New England Baptist Hospital

Autologous cultured chondrocyte transplantation was introduced in Sweden in 1987 for the treatment of large (1.5-12.0 cm2) full thickness chondral defects of the knee. The clinical, arthroscopic, and histologic results from the first 101 patients treated using this technique are reported in this study. Patients were assessed retrospectively using three types of endpoints: patient and physician derived clinical rating scales (five validated and two new); arthroscopic assessment of cartilage fill, integration, and surface hardness; and standard histochemical techniques. Ninety-four patients with 2- to 9-years followup were evaluable. Good to excellent clinical results were seen in individual groups as follows: isolated femoral condyle (92%), multiple lesions (67%), osteochondritis dissecans (89%), patella (65%), and femoral condyle with anterior cruciate ligament repair (75%). Arthroscopic findings in 53 evaluated patients showed good repair tissue fill, good adherence to underlying bone, seamless integration with adjacent cartilage, and hardness close to that of the adjacent tissue. Hypertrophic response of the periosteum or graft or both was identified in 26 arthroscopies; seven were symptomatic and resolved after arthroscopic trimming. Graft failure occurred in seven (four of the first 23 and three of the next 78) patients. Histologic analysis of 37 biopsy specimens showed a correlation between hyalinelike tissue (hyaline matrix staining positive for Type II collagen and lacking a fibrous component) and good to excellent clinical results. The good clinical outcomes of autologous chondrocyte transplantation in this study are encouraging, and clinical trials are being done to assess the outcomes versus traditional fibrocartilage repair techniques.

Chondrogenesis is the earliest phase of skeletal development, involving mesenchymal cell recruitment and migration, condensation of progenitors, and chondrocyte differentiation, and maturation and resulting in the formation of cartilage and bone during endochondral ossification. This process is controlled exquisitely by cellular interactions with the surrounding matrix, growth and differentiation factors, and other environmental factors that initiate or suppress cellular signaling pathways and transcription of specific genes in a temporal-spatial manner. Vertebrate limb development is controlled by interacting patterning systems involving prominently the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and hedgehog pathways. Both positive and negative signaling kinases and transcription factors, such as Sox9 and Runx2, and interactions among them determine whether the differentiated chondrocytes remain within cartilage elements in articular joints or undergo hypertrophic maturation prior to ossification. The latter process requires extracellular matrix remodeling and vascularization controlled by mechanisms that are not understood completely. Recent work has revealed novel roles for mediators such as GADD45beta, transcription factors of the Dlx, bHLH, leucine zipper, and AP-1 families, and the Wnt/beta-catenin pathway that interact at different stages during chondrogenesis.

Bronchiolitis obliterans organizing pneumonia (BOOP) is increasingly recognized as an important cause of diffuse infiltrative lung disease. It is a diagnostic consideration in patients with a febrile flu-like illness of a few weeks' duration and a roentgenogram showing bilateral patchy infiltrates that are not responsive to a typical course of antibiotics. It is defined as granulated tissue plugs within lumens of small airways that extend into alveolar ducts and alveoli. Clinically, a flu-like illness, cough, and crackles are common. Pulmonary function studies of patients show a decreased vital capacity, normal flow rates (except in smokers), and a decreased diffusing capacity. It is generally idiopathic, but it may occur during the resolution of a viral or mycoplasma pneumonia. It is also associated with a variety of systemic illnesses and clinical settings. These include the connective tissue disorders, antineoplastic and other drugs, and immunological disorders, as well as bone marrow and lung transplantation. There are numerous related disorders, including human immunodeficiency virus infection, radiation therapy, thyroiditis, and alcoholic cirrhosis. In idiopathic BOOP, complete resolution occurs in 65% to 85% of patients treated with corticosteroid therapy. This type of therapy is often effective in patients with associated systemic disorders or in other clinical settings, but there may be limited or no response in patients with dermatomyositis, immunosuppression, or interstitial opacities at the lung bases. Respiratory failure leading to death may occur in 5% of patients. It is important to add BOOP to the differential diagnosis of febrile, noninfectious illnesses that are mimics of pneumonia.

Three hundred and thirty orthopaedic surgeons in the United States participated in a study of transfusion requirements associated with total joint arthroplasty. A total of 9482 patients (3920 patients who had a total hip replacement and 5562 patients who had a total knee replacement) were evaluated prospectively from September 1996 through June 1997. Of those patients, 4409 (46 percent [57 percent of the patients who had a hip replacement and 39 percent of the patients who had a knee replacement]) had a blood transfusion. Two thousand eight hundred and ninety patients (66 percent) received autologous blood, and 1519 patients (34 percent) received allogenic blood. Ordered logistic regression analysis showed the most important predictors of the transfusion of allogenic blood to be a low baseline hemoglobin level and a lack of predonated autologous blood. Preoperative donation of autologous blood decreases the risk of transfusion of allogenic blood; however, inefficiencies in the procedures for obtaining autologous blood were identified. Sixty-one percent (5741) of the patients had predonated blood for autologous transfusion, but 4464 (45 percent) of the 9920 units of the predonated autologous blood were not used. Primary procedures and revision total knee arthroplasty were associated with the greatest number of wasted autologous units. Of the 5741 patients who had predonated blood, 503 (9 percent) needed a transfusion of allogenic blood. The frequency of allogenic blood transfusion varied with respect to the type of operative procedure (revision total hip arthroplasty and bilateral total knee arthroplasty were associated with the highest prevalence of such transfusions) and with a baseline hemoglobin level of 130 grams per liter or less. Transfusion of allogenic blood was also associated with infection (p < or = 0.001), fluid overload (p < or = 0.001), and increased duration of hospitalization (p < or = 0.01). These latter findings warrant further evaluation in controlled studies.

BACKGROUND: Our hypothesis that multiple, equally tensioned strands of hamstring graft used for reconstruction of the anterior cruciate ligament are stronger and stiffer than ten-millimeter patellar ligament grafts was tested biomechanically with use of tendons from cadavera. METHODS: In the first part of the study, we measured the strength and stiffness of one, two, and four-strand hamstring grafts, from fresh-frozen cadaveric knees, that had been tensioned equally when clamped. In the second part of the study, we compared four-strand grafts to which tension had been applied by hand and then clamped with similar grafts to which tension had been applied with weights and then clamped. The grafts for the two experiments were obtained from thirty-four paired and ten unpaired knees. We also studied the effects of cooling on the biomechanical properties of grafts by comparing patellar ligament grafts tested at 13 degrees Celsius with those tested at room temperature. RESULTS: Two equally tensioned gracilis strands had 185 percent of the strength and 210 percent of the stiffness (1550+/-428 newtons and 336+/-141 newtons per millimeter, respectively) of one gracilis strand (837+/- 138 newtons and 160+/-44 newtons per millimeter, respectively). Two equally tensioned semitendinosus strands had 220 percent of the strength and 220 percent of the stiffness (2330+/-452 newtons and 469+/-185 newtons per millimeter, respectively) of one semitendinosus strand (1060+/-227 newtons and 213+/-44 newtons per millimeter, respectively). Four combined strands (two gracilis strands and two semitendinosus strands) that were equally tensioned with weights and clamped had the additive tensile properties of the individual strands. With the numbers available, four combined strands that were manually tensioned and clamped were not found to be significantly stronger or stiffer than two semitendinosus strands that were equally tensioned with weights (p>0.07). CONCLUSIONS: Four combined strands that were equally tensioned with weights and clamped were stronger and stiffer than all ten-millimeter patellar ligament grafts that have been described in previous reports. All strands of a hamstring graft must be equally tensioned for the composite to have its optimum biomechanical properties. CLINICAL RELEVANCE: Because of the well recognized donor-site morbidity associated with the use of patellar ligament grafts for reconstruction of the anterior cruciate ligament, multiple-strand hamstring-tendon grafts have become an increasingly popular choice. Our data demonstrate that equally tensioned four-strand hamstring-tendon grafts have initial tensile properties that are higher than those reported for ten-millimeter patellar-ligament grafts; thus, from a biomechanical point of view, they seem to be a reasonable alternative.

