Repair of a pathological radial fracture secondary to radioulnar ischemic necrosis in a dog.

CASE DESCRIPTION: A 3-year-old 2.5-kg (5.5-lb) sexually intact male Pomeranian was presented with a 1-day history of non-weight-bearing lameness of the right forelimb. CLINICAL FINDINGS: Signs of pain were localized to the proximal portion of the right antebrachium. Radiography revealed a minimally displaced fracture of the proximal portion of the radius that had propagated from a well-demarcated, ovoid, osteolytic lesion within the cortex of the caudolateral aspect of the radius. Computed tomographic findings supported the radiographic findings and did not reveal lesions in other evaluated body sites. TREATMENT AND OUTCOME: At surgery, the lateral aspect of the radial cortex appeared expanded, and tenacious fibrous tissue filled the gap between the fracture fragments. Fibrous tissue was resected and submitted for histologic examination, and the fracture was reduced and stabilized with a bone plate and a positional screw. Histologic examination revealed the presence of viable bone, fibrous tissue, and areas of coagulative necrosis. Imaging and histologic findings were consistent with radioulnar ischemic necrosis (RUIN). The patient ambulated normally at reexamination 12 days after surgery. At reexamination 15 weeks after surgery, the patient continued to ambulate normally, and radiography and CT indicated healing of the fracture and resolution of the RUIN lesion. CLINICAL RELEVANCE: RUIN should be considered as a differential diagnosis for a dog with forelimb lameness and radiographic focal osteolysis between the proximal and middle thirds of the diaphysis of the radius or ulna. Prognosis for dogs with RUIN may be good with surgical intervention.

Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Brm inhibits the proliferative response of keratinocytes and corneal epithelial cells to ultraviolet radiation-induced damage.

Ultraviolet radiation (UV) from sunlight is the primary cause of skin and ocular neoplasia. Brahma (BRM) is part of the SWI/SNF chromatin remodeling complex. It provides energy for rearrangement of chromatin structure. Previously we have found that human skin tumours have a hotspot mutation in BRM and that protein levels are substantially reduced. Brm-/- mice have enhanced susceptibility to photocarcinogenesis. In these experiments, Brm-/- mice, with both or a single Trp53 allele were exposed to UV for 2 or 25 weeks. In wild type mice the central cornea and stroma became atrophic with increasing time of exposure while the peripheral regions became hyperplastic, presumably as a reparative process. Brm-/-, Trp53+/-, and particularly the Brm-/- Trp53+/- mice had an exaggerated hyperplastic regeneration response in the corneal epithelium and stroma so that the central epithelial atrophy or stromal loss was reduced. UV induced hyperplasia of the epidermis and corneal epithelium, with an increase in the number of dividing cells as determined by Ki-67 expression. This response was considerably greater in both the Brm-/- Trp53+/+ and Brm-/- Trp53+/- mice indicating that Brm protects from UV-induced enhancement of cell division, even with loss of one Trp53 allele. Cell division was disorganized in Brm-/- mice. Rather than being restricted to the basement membrane region, dividing cells were also present in the suprabasal regions of both tissues. Brm appears to be a tumour suppressor gene that protects from skin and ocular photocarcinogenesis. These studies indicate that Brm protects from UV-induced hyperplastic growth in both cutaneous and corneal keratinocytes, which may contribute to the ability of Brm to protect from photocarcinogenesis.

Polyostotic hyperostosis in a domestic shorthair cat.

CLINICAL PRESENTATION: An 11-year-old male neutered domestic shorthair cat was presented for investigation of weight loss and inappetence. On physical examination there was palpable enlargement and thickening of many bones, and this finding was confirmed radiographically. PROPOSED DIAGNOSIS: Based on clinical, radiological and histopathological findings, a polyostotic bone disease, best described as generalised idiopathic hyperostosis, was diagnosed. This condition has not been reported in cats previously. Canine and human diseases with similarities to this presentation are discussed.

Histological evaluation of repair of the rotator cuff in a primate model.

