Primary repair of patellar tendon rupture without augmentation.

Repair of patellar tendon ruptures has often relied on cerclage augmentation and prolonged immobilization in extension. We are reporting our experience with avulsion injuries as well as midsubstance ruptures, both treated with primary repair without augmentation, allowing early mobilization in the athlete less than 40 years of age. Repairs were performed to allow knee flexion to more than 60 degrees. Rehabilitation was performed with heel slides, allowing flexion to 45 degrees for the first 3 weeks, increasing to 90 degrees at 3 to 6 weeks, and thereafter without restriction. An accelerated weightbearing and muscle strengthening program was adopted. At a mean follow-up of 2.6 years (range, 20 to 61 months), 12 patients had returned to their previous levels of activity. No loss of extension or extensor lag was noted; mean flexion loss was 5 degrees. Patellofemoral symptoms and signs were present in five patients, but activity was limited in only two. Mean peak torque at 60 deg/sec was 92% (range, 73% to 105%). Mean Lysholm score was 94 +/- 2.5 points. Primary repair with immediate, protected range of motion resulted in uniformly excellent results and obviated the need for manipulation or subsequent hardware removal.

Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum.

In lymphocytes, the expression of early immune response genes is regulated by NF-AT transcription factors which translocate to the nucleus after dephosphorylation by the Ca2+-dependent phosphatase, calcineurin. We report here that mice bearing a disruption in the NF-ATc gene fail to develop normal cardiac valves and septa and die of circulatory failure before day 14.5 of development. NF-ATc is first expressed in the heart at day 7.5, and is restricted to the endocardium, a specialized endothelium that gives rise to the valves and septum. Within the endocardium, specific inductive events appear to activate NF-ATc: it is localized to the nucleus only in endocardial cells that are adjacent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia. Treatment of wild-type embryos with FK506, a specific calcineurin inhibitor, prevents nuclear localization of NF-ATc. These data indicate that the Ca2+/calcineurin/NF-ATc signalling pathway is essential for normal cardiac valve and septum morphogenesis; hence, NF-ATc and its regulatory pathways are candidates for genetic defects underlying congenital human heart disease.

Redundant expression but selective utilization of nuclear factor of activated T cells family members.

Nuclear factor of activated T cells (NF-AT) complexes regulate the induction of many early T cell activation molecules. Four related proteins can function as the cytoplasmic subunit of NF-AT, and their overlapping expression patterns and the mild phenotype of the NF-ATp null mice suggest that they may be functionally redundant. We characterized the distribution and activation of cytoplasmic NF-AT proteins in mature lymphocytes and found that NF-ATc, NF-ATp, and NF-AT4/x/c3 are co-expressed and co-regulated in mature T and B cells. Each protein forms independent DNA binding complexes, and at physiologic concentrations, NF-ATc and NF-ATp complexes out-compete NF-AT4/x/c3 for occupancy of NF-AT sites from the IL-2, IL-3/granulocyte-macrophage CSF, IL-4, and CD40 ligand genes. This predicts heavily redundant immune regulatory functions of NF-ATp and NF-ATc, but distinct activities for NF-AT4/x/c3. Additionally, Ab interaction with NF-ATp induces high affinity NF-kappaB site interaction, suggesting that nuclear partners may dramatically vary the specificity of the NF-AT family.

Different nuclear signals are activated by the B cell receptor during positive versus negative signaling.

It is not known how immunogenic versus tolerogenic cellular responses are signaled by receptors such as the B cell antigen receptor (BCR). Here we compare BCR signaling in naive cells that respond positively to foreign antigen and self-tolerant cells that respond negatively to self-antigen. In naive cells, foreign antigen triggered a large biphasic calcium response and activated nuclear signals through NF-AT, NF-kappa B, JNK, and ERK/pp90rsk. In tolerant B cells, self-antigen stimulated low calcium oscillations and activated NF-AT and ERK/pp90rsk but not NF-kappa B or JNK. Self-reactive B cells lacking the phosphatase CD45 did not exhibit calcium oscillations or ERK/pp90rsk activation, nor did they repond negatively to self-antigen. These data reveal striking biochemical differences in BCR signaling to the nucleus during positive selection by foreign antigens and negative selection by self-antigens.

The T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expression in T cells.