The current authors examined the hypothesis that labral lesions contribute to early degenerative hip disease. Between 1993 and 1999, 436 consecutive hip arthroscopies were done by the senior author. In addition, 54 acetabula were harvested from human adult cadavers. Two hundred forty-one of the 436 (55.3%) patients who had arthroscopies had a 261 labral tears, all located at the articular, not capsular margin of the labrum. Stereomicroscopic examination of the 54 acetabula from cadavers revealed 52 labral lesions. Overall, there was no significant difference between the arthroscopic and cadaveric populations in terms of the incidence of labral tears. (Overall, 73% of patients with fraying or a tear of the labrum had chondral change. Arthroscopic and anatomic observations support the concept that labral disruption and degenerative joint disease are frequently part of a continuum of joint disease.

Osteoclasts are specialized macrophages that resorb bone. Mice lacking the AP-1 component c-Fos are osteopetrotic because of a lack of osteoclast differentiation and show an increased number of macrophages. The nature of the critical function of c-Fos in osteoclast differentiation is not known. Microarray analysis revealed that Nfatc1, another key regulator of osteoclastogenesis, was down-regulated in Fos-/- osteoclast precursors. Chromatin immunoprecipitation assay showed that c-Fos bound to the Nfatc1 and Acp5 promoters in osteoclasts. In vitro promoter analyses identified nuclear factor of activated T-cells (NFAT)/AP-1 sites in the osteoclast-specific Acp5 and Calcr promoters. Moreover, in Fos-/- precursors gene transfer of an active form of NFAT restored transcription of osteoclast-specific genes in the presence of receptor activator of the NF-κB ligand (RANKL), rescuing bone resorption. In the absence of RANKL, however, Fos-/- precursors were insensitive to NFAT-induced osteoclastogenesis unlike wild-type precursors. These data indicate that lack of Nfatc1 expression is the cause of the differentiation block in Fos-/- osteoclast precursors and that transcriptional induction of Nfatc1 is a major function of c-Fos in osteoclast differentiation. Osteoclasts are specialized macrophages that resorb bone. Mice lacking the AP-1 component c-Fos are osteopetrotic because of a lack of osteoclast differentiation and show an increased number of macrophages. The nature of the critical function of c-Fos in osteoclast differentiation is not known. Microarray analysis revealed that Nfatc1, another key regulator of osteoclastogenesis, was down-regulated in Fos-/- osteoclast precursors. Chromatin immunoprecipitation assay showed that c-Fos bound to the Nfatc1 and Acp5 promoters in osteoclasts. In vitro promoter analyses identified nuclear factor of activated T-cells (NFAT)/AP-1 sites in the osteoclast-specific Acp5 and Calcr promoters. Moreover, in Fos-/- precursors gene transfer of an active form of NFAT restored transcription of osteoclast-specific genes in the presence of receptor activator of the NF-κB ligand (RANKL), rescuing bone resorption. In the absence of RANKL, however, Fos-/- precursors were insensitive to NFAT-induced osteoclastogenesis unlike wild-type precursors. These data indicate that lack of Nfatc1 expression is the cause of the differentiation block in Fos-/- osteoclast precursors and that transcriptional induction of Nfatc1 is a major function of c-Fos in osteoclast differentiation. AP-1 refers to a family of dimeric transcription factors composed of Fos (c-Fos, Fra1, Fra2, and FosB) and Jun proteins (1Chinenov Y. Kerppola T.K. Oncogene. 2001; 20: 2438-2452Crossref PubMed Scopus (579) Google Scholar, 2Shaulian E. Karin M. Nat. Cell Biol. 2002; 4: E131-E136Crossref PubMed Scopus (2251) Google Scholar). Transcription factors such as nuclear factor-κB (NF-κB) 1The abbreviations used are: NF-κB, nuclear factor-κB; M-CSF, macrophage/colony-stimulating factor; RANKL, receptor activator of NF-κB ligand; NFAT, nuclear factor of activated T-cells; GFP, green fluorescent protein; EMSA, electrophoretic mobility shift assay; IL, interleukin; TRAP, tartrate-resistant acid phosphatase. and AP-1, both critically involved in osteoclast differentiation, are activated in the presence of macrophage/colony-stimulating factor (M-CSF, also known as CSF-1) and receptor activator of NF-κB ligand (RANKL) (3Teitelbaum S.L. Ross F.P. Nat. Rev. Genet. 2003; 4: 638-649Crossref PubMed Scopus (1324) Google Scholar, 4Karsenty G. Wagner E.F. Dev. Cell. 2002; 2: 389-406Abstract Full Text Full Text PDF PubMed Scopus (1204) Google Scholar). These cytokines induce signals via multiple pathways including mitogen-activated protein kinases, phosphatidylinositol 3-kinase and calcium (3Teitelbaum S.L. Ross F.P. Nat. Rev. Genet. 2003; 4: 638-649Crossref PubMed Scopus (1324) Google Scholar, 5Takayanagi H. Kim S. Koga T. Nishina H. Isshiki M. Yoshida H. Saiura A. Isobe M. Yokochi T. Inoue J. Wagner E.F. Mak T.W. Kodama T. Taniguchi T. Dev. Cell. 2002; 3: 889-901Abstract Full Text Full Text PDF PubMed Scopus (2003) Google Scholar, 6Komarova S.V. Pilkington M.F. Weidema A.F. Dixon S.J. Sims S.M. J. Biol. Chem. 2003; 278: 8286-8293Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). The essential role for c-Fos during osteoclast differentiation (7Wang Z.Q. Ovitt C. Grigoriadis A.E. Mohle-Steinlein U. Ruther U. Wagner E.F. Nature. 1992; 360: 741-744Crossref PubMed Scopus (810) Google Scholar, 8Johnson R.S. Spiegelman B.M. Papaioannou V. Cell. 1992; 71: 577-586Abstract Full Text PDF PubMed Scopus (583) Google Scholar, 9Grigoriadis A.E. Wang Z.Q. Cecchini M.G. Hofstetter W. Felix R. Fleisch H.A. Wagner E.F. Science. 1994; 266: 443-448Crossref PubMed Scopus (1082) Google Scholar) is partially explained by the observations that the expression of all Fos family proteins is down-regulated in Fos-/- precursors and that other Fos proteins such as Fra1 can rescue the differentiation of these precursors (10Matsuo K. Owens J.M. Tonko M. Elliott C. Chambers T.J. Wagner E.F. Nat. Genet. 2000; 24: 184-187Crossref PubMed Scopus (273) Google Scholar, 11Fleischmann A. Hafezi F. Elliott C. Reme C.E. Ruther U. Wagner E.F. Genes Dev. 2000; 14: 2695-2700Crossref PubMed Scopus (129) Google Scholar). Therefore, a role of c-Fos appears to enhance production of Fos proteins during osteoclastogenesis. c-Fos also transcriptionally induces β-interferon, which then negatively regulates osteoclastogenesis by down-regulating c-Fos at the protein level (12Takayanagi H. Kim S. Matsuo K. Suzuki H. Suzuki T. Sato K. Yokochi T. Oda H. Nakamura K. Ida N. Wagner E.F. Taniguchi T. Nature. 2002; 416: 744-749Crossref PubMed Scopus (597) Google Scholar). Beyond the Fos family, however, c-Fos target genes that rescue osteoclastogenesis in Fos-/- precursors are not known. NFATc1 is a member of the NFAT (nuclear factor of activated T-cells) family of transcription factors (NFATc1, NFATc2, NFATc3, and NFATc4, as accepted by HUGO and the Genome Data Base, corresponding to NFAT2, NFAT1, NFAT4, and NFAT3, respectively) (13Hoey T. Sun Y.L. Williamson K. Xu X. Immunity. 1995; 2: 461-472Abstract Full Text PDF PubMed Scopus (354) Google Scholar, 14Crabtree G.R. Olson E.N. Cell. 2002; 109: S67-S79Abstract Full Text Full Text PDF PubMed Scopus (1102) Google Scholar, 15Hogan P.G. Chen L. Nardone J. Rao A. Genes Dev. 2003; 17: 2205-2232Crossref PubMed Scopus (1572) Google Scholar). It has been shown to be up-regulated following RANKL treatment and is important for osteoclast differentiation (5Takayanagi H. Kim S. Koga T. Nishina H. Isshiki M. Yoshida H. Saiura A. Isobe M. Yokochi T. Inoue J. Wagner E.F. Mak T.W. Kodama T. Taniguchi T. Dev. Cell. 2002; 3: 889-901Abstract Full Text Full Text PDF PubMed Scopus (2003) Google Scholar, 16Ishida N. Hayashi K. Hoshijima M. Ogawa T. Koga S. Miyatake Y. Kumegawa M. Kimura T. Takeya T. J. Biol. Chem. 2002; 277: 41147-41156Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, 17Hirotani H. Tuohy N.A. Woo J.-T. Stern P.H. Clipstone N.A. J. Biol. Chem. 2004; 279: 13984-13992Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). In this study, we explore the cause of the differentiation block in Fos-/- precursors by analyzing transcriptional target genes of c-Fos, especially Nfatc1, during osteoclast differentiation. Cell Culture—ST2-T cells were established by infecting the mouse stromal line ST2 with the retroviral vector expressing RANKL (18Lean J.M. Matsuo K. Fox S.W. Fuller K. Gibson F.M. Draycott G. Wani M.R. Bayley K.E. Wong B.R. Choi Y. Wagner E.F. Chambers T.J. Bone. 2000; 27: 29-40Crossref PubMed Scopus (47) Google Scholar). For co-culture, bone marrow cells or splenocytes were seeded at 6 × 105 cells/cm2 with 6 × 104/cm2 ST2-T cells and cultured in the presence of 10-8m 1,25-dihydroxyvitamin D3 and 10-7m dexamethasone. For osteoblast-free culture, non-adherent hematopoietic precursor cells were cultured in the presence of 10 ng/ml recombinant human M-CSF (Genzyme) and 10–30 ng/ml recombinant mouse RANKL (R&D Systems). RAW264.7 cells were obtained from ATCC (TIB-71). Transient transfection was performed using LipofectAMINE (Invitrogen). Microarray—Oligonucleotide microarrays (GeneChip Murine Genome U74Av2, Affymetrix) were used to monitor the relative abundance of transcripts. Gene Expression Omnibus accession numbers: Fos+/+ splenocytes (GSM10341), Fos-/- splenocytes (GSM10342), Fos+/+ bone marrow (GSM10343), Fos-/- splenocytes expressing ΔNFAT (GSM10344), Fos-/- splenocytes expressing green fluorescent protein (GFP) (GSM10345). Western Blotting—Total cell extracts were prepared in a standard SDS lysis buffer. Nuclear extracts were prepared as described (19Schreiber E. Matthias P. Muller M.M. Schaffner W. Nucleic Acids Res. 1989; 17: 6419Crossref PubMed Scopus (3918) Google Scholar). Immunofluorescence—Mature osteoclasts were prepared from femurs of 3-day-old wild-type mice by curetting with a scalpel into medium. After 1 h incubation, cells were fixed in 4% paraformaldehyde and permeabilized in 0.1% Triton X-100 and 1% bovine serum albumin in phosphate-buffered saline. Primary antibodies used were anti-NFATc1 (7A6) or anti-NFATc2 (G1-D10). Plasmids—Mouse Acp5-luciferase reporter plasmid was constructed in pGL3 vector (Promega) by transferring the promoter regions (-1453 down to the end of intron 1) from pKB5 (a gift from D. Roodman), and the NFAT site mutation was introduced by using the QuikChange kit (Stratagene). ΔNFAT was constructed by assembling PCR-amplified fragments encoding amino acids 1–239 of enhanced GFP (Clontech) followed by Ser-Arg (an XbaI site) and amino acids 317–902 of human NFATc4 (20Molkentin J.D. Lu J.R. Antos C.L. Markham B. Richardson J. Robbins J. Grant S.R. Olson E.N. Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2219) Google Scholar). The 2.5-kb ΔNFAT fragment was cloned into both the cytomegalovirus-driven expression vector pRK5 and the retroviral vector pMX (21Onishi M. Kinoshita S. Morikawa Y. Shibuya A. Phillips J. Lanier L.L. Gorman D.M. Nolan G.P. Miyajima A. Kitamura T. Exp. Hematol. 1996; 24: 324-329PubMed Google Scholar). pBJ5-human NFATc1 expression plasmid (pSH102) was a gift from G. R. Crabtree. The -797 and -94 Calcr-P3-pGL3basic constructs have been described (22Anusaksathien O. Laplace C. Li X. Ren Y. Peng L. Goldring S.R. Galson D.L. J. Biol. Chem. 2001; 276: 22663-22674Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). Additional Calcr-P3 5′-deletion constructs were generated by PCR using different forward Calcr primers with a BglII site and a common reverse Calcr primer with a HindIII site. The NFAT site mutations were incorporated into each deletion by sequential PCR reactions using mutant Calcr primers and vector primers. The c-Fos expression vector pMX-c-Fos-IRES-GFP was constructed by inserting the BamHI-SalI fragment of mouse c-Fos cDNA in pBabe-c-Fos (10Matsuo K. Owens J.M. Tonko M. Elliott C. Chambers T.J. Wagner E.F. Nat. Genet. 2000; 24: 184-187Crossref PubMed Scopus (273) Google Scholar). The sequence of each construct was confirmed. The small interfering RNA vectors were based on RVH1 and LTRH1 (23Barton G.M. Medzhitov R. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 14943-14945Crossref PubMed Scopus (263) Google Scholar) (a gift from R. Medzhitov). The oligonucleotides encoding the mouse c-Fos small interfering RNA were: RNAi1, 5′-gatcccctgatgttctcgggtttcaattcaagagattgaaacccgagaacatcatttttggaac-3′ and 5′-tcgagttccaaaaatgatgttctcgggtttcaatctcttgaattgaaacccgagaacatcaggg-3′; RNAi2, 5′-gatcccctccaagcggagacagatcattcaagagatgatctgtctccgcttggatttttggaac-3′ and 5′-tcgagttccaaaaatccaagcggagacagatcatctcttgaatgatctgtctccgcttggaggg-3′. Electrophoretic Mobility Shift Assay (EMSA)—Oligonucleotide sequences for Acp5 EMSA were: Acp5-120 (the NFAT/AP-1 site in the human Acp5 promoter), 5′-cgagccctcggagaaactgcatcatcctcg-3′, 5′-tcgacgaggatgatgcagtttctccgagggctcgagct-3′; IL-2 (the distal NFAT/AP-1 site in the human IL-2 promoter), 5′-cgagaaggaggaaaaactgtttcatacagg-3′, 5′-tcgacctgtatgaaacagtttttcctccttctcgagct-3′; consensus AP-1 (the AP-1 site in the human collagenase promoter), 5′-cgagataaagcatgagtcagacacctcg-3′, 5′-tcgacgaggtgtctgactcatgctttatctcgagct-3′; mutated AP-1, 5′-cgagataaagcaagagtctgacacctcg-3′, 5′-tcgacgaggtgtcagactcttgctttatctcgagct-3′. Oligonucleotide sequences for Calcr EMSA were: Calcr-2, 5′-ggaacatgacagctcatttccatgttccct-3′; Calcr-2mA, 5′-ggaacattcacgctcatttccatgttccct-3′; Calcr-2mN, 5′-ggaacatgacagctccgggccatgttccct-3′; AP-1, 5′-cgcttgatgactcagccggaa-3′. Recombinant NFATc1 protein was synthesized in vitro from wtNFATc1-pCITE4 plasmid (a gift from N. A. Clipstone). Competition reactions included a 200-fold molar excess of unlabeled oligonucleotides. Real-time Reverse Transcriptase-PCR—Calcr transcripts were quantitated on ABI PRISM 7000 (Applied Biosystems) using SYBR Green and were normalized to c-fms and Gapdh transcripts for co-cultures and osteoblast-free cultures, respectively. Bone Resorption Assay—The surface of bone slices was visualized by backscattered electron imaging using a electron The of bone was with Chromatin immunoprecipitation assay was performed as described 2002; Scopus Google Scholar). or were fragments were by PCR on ABI PRISM The PCR primers used were: NFATc1 in to c-Fos target genes in the osteoclast from wild-type and Fos-/- splenocytes and wild-type bone marrow were prepared and with stromal ST2-T the wild-type which were tartrate-resistant acid such cells were generated in the Fos-/- not The cells were in and gene expression was by The genes in which expression was in wild-type or in the Fos-/- are in The for wild-type splenocytes Fos-/- splenocytes and wild-type bone marrow cells are RNA In the Fos-/- culture, the expression of Nfatc1 was and the expression of known osteoclast genes D.L. E. T. Elliott R. A. Elliott G. S. H. J. N. E. C. A. S. V. G. J. J. Cell. 1998; 93: Full Text Full Text PDF PubMed Scopus Google Scholar) was These Acp5 and Calcr a was not in the Fos-/- of c-Fos target genes by transcriptional and Fos-/- splenocytes in in a the expression at the protein Western analysis was performed using protein extracts prepared on 6 from the with the RNA NFATc1 was not in the Fos-/- The of NFATc1 in the wild-type bone marrow be by or by different of NFATc1 D.L. J. Google Scholar, S. E. D. A. D. J. B. E. T. A. E. F. A. E. Immunity. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). we the of NFATc1 in osteoclasts from the femurs of showed nuclear of NFATc1 not in osteoclasts generated in Western analysis of nuclear extracts from the precursor RAW264.7 cells that nuclear NFATc1 was RANKL These data that RANKL NFATc1 via c-Fos to the Nfatc1 c-Fos sites have been in the promoter of Nfatc1 S. E. D. A. D. J. B. E. T. A. E. F. A. E. Immunity. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, B. B. A. Wang S. P. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). the Nfatc1 promoter be by c-Fos in osteoclast we performed a immunoprecipitation assay using wild-type bone marrow cells and Fos-/- splenocytes with The promoter fragment the distal block of human and mouse sequences S. E. D. A. D. J. B. E. T. A. E. F. A. E. Immunity. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) was with an in prepared from wild-type cells with RANKL The block of not be because of in PCR also the Acp5 promoter was by In wild-type c-Fos is on the Acp5 promoter in the absence of RANKL, and c-Fos of the Acp5 promoter RANKL These that c-Fos to the NFATc1 and Acp5 promoters during of NFAT/AP-1 site in Acp5 promoter sequences in mouse human and indicate to the mouse IL-2 distal NFAT/AP-1 site. indicate PCR primers for the immunoprecipitation assay in EMSA using Acp5-120 IL-2 distal NFAT/AP-1 site and AP-1 consensus or mutant sites for and Nuclear extracts NFAT were prepared from transfection assay in RAW264.7 cells using wild-type and mutant mouse Acp5 The activator plasmid expressing ΔNFAT was relative to and relative to the wild-type the Acp5 construct was activated by c-Fos expression vector and by Fos small interfering RNA vectors in in RAW264.7 Acp5 and Calcr NFAT/AP-1 is known that AP-1 composed of and NFAT transcription factors can to promoter regions of genes including the IL-2 gene L. P.G. Rao A. Nature. 1998; PubMed Scopus Google Scholar, N. Kerppola T.K. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). the by which NFAT is involved in the of osteoclast-specific gene expression we promoter sequences of Acp5 and c-Fos target genes we for such sites for NFAT and AP-1 in and Acp5 promoter were the multiple transcription which we and at and relative to the end of of the Acp5-120 were to be to the NFAT/AP-1 site in the IL-2 promoter P.G. Chen L. Nardone J. Rao A. Genes Dev. 2003; 17: 2205-2232Crossref PubMed Scopus (1572) Google Scholar) the site for the transcription factor A. S. T. T.J. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). EMSA the at Acp5-120 was from that with the IL-2 site of c-Fos to the Acp5 promoter in osteoclasts was by immunoprecipitation assay we mutated the NFAT site in Acp5-120 from to in Acp5-luciferase reporter human and mouse wild-type Acp5-luciferase constructs were activated with NFATc4 with NFATc2, and in transfection not we constructed a active nuclear form of NFATc4, ΔNFAT (20Molkentin J.D. Lu J.R. Antos C.L. Markham B. Richardson J. Robbins J. Grant S.R. Olson E.N. Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2219) Google to the and mutant reporter were with a ΔNFAT expression plasmid into RAW264.7 ΔNFAT activated the wild-type Acp5 promoter the mutant promoter the Acp5 promoter was enhanced by a c-Fos expression vector and by small interfering RNA vectors for c-Fos in transfection These data that Acp5-120 is a NFAT/AP-1 site in the Acp5 we for NFAT/AP-1 sites in the mouse osteoclast-specific Calcr-P3 promoter (22Anusaksathien O. Laplace C. Li X. Ren Y. Peng L. Goldring S.R. Galson D.L. J. Biol. Chem. 2001; 276: 22663-22674Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar) and NFAT/AP-1 sites in the -797 Calcr-P3 promoter of both the reporter and the vector into RAW264.7 cells in a in promoter deletion of the Calcr-P3 promoter that the construct the NFAT/AP-1 sites was for of each NFAT site from to revealed that site at was critical and that sites and to with site In EMSA, site was bound by NFATc1 using RAW264.7 nuclear extracts or in vitro we RAW264.7 cells with and with the calcium that the Calcr promoter were enhanced site was of NFAT the of was by of the cells with These data that site is the critical NFAT site in the Calcr NFAT in NFAT rescue osteoclastogenesis in the absence of c-Fos, we introduced GFP or the GFP ΔNFAT into Fos-/- splenocytes by retroviral gene cells were with the ST2-T cells was and analysis was performed to gene expression GFP and ΔNFAT Fos-/- expression of ΔNFAT activated of the genes that to be in Fos-/- cells including and Nfatc1 that the differentiation block was to a by ΔNFAT in the absence of c-Fos RANKL from ST2-T cells was cells were by 6 with both cells were generated with ΔNFAT we the Fos-/- osteoclasts resorb bone. were not on bone slices in of GFP Fos-/- co-cultures ΔNFAT Fos-/- cells generated multiple surface we the rescue in of cultures, using ST2-T cells and osteoblast-free using M-CSF and In the rescue with ΔNFAT was with that with c-Fos as by Calcr cell and In in the absence of stromal cells the rescue with ΔNFAT was that of c-Fos based on all from the in in both cultures, ΔNFAT at in for the function of c-Fos to the that Fos-/- splenocytes bone in the presence of In gene transfer of the human NFATc1 also Fos-/- osteoclastogenesis in vitro not These data indicate that the lack of NFATc1 is a major for the differentiation block in Fos-/- osteoclast precursors. NFAT of the role of RANKL in NFAT-induced osteoclast we introduced the GFP ΔNFAT into RAW264.7 cells by in the induction of the Acp5 and Calcr genes as as 1 transfection in the absence of RANKL is with the of NFATc1 in the absence of RANKL (5Takayanagi H. Kim S. Koga T. Nishina H. Isshiki M. Yoshida H. Saiura A. Isobe M. Yokochi T. Inoue J. Wagner E.F. Mak T.W. Kodama T. Taniguchi T. Dev. Cell. 2002; 3: 889-901Abstract Full Text Full Text PDF PubMed Scopus (2003) Google Scholar). we ΔNFAT rescue Fos-/- precursors in the absence of ΔNFAT cells from wild-type precursors in the absence or presence of RANKL Fos-/- precursors cells of ΔNFAT in the absence of RANKL and bone were not These data that the rescue of Fos-/- cells with NFAT receptor activator of NF-κB It has been established that the lack of c-Fos expression in a differentiation block in the osteoclast (7Wang Z.Q. Ovitt C. Grigoriadis A.E. Mohle-Steinlein U. Ruther U. Wagner E.F. Nature. 1992; 360: 741-744Crossref PubMed Scopus (810) Google Scholar, 8Johnson R.S. Spiegelman B.M. Papaioannou V. Cell. 1992; 71: 577-586Abstract Full Text PDF PubMed Scopus (583) Google Scholar, 9Grigoriadis A.E. Wang Z.Q. Cecchini M.G. Hofstetter W. Felix R. Fleisch H.A. Wagner E.F. Science. 1994; 266: 443-448Crossref PubMed Scopus (1082) Google Scholar). this is a of c-Fos target genes or an of critical c-Fos target gene is show that the absence of Nfatc1 expression in Fos-/- precursors is the major cause of the differentiation block because an active form of NFAT osteoclast-specific gene expression and bone have identified NFAT/AP-1 sites in the Acp5 and Calcr promoters. EMSA showed that NFAT and AP-1 to the Acp5 NFAT/AP-1 and the immunoprecipitation assay that c-Fos to the Acp5 promoter in osteoclasts. These observations are with the that NFATc1 and c-Fos to the Acp5 promoter (5Takayanagi H. Kim S. Koga T. Nishina H. Isshiki M. Yoshida H. Saiura A. Isobe M. Yokochi T. Inoue J. Wagner E.F. Mak T.W. Kodama T. Taniguchi T. Dev. Cell. 2002; 3: 889-901Abstract Full Text Full Text PDF PubMed Scopus (2003) Google Scholar). the other the rescue of osteoclastogenesis by ΔNFAT in the absence of c-Fos that c-Fos is not essential for of the Acp5 these promoters in Fos-/- ΔNFAT with F. C. Rao A. Oncogene. 2001; 20: PubMed Scopus Google Scholar) or in the absence of Chen L. J. Biol. 2003; PubMed Scopus Google Scholar). EMSA using Fos-/- cell in with in vitro NFATc1 to this of NFAT to the Calcr promoter was by EMSA, of AP-1 to the Calcr promoter to be in the osteoclast-specific gene expression is not with genes for which expression is not for be on c-Fos or transcription the rescue of ΔNFAT was to that of c-Fos Fos-/- precursors were with was that of c-Fos M-CSF and RANKL were Therefore, c-Fos appears to as stromal factors of the stromal factors involved be the ligand of receptor N. M. J. R. Choi Y. J. Exp. 2002; PubMed Scopus (223) Google Scholar). in wild-type precursors ΔNFAT or NFATc1 induce osteoclast differentiation in the absence of RANKL (5Takayanagi H. Kim S. Koga T. Nishina H. Isshiki M. Yoshida H. Saiura A. Isobe M. Yokochi T. Inoue J. Wagner E.F. Mak T.W. Kodama T. Taniguchi T. Dev. Cell. 2002; 3: 889-901Abstract Full Text Full Text PDF PubMed Scopus (2003) Google ΔNFAT expression in Fos-/- precursors to rescue osteoclast differentiation in the absence of that in the absence of RANKL, NFAT c-Fos, as a or to It also that RANKL induce an for NFAT that can for c-Fos function in Fos-/- these that a major function of c-Fos during osteoclast is to a transcriptional by and with a number of target genes involved in osteoclast differentiation and These to be identified target genes with Nfatc1 for bone including and H. for with T. Chambers for with the of T. for electron H. Peng for G. D. for Acp5-luciferase T. and N. A. Clipstone for NFAT and G. R. for NFAT antibodies and R. 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BACKGROUND: Cervical spondylotic myelopathy is the leading cause of spinal cord dysfunction worldwide. The objective of this study was to evaluate the impact of surgical decompression on functional, quality-of-life, and disability outcomes at one year after surgery in a large cohort of patients with this condition. METHODS: Adult patients with symptomatic cervical spondylotic myelopathy and magnetic resonance imaging evidence of spinal cord compression were enrolled at twelve North American centers from 2005 to 2007. At enrollment, the myelopathy was categorized as mild (modified Japanese Orthopaedic Association [mJOA] score ≥ 15), moderate (mJOA = 12 to 14), or severe (mJOA < 12). Patients were followed prospectively for one year, at which point the outcomes of interest included the mJOA score, Nurick grade, Neck Disability Index (NDI), and Short Form-36 version 2 (SF-36v2). All outcomes at one year were compared with the preoperative values with use of univariate paired statistics. Outcomes were also compared among the severity classes with use of one-way analysis of variance. Finally, a multivariate analysis that adjusted for baseline differences among the severity groups was performed. Treatment-related complication data were collected and the overall complication rate was calculated. RESULTS: Eighty-five (30.6%) of the 278 enrolled patients had mild cervical spondylotic myelopathy, 110 (39.6%) had moderate disease, and 83 (29.9%) had severe disease preoperatively. One-year follow-up data were available for 222 (85.4%) of 260 patients. There was a significant improvement from baseline to one year postoperatively (p < 0.05) in the mJOA score, Nurick grade, NDI score, and all SF-36v2 health dimensions (including the mental and physical health composite scores) except general health. With the exception of the change in the mJOA, the degree of improvement did not depend on the severity of the preoperative symptoms. These results remained unchanged after adjusting for relevant confounders in the multivariate analysis. Fifty-two patients experienced complications (prevalence, 18.7%), with no significant differences among the severity groups. CONCLUSIONS: Surgical decompression for the treatment of cervical spondylotic myelopathy was associated with improvement in functional, disability-related, and quality-of-life outcomes at one year of follow-up for all disease severity categories. Furthermore, complication rates observed in the study were commensurate with those in previously reported cervical spondylotic myelopathy series.