The establishment of a suitable animal model of repair of the rotator cuff is difficult since the presence of a true rotator cuff anatomically appears to be restricted almost exclusively to advanced primates. Our observational study describes the healing process after repair of the cuff in a primate model. Lesions were prepared and repaired in eight 'middle-aged' baboons. Two each were killed at four, eight, 12 and 15 weeks post-operatively. The bone-tendon repair zones were assessed macroscopically and histologically. Healing of the baboon supraspinatus involved a sequence of stages resulting in the reestablishment of the bone-tendon junction. It was not uniform and occurred more rapidly at the sites of suture fixation than between them. Four weeks after repair the bone-tendon healing was immature. Whereas macroscopically the repair appeared to be healed at eight weeks, the Sharpey fibres holding the repair together did not appear in any considerable number before 12 weeks. By 15 weeks, the bone-tendon junction was almost, but not quite mature. Our results support the use of a post-operative rehabilitation programme in man which protects the surgical repair for at least 12 to 15 weeks in order to allow maturation of tendon-to-bone healing.

Use of an elastic stain to show venous invasion in colorectal carcinoma: a simple technique for detection of an important prognostic factor.

BACKGROUND: Venous invasion (VI) is an important prognostic factor in colorectal cancer; it is positively associated with visceral metastases and may affect the decision to treat with adjuvant therapy. AIMS: To evaluate whether an elastic tissue (Movat) stain facilitates identification of VI, the number of Movat-stained blocks needed to detect VI, and whether VI identified with a Movat stain is prognostically equivalent to VI identified on H&E-stained slides. METHODS: H&E-stained sections from colorectal carcinomas from the year 2000 (n = 92) were examined for VI and compared to Movat-stained slides. Clinical charts were reviewed to compare rates of metastases in VI-positive versus VI-negative patients. RESULTS: With the Movat stain, VI was identified in 44% of cases previously categorised as negative (p<0.001) on review of H&E slides alone. One Movat-stained section was often sufficient to identify VI, with a statistically significant benefit to performing multiple stains if necessary. In H&E sections, two clues helped identify VI: the "unaccompanied artery" sign, where large arteries were seen without an accompanying vein; and the "protruding tongue" sign, where smooth tongues of tumour extended into pericolic/rectal fat. Metastases were present in 61% of cases positive for VI compared to 35% in VI-negative cases (p = 0.03). 45% of cases positive for intramural VI only developed metastases (p = 0.39), while 65% of cases positive for extramural VI only developed metastases (p = 0.03). CONCLUSIONS: Pathologists should look for morphological clues of VI in H&E stained sections; when VI is not apparent, an elastic tissue stain on all tumour blocks significantly improves identification of VI. Morphological clues include the "unaccompanied artery" and "protruding tongue" signs.

S100A8/S100A9 and their association with cartilage and bone.

S100A8 and S100A9 are calcium-binding proteins expressed in myeloid cells and are markers of numerous inflammatory diseases in humans. S100A9 has been associated with dystrophic calcification in human atherosclerosis. Here we demonstrate S100A8 and S100A9 expression in murine and human bone and cartilage cells. Only S100A8 was seen in preosteogenic cells whereas osteoblasts had variable, but generally weak expression of both proteins. In keeping with their reported high-mRNA expression, S100A8 and S100A9 were prominent in osteoclasts. S100A8 was expressed in alkaline phosphatase-positive hypertrophic chondrocytes, but not in proliferating chondrocytes within the growth plate where the cartilaginous matrix was calcifying. S100A9 was only evident in the invading vascular osteogenic tissue penetrating the degenerating chondrocytic zone adjacent to the primary spongiosa, where S100A8 was also expressed. Whilst, S100A8 has been shown to be associated with osteoblast differentiation, both S100A8 and S100A9 may contribute to calcification of the cartilage matrix and its replacement with trabecular bone, and to regulation of redox in bone resorption.

Bone formation within alumina tubes: effect of calcium, manganese, and chromium dopants.