Clinical deterioration in human immunodeficiency virus type 1 (HIV-1) infection is associated with increased levels of viral replication and burden in the peripheral blood and lymphoid organs. T cell activation and ensuing cellular gene activation can be critical for HIV-1 replication. The hypothesis that the nuclear factor of activated T cells (NF-AT) may influence HIV-1 replication is therefore compelling given the tight correlation of HIV-1 transcriptional induction to T cell activation. We report that certain NF-AT(Rel) family members productively bind the kappaB regulatory elements, synergize with NF-kappaB and Tat in transcriptional activation of HIV-1, and enhance HIV-1 replication in T cells. These results link regulatory factors critical to T cell commitment directly to HIV-1 replication.

Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression.

Cells need to distinguish between transient Ca2+ signals that induce events such as muscle contraction, secretion, adhesion and synaptic transmission, and sustained Ca2+ signals that are involved in cell proliferation and differentiation. The latter class of events is blocked in lymphocytes by the immunosuppressive drugs cyclosporin A and FK506, which inhibit calcineurin, a Ca2+-activated serine/threonine phosphatase necessary for the nuclear import of NF-AT transcription factors. Here we report that sustained high concentrations of Ca2+, but not transient pulses, are required to maintain NF-AT transcription factors in the nucleus, where they participate in Ca2+-dependent induction of genes required for lymphocyte activation and proliferation. Furthermore, overexpression and constitutive nuclear localization of NF-AT, but not Jun, Fos, NF-kappaB, Oct or Ets family members, renders the interleukin-2 enhancer in Jurkat T lymphocytes resistant to FK506 and cyclosporin A. Thus a primary effect of these immunosuppressive reagents is to control the subcellular localization of the NF-AT family of transcription factors.

Nuclear factor of activated T cells is associated with a mast cell interleukin 4 transcription complex.

Interleukin 4 (IL-4), an immunoregulatory cytokine, is produced only by a subset of activated T cells and cells of the mast cell-basophil lineage. The production of IL-4 by mast cells likely represents a significant source of this protein in local immune-inflammatory responses in the skin, brain, gastrointestinal, and respiratory tracts, in which mast cells are prevalent. In the present study, the cis- and trans-acting elements that control inducible mast cell IL-4 gene transcription were examined and compared with those that function in T cells. We demonstrate that, as in T cells, sequences between bp -87 and -70 are critical for protein association and activation-dependent gene transcription and that this region (termed the activation-responsive element region) is the target of an inducible, cyclosporin A-sensitive, DNA-protein interaction. When assessed by electrophoretic mobility shift assays and UV cross-linking analyses, multiple proteins in both T- and mast cell nuclear extracts associate with the activation-responsive element in vitro, and some of these appear identical. However, distinct proteins are associated with each of the complexes as well. AP-1 family members are unique to the T-cell-stimulation-dependent complex, whereas mast cell complexes contain factors that are reactive with anti-nuclear factor of activated T cells p (NF-ATp) and anti-NF-ATc antibodies but have distinct molecular masses compared with those of T-cell-derived NF-AT. Furthermore, an anti-NF-ATp-reactive factor with a molecular mass of approximately 41 kDa is present in the nuclei of unstimulated cells and binds independently of cell activation, unlike the previously described NF-AT family members. These data support the idea that there are uniquely regulated, cell lineage-specific transcription factors related to T-cell-derived NF-AT that mediate inducible IL-4 transcription in mast cells. These differences likely reflect the distinct cell surface signaling requirements for IL-4 production in T and mast cells.

Hip pains in a recreational runner.

A 29 year old female recreational runner presented with two separate episodes of hip pain. The first, affecting the right hip was an uncommon cause of hip pain--an osteoid osteoma. The second, affecting the left hip was a more predictable cause of hip pain in a runner--a femoral stress fracture. Management of the subsequent stress fracture enabled more detailed and prolonged observation of the natural history and clinical course of the osteoid osteoma. The presentation and management of each of the conditions is discussed.

NFATc3, a lymphoid-specific NFATc family member that is calcium-regulated and exhibits distinct DNA binding specificity.