BACKGROUND AND PURPOSE: The International Knee Documentation Committee Subjective Knee Form was developed to measure change in symptoms, function, and sports activity in patients treated for a variety of knee conditions. Although previous research has demonstrated reliability and validity of the form, its responsiveness has not been evaluated. The purpose of this study was to determine responsiveness of the International Knee Documentation Committee Subjective Knee Form. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 1. METHODS: Patients who participated in the original validation study for the International Knee Documentation Committee Subjective Knee Form completed the form and a 7-level global rating of change scale that ranged from greatly worse to greatly better after a mean of 1.6 years (range, 0.5-2.3 years). Analyses included calculation of the standardized response mean and mean change in International Knee Documentation Committee Subjective Knee Form score compared to the patient's perception of change on the global rating of change scale. In addition, a receiver operating characteristic curve was plotted to determine the change in score that best distinguished patients who improved from those who did not. RESULTS: The overall standardized response mean was 0.94, which is considered large. With the exception of those who were slightly worse or unchanged, the mean change in the International Knee Documentation Committee Subjective Knee Form score compared to the patients' perceived global ratings of change was as expected (greatly worse, -15.1; somewhat worse, -8.4; slightly worse, 20.6; no change, 10.7; slightly better, 5.9; somewhat better, 18.1; greatly better, 38.7). The receiver operating characteristic curve analysis revealed that a change score of 11.5 points had the highest sensitivity, and a change score of 20.5 points had the highest specificity to distinguish between those who were or were not improved. CONCLUSION: The International Knee Documentation Committee Subjective Knee Form is a responsive measure of symptoms, function, and sports activity for patients with a variety of knee conditions.