Alumina tubes (1.3mm outer diameter, 0.6mm inner diameter, 15 mm length) doped with Ca, Mn, or Cr at nominal concentrations of 0.5 and 5.0 mol% were implanted into femoral medullary canals of female rats for 16 weeks. Tissue formation within tubes was determined by histology and histomorphometry. Addition of Ca to alumina promoted hypertrophic bone formation at the advancing tissue fronts and tube entrances, and appeared to retard angiogenesis by limiting ongoing cellular migration into the tube. It is speculated that the presence of a secondary phase of calcium hexaluminate, probably having a solubility greater than that of alumina, possibly increased the level of extracellular Ca and, consequently, stimulated osteoclastic activity at the bone-ceramic interface. Addition of Mn significantly enhanced osteogenesis within the tubes. However, it is not possible to determine whether phase composition or microstructure of the ceramic was responsible for this because both were significantly altered by Mn addition. Addition of Cr to the alumina apparently stimulated bone remodelling as indicated by increased cellular activity and bone resorption at the tissue-implant interface. Cr was incorporated into the alumina as a solid solution and the tissue response was speculated to be an effect of surface chemistry rather than microstructure. The work demonstrates that doping a bioinert ceramic with small amounts of specific elements can significantly alter tissue ingrowth, differentiation, and osteogenesis within a porous implant.

Effect of rapidly resorbable calcium phosphates and a calcium phosphate bone cement on the expression of bone-related genes and proteins in vitro.

The use of biodegradable bone substitutes is advantageous for alveolar ridge augmentation because it avoids second-site surgery for autograft harvesting. This study examines the effect of novel, rapidly resorbable calcium phosphates and a calcium phosphate bone cement on the expression of bone-related genes and proteins by human bone-derived cells (HBDCs) and compares this behavior to that of tricalciumphosphate (TCP). Test materials were alpha-TCP, two materials with a crystalline phase Ca(2)KNa(PO(4))(2) and with a small amorphous portion containing either magnesium potassium phosphate (material denominated GB14) or silica phosphate (material denominated GB9), and a calcium phosphate bone cement (material denominated Biocement D). HBDCs were grown on the substrata for 3, 7, 14, and 21 days, counted, and probed for various mRNAs and proteins (type I collagen, osteocalcin, osteopontin, osteonectin, alkaline phosphatase, and bone sialoprotein). All substrates supported continuous cellular growth for 21 days. In the presence of GB14 and Biocement D specimens cell proliferation was reduced and cell differentiation increased. At day 21, the greatest number of cells was found on GB9 expressing significantly higher levels of bone-related proteins than cells grown on all other surfaces. Because all novel materials facilitated the expression of the osteoblastic phenotype at least as much as TCP and the polystyrene control, these biomaterials can be regarded as excellent candidate bone substitute materials. GB9 induced the highest proliferation and cellular differentiation after 21 days of incubation, suggesting that this material may possess a higher potency for enhancing osteogenesis than TCP.

The functional expression of human bone-derived cells grown on rapidly resorbable calcium phosphate ceramics.

The use of biodegradable bone substitutes is advantageous for alveolar ridge augmentation, since it avoids second-site surgery for autograft harvesting. This study examines the effect of novel, rapidly resorbable calcium phosphates on the expression of bone-related genes and proteins by human bone-derived cells (HBDC) and compares this behavior to that of tricalciumphosphate (TCP). Test materials were alpha-TCP, and four materials which were created from beta-Rhenanite and its derivatives: R1-beta-Rhenanite (CaNaPO(4)); R1/M2 composed of CaNaPO(4) and MgNaPO(4); R1+SiO(2) composed of CaNaPO(4) and 9% SiO(2) (wt%); and R17-Ca(2)KNa(PO(4))(2). HBDC were grown on the substrata for 3, 5, 7, 14 and 21 days, counted and probed for various mRNAs and proteins (Type I collagen, osteocalcin, osteopontin, osteonectin, alkaline phosphatase and bone sialoprotein). All substrata supported continuous cellular growth for 21 days. At day 21, surfaces of R1+SiO(2) and R17 had the highest number of HBDC. At 14 and 21 days, cells on R1 and on R1+SiO(2) displayed significantly enhanced expression of all osteogenic proteins. Since all novel calcium phosphates supported cellular proliferation together with expression of bone-related proteins at least as much as TCP, these ceramics can be regarded as potential bone substitutes. R1 and R1+SiO(2) had the most effect on osteoblastic differentiation, thus suggesting that these materials may possess a higher potency to enhance osteogenesis than TCP.

