-18 paint showed that the segment 18q21.3-18qter had become sandwiched on a derivative chromosome X between segments Xqter-c-Xq28 and 13q12-qter, with the centrometric site of 18q21.3 subband juxtaposed to the X sequences. Pulsed-field DNA blots failed to detect rearrangement of the BCL2 gene. Conventional DNA blots using a variety of restriction digests and both 5' and 3' BCL2 and FVT 1 probes also failed to detect rearrangement in Karpas 1106. A rearranged fragment seen only in HindIII digests with 5' BLC2 probes may represent a local microalteration, which is either a mutation or small deletion involving the HindIII site as seen in other cases of B-NHL. Neither BCL2 RNA nor BCL2 protein expression were detected. These and other data suggest that genes at 18q21.3, other than BCL2 and FVT1, may be targets for translocation in certain subgroups of B-NHL.

Salmonella paratyphi--an unusual cause of primary septic arthritis of the hip.

Salmonella paratyphi is an extremely rare cause of primary septic arthritis of the hip, especially in the U.K. The presentation is no different from other causative organisms. A case is described illustrating that uncommon organisms can cause septic arthritis and that for successful treatment correct organism identification is paramount.

C-MYC translocations in de novo B-cell lineage acute leukemias with t(14;18)(cell lines Karpas 231 and 353).

Rare de novo acute leukemias of mature B cells may exhibit the chromosomal translocation t(14;18)(q32.3; q21.3). We report the preliminary characterization of two cases that exhibited not only t(14;18)(q32.3;q21.3) but also the novel translocation t(8;9)(q24.1;p13.3), involving the C-MYC locus with unknown sequences at 9p13.3. From these cases, two Epstein-Barr virus negative cell lines (Karpas 231 and 353) with features identical to those seen in fresh cells from the patient have been derived. Both cell lines have complex karyotypes: in addition to both t(14;18)(q32.3;q21.3) and t(8;9)(q24.1;p13.3), cell line Karpas 231 exhibited three-way translocation t(1;3;11) (q42.3;q27.1;q23.1), whereas Karpas 353 exhibited t(1;3;7)(p32.1;q21.1;q22.1). Both cases retained immunophenotypes characteristic of mature B cells with no evidence for commitment to other hematopoietic lineages. Both cases expressed abundant, normal-sized C-MYC transcript, but no rearrangement of C-MYC DNA sequences could be detected using probes that span 80 kb around the C-MYC coding sequences. Breakpoints within the BCL-2 gene were divergent. In Karpas 353 the BCL-2 breakpoint occurred within the 3' untranslated major breakpoint region (mbr) of the gene, whereas, in Karpas 231, breaks in both the 3' mbr and in the region 5' of the gene were detected. The cytogenetic combination of t(14;18)(q32.3;q21.3) and t(8;9)(q24.1;p13.3) has been previously reported in diffuse B cell lymphomas. This combination may be a new recurrent abnormality, of central pathogenic importance in the transformation of B cells to high grade malignancies through simultaneous deregulation of BCL-2 and C-MYC genes, constitutive expression of C-MYC being driven by currently unknown DNA sequences on chromosome 9p13.3. The presence of other complex translocations including those affecting 11q23.1 may further accelerate the process of acute transformation.

The A-V Impulse System reduces deep-vein thrombosis and swelling after hemiarthroplasty for hip fracture.

We performed a prospective randomised controlled trial of the A-V Impulse System in 82 patients treated by hemiarthroplasty for subcapital fracture of the femoral neck. The incidence of proximal deep-vein thrombosis as assessed by Doppler ultrasonography was 23% in the control group and 0% in those using the device (p less than 0.01). Calf and thigh circumferences were measured in both groups at seven to ten days after operation. In the treatment group there was a mean relative reduction of postoperative swelling of the thigh by 3.27 cm (p less than 0.001) and of the calf by 1.55 cm (p less than 0.001). The A-V Impulse System appears to be a safe and effective method of reducing the incidence of proximal deep-vein thrombosis, and of postoperative swelling.

Primary malignant melanoma of the oesophagus: case report and review of surgical pathology.

Primary malignant melanoma of the oesophagus is both a rare presentation for melanoma and a cause of oesophageal neoplasm. It accounts for less than 0.1% of all primary oesophageal neoplasms. It was first recognised as a primary tumour by de la Pava et al who showed the presence of melanocytes within oesophageal mucosa. This case report includes a review of the surgical pathology. Even though it is a rare lesion it must be considered as a cause of polypoidal oesophageal lesions as both its diagnosis and treatment can present problems. It is usually fatal within one year.

Impact of duplex scanning on carotid endarterectomy.

Duplex ultrasound permits safe and accurate assessment of the extracranial vasculature. This paper reports the change in patterns of referral to a specialized vascular unit following its introduction; increased referrals were seen in all specialties except neurology. A widely available and reliable duplex service has revealed more extracranial vascular disease than was previously recognized, and has increased referrals for carotid endarterectomy, thereby increasing surgical workload.

Ranitidine disposition in patients with renal impairment.

Ranitidine disposition has been studied in 12 patients with renal impairment following 50 mg given intravenously and 150 mg given by mouth on separate occasions. The clearance of ranitidine from plasma (y) was correlated with creatinine clearance (x): y = 10.47 + 0.289x,r2 = 0.751, but there was no significant correlation of creatinine clearance with distribution volume or bioavailability. The mean (s.e. mean) distribution volume was 1.62 (0.08) 1/kg and the mean bioavailability 0.81 (0.05). These data suggest that in order to obtain similar ranitidine plasma concentrations in anephric patients and patients with normal renal function, the maintenance dose in the anephric patients should be 25-30% of that for patients with normal renal function.

Gastric proton pump localization. Application of triphosphatase and monophosphatase techniques.

Potassium-dependent phosphatase activity can be demonstrated in unfixed frozen sections of mouse stomach using either adenosine triphosphate (ATP) or p-nitrophenyl phosphate (NPP) as substrate. In both cases the potassium-dependent reaction is confined to oxyntic cells, but with ATP, a strong, potassium-independent reaction occurs in the connective tissue of the lamina propria and elsewhere. In the NPP system potassium-independent reaction is very slight, and the oxyntic cell reaction shows responses to inhibitors that differentiate it from Na+, K+-ATPase and that are consistent with its identification with the dephosphorylation step of the proton pump enzyme H+, K+-ATPase, recognized as the active transport component in gastric acid secretion.