BACKGROUND: Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous blistering disease. Conventional therapy consists of high-dose corticosteroids, immunosuppressive agents, and intravenous immune globulin. METHODS: We studied patients with refractory pemphigus vulgaris involving 30% or more of their body-surface area, three or more mucosal sites, or both who had inadequate responses to conventional therapy and intravenous immune globulin. We treated the patients with two cycles of rituximab (375 mg per square meter of body-surface area) once weekly for 3 weeks and intravenous immune globulin (2 g per kilogram of body weight) in the fourth week. This induction therapy was followed by a monthly infusion of rituximab and intravenous immune globulin for 4 consecutive months. Titers of serum antibodies against keratinocytes and numbers of peripheral-blood B cells were monitored. RESULTS: Of 11 patients, 9 had rapid resolution of lesions and a clinical remission lasting 22 to 37 months (mean, 31.1). All immunosuppressive therapy, including prednisone, could be discontinued before ending rituximab treatment in all patients. Two patients were treated with rituximab only during recurrences and had sustained remissions. Titers of IgG4 antikeratinocyte antibodies correlated with disease activity. Peripheral-blood B cells became undetectable shortly after initiating rituximab therapy but subsequently returned to normal values. Side effects that have been associated with rituximab were not observed, nor were infections. CONCLUSIONS: The combination of rituximab and intravenous immune globulin is effective in patients with refractory pemphigus vulgaris.