Reversible metaphyseal dysplasia, a novel bone phenotype, in two unrelated children with autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy: clinical and molecular studies.

We report the association of an undescribed, reversible metaphyseal dysplasia (RMD) with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in two patients, one homozygous and one heterozygous for a 13-bp deletion in exon 8 of the autoimmune regulator (AIRE) gene. One patient also had a novel deletion in exon 6, resulting in a frameshift mutation and introduction of a STOP codon in exon 10. Their APECED phenotypes differed, but both patients developed progressive skeletal deformities and growth failure from early childhood. Radiological examination suggested a generalized abnormality of endochondral ossification, with irregular, flared, radioopaque regions in the metaphyses, subjacent to the growth plates. Histopathology in patient 1 showed islands of calcified cartilage within bone, consistent with impaired coupling of cartilage resorption with vascular invasion and ossification. Despite discordance for puberty, both patients experienced radiological resolution of their bone disease in their mid-teens, with improvement in histopathology in patient 1. RMD may constitute a rare phenotypic variation of APECED, possibly resulting from autoimmunity directed against skeletal proteins. We also demonstrated AIRE expression in chondrocytes derived from human fetal growth plates, primary culture of human chondrocytes, and two chondrosarcoma cell lines, suggesting a potential role for abnormal AIRE expression in the development of RMD.

Macrophages at the skeletal tissue-device interface of loosened prosthetic devices express bone-related genes and their products.

Aseptic loosening of prosthetic arthroplasty is the most common reason for implant failure in adult orthopaedic reconstruction. At the interface of aseptic loosened prostheses, there is an abundance of particle-activated macrophages and other inflammatory cells. The role of these particle-laden macrophages in the osteogenic arm of the remodeling skeleton in this pathological condition is poorly understood. Molecular signaling by mesenchymal cells and mononuclear inflammatory cells residing in the interfacial tissues between bone and cement or prosthetic material of aseptically loosened joint prostheses was studied using in situ hybridization and immunohistochemical techniques. We found that a range of collagenous and noncollagenous matrix proteins, including osteopontin, osteocalcin, bone sialoprotein, and type I collagen, were produced in the periprosthetic tissue by foamy macrophages, as well as nearby osteogenic cells. The former accumulated in profusion in the three zones of interfacial tissues: pseudomembranous, fibrous, and osseous. Spindle mesenchymal cells in the fibrous zone failed to express any of the osteogenic mRNAs or proteins sought. The expression of bone-related genes and proteins by foamy macrophages at the interface of an aseptic loosened prosthesis may contribute to the disturbance of bone remodeling at this site.

Prosthetic particles modify the expression of bone-related proteins by human osteoblastic cells in vitro.

Loss of bone near joint prostheses is thought to be caused by activation of recruited osteoclasts by osteolytic mediators induced by wear particles. It is proposed that particles inhibit osteogenesis during bone remodelling causing a reduction in the levels of peri-implant bone. This study explores whether prosthetic particles modulate bone formation by affecting osteoblastic bone-related mRNAs (alkaline phosphatase, pro-collagen Ialpha1, osteopontin, osteonectin, osteocalcin, bone sialoprotein and thrombospondin) or their translated proteins using titanium alloy, commercially pure titanium, and cobalt-chrome particles. The direct effect of the particles revealed no change to the expression of the bone-related mRNAs in human bone-derived cells (HBDC) at the time points investigated; although non-collagenous translated proteins expressed by these HBDC were significantly effected (p<0.05). Different patterns of expression for bone-related proteins were induced by the different particles both directly and indirectly. Inflammatory mediators (interleukin-1beta, tumor necrosis factor alpha, interleukin-6, and prostaglandin E2) had similar effects on HBDC to the media obtained from monocytes incubated with particles. This study shows that prosthetic wear particles can significantly modify the expression of bone-related proteins by osteogenic cells in vitro. These alterations in osteogenic activity at the interface of the implant and bone may be an important factor in the failure of many orthopaedic implants.