Signals transduced by the T cell antigen receptor (TCR) regulate developmental transitions in the thymus and also mediate the immunologic activation of mature, peripheral T cells. In both cases TCR stimulation leads to the assembly of the NFAT transcription complex as a result of the calcium-dependent nuclear translocation of cytosolic subunits, NFATc, and the Ras/protein kinase C-dependent induction of a nuclear subunit, NFATn. To further understand the diverse roles of antigen receptor signaling throughout T cell development, we have identified a new NFATc family member, NFATc3, that is expressed at highest levels in the thymus. NFATc3 is the product of a gene on murine chromosome 8 that is not linked to the other NFATc genes. NFATc3, like other NFATc family members, contains a conserved rel similarity domain, and also defines a region conserved among NFATc family members, the SP repeat region, characterized by the repeated motif SPxxSPxxSPrxsxx (D/E)(D/E)swl. NFATc3 activates NFAT site-dependent transcription when overexpressed, yet exhibits a pattern of DNA site specificity distinct from other NFATc proteins. Additionally, thymic NFATc3 undergoes modifications in response to agents that mimic T cell receptor signaling, including a decrease in apparent molecular mass upon elevation of intracellular calcium that is inhibited by the immunosuppressant FK506. Given the preferential expression of NFATc3 in the thymus, NFATc family members may regulate distinct subsets of genes during T cell development.

Outcome of elbow surgery in professional baseball players.

We reviewed the records of 72 professional baseball players who underwent arthroscopic or open elbow surgery. The most common diagnoses were posteromedial olecranon osteophyte (65%), ulnar collateral ligament injury (25%), and ulnar neuritis (15%). Intraarticular loose bodies were found in 39% of the patients. Fifty-nine patients (82%) were observed for a minimum of 24 months, with an average of 42 months' followup. Forty-seven players (80%) returned to play for a minimum of one season (73% at the same or higher level of play), and 17% of the players retired initially because of their elbow injury. One third of the players required two or more surgical procedures, with 25% of these patients requiring an ulnar collateral ligament reconstruction after removal of a posteromedial olecranon osteophyte. The patients with posteromedial olecranon osteophytes had the highest rate of reoperation, and patients who underwent ulnar collateral ligament reconstruction had a higher rate of return to play. The incidence of ulnar collateral ligament injuries was most likely underestimated in this group of athletes, with initial treatment directed at the secondary injuries instead of the primary ulnar collateral ligament injury.

Cloning and chromosomal localization of the human and murine genes for the T-cell transcription factors NFATc and NFATp.

The nuclear factor of activated T cells (NFAT) is a transcription factor complex involved in the activation of cytokines and cell surface molecules associated with coordinating the actions of different cells required for an immune response. Two different genes have recently been cloned that encode proteins capable of functioning as the pre-existing (p) and cytosolic (c) component of the NFAT transcription complex, NFATc of human and NFATp of murine origin (Northrop et al., 1994; McCaffrey et al., 1993b). We report here the partial cDNA cloning of the murine homolog of NFATc and the human homolog of NFATp, and the chromosomal localization of both genes in both species to conserved syntenic regions. Through the use of mapping panels of human x Chinese hamster and mouse x rodent cells hybrids, the NFATc genes were mapped to human and mouse chromosomes 18. By analyzing a chromosome 18 radiation hybrid panel, the human NFATc gene was localized to the q terminus, closely linked to STS marker D18S497. The murine Nfatc gene was sublocalized to chromosome band 18E4 by FISH. The NFATp genes were mapped by somatic cell hybrid analysis to human chromosome 20 and mouse chromosome 2. Human NFATp was assigned to chromosome region 20q13.2-->q13.3 by FISH. Based on the conserved syntenic region on human chromosome 20 and mouse chromosome 2, murine Nfatp is predicted to reside in the vicinity of a mutant locus wasted. Homozygous wst/wst mice display a phenotype reminiscent of severe combined immune deficiency or ataxia telangiectasia, disorders that could therefore be considered candidates for NFATp mutations.

Fracture of the trochlea.

Isolated fracture of the humeral trochlea is rare. Recent fracture classification schemes do not specifically address this injury in regards to treatment. This case report describes an isolated fracture of the humeral trochlea treated with open reduction internal fixation. Radiographic union was present at 13 weeks, and at 20 weeks post-op, the patient had regained full elbow range of motion minus 5 degrees of terminal flexion. Open reduction and internal fixation can be performed with success if the trochlear fragment is large enough.

Histology and arthroscopic anatomy of the ulnar collateral ligament of the elbow.