The purpose of the current study was to assess the validity, internal consistency, and reproducibility of a short, self-administered hip score designed for use in younger patients with higher demands and expectations than older patients with degenerative joint disease. Validity and internal consistency was studied with 48 consecutive patients with a mean age of 33 years with intractable hip pain and normal plain radiographs. Reproducibility was assessed from data on an additional random sample of 17 patients with hip pain. The Pearson correlation coefficients were 0.82 and 0.59 between the nonarthritic hip score and the Harris hip score and Short Form-12, respectively showing validity. Cronbach’s coefficient alpha measuring the internal consistency within each of the score’s four domains ranged from 0.69 to 0.92. The test and retest reproducibility ranged from 0.87 to 0.95 for the four subsets and was 0.96 overall. This short, self-administered questionnaire regarding hip pain in young patients with increased activity demands and high treatment expectations is valid compared with previous measures of hip performance, is internally consistent, and is reproducible.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To determine prevalence rates of spondylolysis, isthmic, and degenerative spondylolisthesis in an unselected adult community-based population; and to evaluate the association of spondylolysis, isthmic, and degenerative spondylolisthesis with low back pain (LBP). SUMMARY OF BACKGROUND DATA: Spondylolysis and spondylolisthesis are prevalent in the general population; however, the relationship between these conditions and LBP is controversial. METHODS: This study was an ancillary project to the Framingham Heart Study. A sample of 3529 participants of the Framingham Heart Study aged 40 to 80 years underwent multidetector CT imaging to assess aortic calcification. One hundred eighty-eight individuals were consecutively enrolled in this study to assess radiographic features potentially associated with LBP. The occurrence of LBP in the preceding 12 months was evaluated using a self-report questionnaire. The presence of spondylolysis and spondylolisthesis was characterized by CT imaging. We used multiple logistic regression models to examine the association between spondylolysis, spondylolisthesis, and LBP, while adjusting for gender, age, and BMI. RESULTS: Twenty-one study subjects demonstrated spondylolysis on computed tomography (CT) imaging. The male-to-female ratio was approximately 3:1. Twenty-one percent of subjects with bilateral spondylolytic defects demonstrated no measurable spondylolisthesis. The male-to-female ratio of degenerative spondylolisthesis was 1:3, and the prevalence of degenerative spondylolisthesis increased from the fifth through 8 decades of life. Thirty-eight subjects (20.4%) reported significant LBP. No significant association was identified between spondylolysis, isthmic spondylolisthesis, or degenerative spondylolisthesis, and the occurrence of LBP. CONCLUSION: Based on CT imaging of an unselected community-based population, the prevalence of lumbar spondylolysis is 11.5%, nearly twice the prevalence of previous plain radiograph-based studies. This study did not reveal a significant association between the observation of spondylolysis on CT and the occurrence of LBP, suggesting that the condition does not seem to represent a major cause of LBP in the general population.