Differentiation of human bone-derived cells grown on GRGDSP-peptide bound titanium surfaces.

Various surface modifications have been applied to titanium alloy (Ti-6Al-4V) implants, in an attempt to enhance osseointegration; crucial for ideal prosthetic fixation. Despite the numerous studies demonstrating that peptide-modified surfaces influence in vitro cellular behavior, there is relatively little data reporting their effects on bone remodeling. The objective of this article was to examine the effects of chemically modifying Ti-6Al-4V surfaces with a common RGD sequence, a 15-residue peptide containing GRGDSP (glycine-arginine-glycine-aspartate-serine-proline), on the modulation of bone remodeling. The expression of proteins known to be associated with osseous matrix and bone resorption were studied during the growth of human bone-derived cells (HBDC) on these peptide-modified surfaces. HBDC grown for 7 days on RGD surfaces displayed significantly increased levels of osteocalcin, and pro-collagen Ialpha1 mRNAs, compared with the production by HBDC grown on the native Ti-6Al-4V. A pattern that was also reflected at the protein levels for osteocalcin, type I collagen, and bone sialoprotein. Moreover, HBDC grown for 7 and 14 days on RGD-modified Ti-6Al-4V expressed significantly higher level of osteoclast differentiation factors and lower levels of osteoprotegerin and IL-6 proteins compared with other surfaces tested. These results suggest that different chemical treatments of implant material (Ti-6Al-4V) surface result in differential bone responses, not only their ability to form bone but also to stimulate osteoclastic formation.

Mechanisms of magnesium-stimulated adhesion of osteoblastic cells to commonly used orthopaedic implants.

Poor cell adhesion to orthopaedic and dental implants may result in implant failure. Cellular adhesion to biomaterial surfaces primarily is mediated by integrins, which act as signal transduction and adhesion proteins. Because integrin function depends on divalent cations, we investigated the effect of magnesium ions modified bioceramic substrata (Al(2)O(3)-Mg(2+)) on human bone-derived cell (HBDC) adhesion, integrin expression, and activation of intracellular signalling molecules. Immunohistochemistry, flow cytometry, cell adhesion, cell adhesion blocking, and Western blotting assays were used. Our findings demonstrated that adhesion of HBDC to Al(2)O(3)-Mg(2+) was increased compared to on the Mg(2+)-free Al(2)O(3). Furthermore, HBDC adhesion decreased significantly when the fibronectin receptor alpha5beta1- and beta1-integrins were blocked by functional blocking antibodies. HBDC grown on the Mg(2+)-modified bioceramic expressed significantly enhanced levels of beta1-, alpha5beta1-, and alpha3beta1-integrins receptors compared to those grown on the native unmodified Al(2)O(3). Tyrosine phosphorylation of intracellular integrin-dependent signalling proteins as well as the expression of key signalling protein Shc isoforms (p46, p52, p66), focal adhesion kinase, and extracellular matrix protein collagen type I were significantly enhanced when HBDC were grown on Al(2)O(3)-Mg(2+) compared to the native Al(2)O(3). We conclude that cell adhesion to biomaterial surfaces is probably mediated by alpha5beta1- and beta1-integrin. Cation-promoted cell adhesion depends on 5beta1- and beta1-integrins associated signal transduction pathways involving the key signalling protein Shc and results also in enhanced gene expression of extracellular matrix proteins. Therefore, Mg(2+) supplementation of bioceramic substrata may be a promising way to improve integration of implants in orthopaedic and dental surgery.

Productive infection of the bone marrow cells in feline immunodeficiency virus infected cats.

Bone marrow stromal cells (BMSC) from cats experimentally infected with feline immunodeficiency virus (FIV) were shown to contain FIV provirus using polymerase chain reaction and viral products were detected in culture supernatant using reverse transcriptase and enzyme linked immunosorbent assay techniques. Peripheral blood mononuclear cells from FIV-free cats co-cultured with infected bone marrow cells became productively infected with FIV. Such evidence supports the hypothesis that BMSC are a reservoir for FIV. Furthermore, BMSC produced virions capable of infecting susceptible cells and may represent an important source of infectious virus to cells of the macrophage lineage and/or hemopoietic progenitor cells, both of which ultimately become widely disseminated throughout the body.

Effects of glass ionomer cements on bone tissue.

In vivo biocompatibility of glass ionomer cements (GICs) was evaluated for use in orthopaedic surgery using a rat model and compared with conventional bone cement, Polymethyl methacrylate, PMMA. The unset GICs and PMMA were inserted into the marrow cavities of rat femora and retained in situ for various periods of time. The PMMA bone cement showed complete biocompatibility with no interference with reparative bone. The conventional GIC with smaller glass particles and lower powder/liquid ratio showed an initial minor toxic effect on rat bone tissue with later disturbance of adjacent bone formation. The conventional GIC with larger-size glass particles and higher powder/liquid ratio and resin-modified GIC showed more severe toxic effect on rat tissue with the resin-modified GIC affecting the rat bone tissue later. The causes of toxicity associated with the conventional GIC with larger glass particles and higher powder/liquid ration and the resin-modified GIC are thought to be related with the unreacted acid component of both materials and longer ongoing metallic ion release.

Inflammatory gene transcription in human astrocytes exposed to hypoxia: roles of the nuclear factor-kappaB and autocrine stimulation.

Mechanisms of hypoxia-induced activation of nuclear factor-kappaB (NF-kappaB) and inflammatory genes were investigated in fetal human astrocytes in culture. Astrocytes were subjected to interleukin-1beta (IL-1beta; 50-100 u/ml; 4-24 h), or to a 4-h hypoxia (<2% O2) followed by a 4-24-h reoxygenation. NF-kappaB binding and transcriptional activity increased up to 10-fold in astrocytes exposed to IL-1beta, and up to 3-fold in astrocytes subjected to hypoxia followed by reoxygenation. Both IL-1beta- mRNAs and proteins hypoxia-induced NF-kappaB activation were blocked by the proteasome inhibitor, MG-132. MG-132 inhibited IL-1beta-induced up-regulation of IL-1beta and IL-8 mRNA and protein but increased hypoxia-stimulated expression/release of IL-1beta and IL-8. IL-1 receptor antagonist (IL-1Ra) blocked both hypoxic astrocyte-conditioned media-induced NF-kappaB activation and the expression/release of IL-1beta and IL-8. Astrocytes subjected to hypoxia in the presence of IL-1Ra failed to activate NF-kappaB, but expressed elevated levels of IL-1beta and IL-8. The data suggest that hypoxia/reoxygenation-induced up-regulation of IL-1beta and IL-8 in human astrocytes has two components, a NF-kappaB independent up-regulation during hypoxia, followed by amplification through autocrine IL-1beta-induced NF-kappaB activation during reoxygenation.

Laminated tears of the human rotator cuff: a histologic and immunochemical study.

Laminated tears of the rotator cuff are often lined by a cellular layer that has an appearance suggestive of synovium. This study demonstrates, by histologic and immunohistochemical means, that the lining cells are synovial. It remains unclear whether these cells arise by synovial extension from the joint or bursa, or by metaplasia in the presence of synovial fluid, and this has implications for surgical repair of laminated cuff defects. We suggest that these defects be curetted, to remove at least some of this synovial lining, before suture repair.