Rheumatoid arthritis, juvenile idiopathic arthritis, the seronegative spondyloarthropathies including psoriatic arthritis, and systemic lupus erythematosus are all examples of rheumatic diseases in which inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or on the axial or appendicular skeleton. Studies in human disease and in animal models of arthritis have identified the osteoclast as the predominant cell type mediating bone loss in arthritis. Many of the cytokines and growth factors implicated in the inflammatory processes in rheumatic diseases have also been demonstrated to impact osteoclast differentiation and function either directly, by acting on cells of the osteoclast-lineage, or indirectly, by acting on other cell types to modulate expression of the key osteoclastogenic factor receptor activator of nuclear factor (NF) kappaB ligand (RANKL) and/or its inhibitor osteoprotegerin (OPG). Further elucidation of the mechanisms responsible for inflammation-induced bone loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases. In this review, we provide an overview of the cell types, inflammatory mediators, and mechanisms that are implicated in bone loss and new bone formation in inflammatory joint diseases.

Untreated femoro-acetabular impingement is a common cause of osteoarthrosis of the hip. Surgical debridement of the adult hip with femoro-acetabular impingement recently has been advocated with the aim of relieving symptoms and slowing or halting progression of the arthrosis. At surgery, femoral sources of impingement are relieved by debriding the aspheric peripheral portion of the femoral head and the adjacent femoral neck. Acetabular sources of impingement can be relieved by debridement of the anterior rim. The most fundamental questions concerning these procedures relate to the preoperative and postoperative function, postoperative survivorship of these hips and the incidence of osteonecrosis. The current study assesses a group of 23 hips in 23 patients treated by surgical debridement for impingement. Twenty-two patients were treated by full surgical dislocation and one patient was treated by relief of impingement without dislocation. Followup ranged from a minimum of 2 years to 12 years. At most recent evaluation, seven patients had been converted to total hip arthroplasty, one had arthroscopic debridement of a recurrent labral tear, and 15 patients have had no further surgery. No hips developed osteonecrosis. Of the seven patients who had to have their procedure converted to total hip arthroplasty, three of these hips failed early and four patients' hips recovered and functioned well and subsequently deteriorated with total hip arthroplasty done between 6.4 and 9.5 years after debridement. Hips at greatest risk of failure have advanced arthrosis or a combination of impingement and instability preoperatively. The procedure effectively treats hips with impingement and without considerable secondary arthrosis or instability.

Lumbar foraminal stenosis is an important pathologic entity to identify in the patient being treated for radicular symptoms. This update reviews the anatomy, clinical presentation, neuroradiographic evaluation, and treatment of pathology located in the intervertebral foramen. Patients with significant leg pain refractory to conservative treatment and concordance between the demonstrated area of stenosis and radicular symptoms and signs are candidates for the decompressive procedures discussed. The role of arthrodesis and spinal instrumentation in the management of foraminal stenosis also is addressed.

PURPOSE: No graft tissue has consistently shown superiority over others for reconstruction of the anterior cruciate ligament (ACL). Bone-patellar tendon-bone (BPTB) and doubled hamstring tendon (semitendinosus and gracilis) (HT) are the most commonly used autologous grafts. We performed a meta-analysis to compare the effectiveness of ACL reconstruction using either BPTB or HT grafts. TYPE OF STUDY: Systematic review and meta-analysis. METHODS: We searched the MEDLINE database (1966 to April 2003) for English-language randomized or prospective studies comparing BPTB and 3- or 4-strand HT grafts used for ACL reconstruction. For inclusion, studies were required to follow identical rehabilitation protocols within each study, and provide subjective or objective outcome data after a minimum average 2-year follow-up. Comparison data between BPTB and HT for each identified outcome measure were combined using a random-effects model meta-analysis. RESULTS: Eleven reports fulfilled the criteria for inclusion. Outcomes favoring BPTB were found in the following outcome measures: normal Lachman examination (relative risk [RR], 0.91; 95% confidence interval [CI], 0.83-0.99; P = .025), normal pivot-shift (RR, 0.94; 95% CI, 0.88-1.0; P = .067), KT-1000 manual-maximum side-to-side difference of < or = 3 mm (RR, 0.75; 95% CI, 0.55-1.01; P = .057), and fewer reconstructions resulting in flexion loss > 5 degrees (RR, 1.41; 95% CI, 1.01-1.96; P = .04). Intermediate level laxity was more common with the HT graft, as shown by higher rates of abnormal Lachman > 0 (RR, 1.22; 95% CI, 0.99-1.5; P = .06), pivot-shift > 0 (RR, 1.3; 95% CI, 0.96-1.75; P = .09), and KT-1000 manual-maximum side-to-side differences > 3 mm (RR, 1.64; 95% CI, 1.13-2.39; P = .01). Outcome measures that favored HT were absence of patellofemoral crepitance (RR, 1.08; 95% CI, 1.01-1.15; P = .03), fewer results with extension loss > 5 degrees (RR, 0.56; 95% CI, 0.3-1.03; P = .06), and kneeling pain. The incidence of instability, as defined by Lachman grade 2, pivot-shift grade 2, or KT-1000 manual-maximum side-to-side difference > 5 mm, was not significantly different between the 2 grafts. All other outcome measures were not significantly different. CONCLUSIONS: The data presented in this meta-analysis show that the incidence of instability is not significantly different between the BPTB and HT grafts. However, BPTB was more likely to result in reconstructions with normal Lachman, normal pivot-shift, KT-1000 manual-maximum side-to-side difference < 3 mm, and fewer results with significant flexion loss. In contrast, HT grafts had a reduced incidence of patellofemoral crepitance, kneeling pain, and extension loss. The choice of graft by the patient and surgeon must be individualized, and the results of this meta-analysis can aid in the decision by clarifying the risks and benefits of each surgical approach. LEVEL OF EVIDENCE: Level I.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To evaluate the association between lumbar spine facet joint osteoarthritis (FJ OA) identified by multidetector computed tomography (CT) and low back pain (LBP) in the community-based Framingham Heart Study. SUMMARY OF BACKGROUND DATA: The association between lumbar FJ OA and LBP remains unclear. METHODS: This study was an ancillary project to the Framingham Heart Study. A sample of 3529 participants of the Framingham Heart Study aged 40 to 80 underwent multidetector CT imaging to assess aortic calcification. One hundred eighty-eight individuals were consecutively enrolled in this ancillary study to assess radiographic features associated with LBP. LBP in the preceding 12 months was evaluated using a self-report questionnaire. FJ OA was evaluated on CT scans using a 4-grade scale. The association between FJ OA and LBP was examined used multiple logistic regression models, while adjusting for gender, age, and BMI. RESULTS: CT imaging revealed a high prevalence of FJ OA (59.6% of males and 66.7% of females). Prevalence of FJ OA increases with age. By decade, FJ OA was present in 24.0% of <40-years-olds, 44.7% of 40- to 49-years-olds, 74.2% of 50- to 59-years-olds, 89.2% of 60- to 69-year-olds, and 69.2% of >70-years-olds. By spinal level the prevalence of FJ OA was: 15.1% at L2-L3, 30.6% at L3-L4, 45.1% at L4-L5, and 38.2% at L5-S1. In this community-based population, individuals with FJ OA at any spinal level showed no association with LBP. CONCLUSION: There is a high prevalence of FJ OA in the community. Prevalence of FJ OA increases with age with the highest prevalence at the L4-L5 spinal level. At low spinal levels women have a higher prevalence of lumbar FJ OA than men. In the present study, we failed to find an association between FJ OA, identified by multidetector CT, at any spinal level and LBP in a community-based study population.

In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)-alpha was also required, although seemingly less critically than IL-1, because a proportion of TNF-alpha-deficient mice developed robust disease. There was no evidence for an important role for IL-6. Bone destruction and reconstruction were also examined. We found that all mice with strong inflammation exhibited the bone erosion and reconstruction phenomena typical of K/BxN arthritis, with no evidence of any particular requirement for TNFalpha for bone destruction. The variability in the requirement for TNF-alpha, reminiscent of that observed in treated rheumatoid arthritis patients, did not appear genetically programmed but related instead to subtle environmental changes.

PURPOSE: The purpose of this study was to define the entire rotator cuff footprint and relate it to known, easily identifiable landmarks as a guide for both open and arthroscopic rotator cuff repair. Anatomic: Gross and microscopic. METHODS: The myotendinous units of the rotator cuff and their insertions onto the humerus were dissected in 20 fresh-frozen cadavers. The separate tendon insertions were identified, and their length and width measured. The character and exact anatomy of the tendons were also noted. The entire insertion was measured and referenced to the articular surface, biceps groove, and bare area of the humerus. In a separate part of the study, 6 cadavers were decalcified and thin-sliced through the supraspinatus tendon insertion. This insertion was evaluated via scanning electron microscopy (SEM). RESULTS: Our findings demonstrated a consistent pattern at the insertion of the rotator cuff. The horseshoe-shaped insertion tapers away from the articular surface in a superior-to-inferior direction. Interdigitation of the muscle units may be noted, particularly between the supraspinatus and the infraspinatus. Average maximum insertional lengths and widths were as follows: subscapularis (SC): 40 x 20 mm; infraspinatus (IS): 29 x 19 mm; supraspinatus (SS): 23 x 16 mm; and teres minor (TM): 29 x 21 mm. The SC inserted on the lesser tuberosity adjacent to the biceps groove at the edge of the articular surface. It tapered away 18 mm at its inferior border. The SS inserted at the articular surface along its entire insertion from the bicipital groove to the top of the bare area. The IS wrapped the posterior border of the SS superiorly at the articular surface and tapered away inferiorly, framing the bare area. SEM microscopy showed the SS to be adherent to the edge of the articular surface medially. As it filled the sulcus, its lateral edge extended over the edge of the greater tuberosity. CONCLUSIONS: A consistent pattern was noted at the insertional anatomy of the rotator cuff. This anatomy was related to known, easily identifiable landmarks and may serve as a guide for evaluation of size, location, and propagation patterns of rotator cuff tears, as well as for their repair. CLINICAL RELEVANCE: Knowledge of the insertional anatomy of the rotator cuff can facilitate grading and repair of rotator cuff tears.

T2 and T1rho have potential to nondestructively detect cartilage degeneration. However, reports in the literature regarding their diagnostic interpretation are conflicting. In this study, T2 and T1rho were measured at 8.5 T in several systems: 1) Molecular suspensions of collagen and GAG (pure concentration effects): T2 and T1rho demonstrated an exponential decrease with increasing [collagen] and [GAG], with [collagen] dominating. T2 varied from 90 to 35 ms and T1rho from 125 to 55 ms in the range of 15-20% [collagen], indicating that hydration may be a more important contributor to these parameters than previously appreciated. 2) Macromolecules in an unoriented matrix (young bovine cartilage): In collagen matrices (trypsinized cartilage) T2 and T1rho values were consistent with the expected [collagen], suggesting that the matrix per se does not dominate relaxation effects. Collagen/GAG matrices (native cartilage) had 13% lower T2 and 17% lower T1rho than collagen matrices, consistent with their higher macromolecular concentration. Complex matrix degradation (interleukin-1 treatment) showed lower T2 and unchanged T1rho relative to native tissue, consistent with competing effects of concentration and molecular-level changes. In addition, the heterogeneous GAG profile in these samples was not reflected in T2 or T1rho. 3) Macromolecules in an oriented matrix (mature human tissue): An oriented collagen matrix (GAG-depleted human cartilage) showed T2 and T(1rho) variation with depth consistent with 16-21% [collagen] and/or fibril orientation (magic angle effects) seen on polarized light microscopy, suggesting that both hydration and structure comprise important factors. In other human cartilage regions, T2 and T1rho abnormalities were observed unrelated to GAG or collagen orientation differences, demonstrating that hydration and/or molecular-level changes are important. Overall, these studies illustrate that T2 and T1rho are sensitive to biologically meaningful changes in cartilage. However, contrary to some previous reports, they are not specific to any one inherent tissue parameter.