The histology and arthroscopic anatomy of the ulnar collateral ligament of the elbow were studied in cadaveric specimens. The capsule consists of two layers of collagen fibers, with two distinct ligamentous bundles corresponding to anterior and posterior portions of the ulnar collateral ligament. The posterior bundle consists of distinct collagen bundles within the layers of the capsule; the anterior bundle consists of a similar thickening within the capsular layers, with an additional ligament complex superficial to the capsular layers. With arthroscopy only the anterior 20% to 30% of the anterior bundle of the ulnar collateral ligament could be visualized via the anterior portal. Only the posterior 30% to 50% of the posterior bundle could be seen via the posterior portals. After sectioning of the anterior bundle, joint instability was noted arthroscopically by an increased opening in the ulnohumeral joint with application of valgus stress. At arthroscopy ulnar collateral ligament tears may be visualized in part or not at all. To diagnose a tear or laxity in the ulnar collateral ligament, a demonstration of an increase in the opening of the ulnohumeral joint in response to valgus stress is useful.

NF-AT components define a family of transcription factors targeted in T-cell activation.

The NF-AT transcription complex is required for the expression of a group of proteins that collectively coordinate the immune response. Here we purify two proteins encoded by separate genes that represent the pre-existing (p) and cytosolic (c) components of NF-AT. Expression of the full-length complementary DNA encoding NF-ATc activates the interleukin (IL-2) promoter in non-T lymphocytes, whereas a dominant negative of NF-ATc specifically blocks activation of the IL-2 promoter in T lymphocytes, indicating that NF-ATc is required for IL-2 gene expression. NF-ATc RNA expression is largely restricted to lymphoid tissues and is induced upon T-cell activation. The other protein, NF-ATp, is highly homologous to NF-ATc over a limited domain which shows similarity to the Dorsal/Rel family, but has a wider tissue distribution. Agents that increase intracellular Ca2+ or activate protein kinase C independently modify NF-ATc, indicating that distinct signalling pathways converge on NF-ATc to regulate its function.

Arthroscopic treatment of posttraumatic elbow pain and stiffness.

Nineteen consecutive cases of posttraumatic arthrofibrosis of the elbow secondary to a fracture or fracture-dislocation and treated with arthroscopic debridement and manipulation were retrospectively reviewed. All of the patients had pain and stiffness in their elbows, and all had failed a conservative therapy program. All 19 patients were followed postoperatively for an average of 29 months (range, 12 to 51). One hundred-point scoring systems were used to evaluate subjective (pain, swelling, locking, and activities) and objective (range of motion) results. The average preoperative subjective score of 39 improved to 91 postoperatively (P = 0.0001); the objective score improved from 46 preoperatively to 81 postoperatively (P = 0.0001). Extension improved from a mean of 29 degrees to 11 degrees; flexion improved from an average of 123 degrees to 134 degrees. Fourteen patients had limitations in their sports activity preoperatively; 11 were able to return to their preinjury levels of activity after surgery. This study demonstrated good-to-excellent overall results in 79% of the patients treated with arthroscopic debridement for posttraumatic elbow arthrofibrosis. Although complete return of preinjury motion was not obtained, each patient showed a significant improvement in motion and subjective symptoms.

Preoperative evaluation of the ulnar collateral ligament by magnetic resonance imaging and computed tomography arthrography. Evaluation in 25 baseball players with surgical confirmation.

A prospective study was completed on 25 baseball players with medial side elbow pain. They were evaluated preoperatively with both computed tomography arthrogram and magnetic resonance imaging examinations of the elbow to assess the ulnar collateral ligament. At surgery, 16 of 25 patients had an abnormal ulnar collateral ligament and 9 patients had a normal ulnar collateral ligament. The computed tomography arthrogram detected abnormalities in 12 of the 14 patients with ulnar collateral ligament tearing (sensitivity, 86%). The magnetic resonance imaging scan indicated abnormalities in 8 of 14 patients (sensitivity, 57%). The specificity of the computed tomography arthrogram was 91% and the magnetic resonance imaging was 100%. A newly described "T-sign" was seen on the computed tomography arthrogram in the patients with an undersurface tear of the ulnar collateral ligament. This represented the dye leaking around the detachment of the ulnar collateral ligament from its bony insertion but remaining contained within the intact superficial layer of the ulnar collateral ligament and capsule. Both the computed tomography arthrogram and the magnetic resonance imaging scan were accurate in diagnosing a complete tear of the ulnar collateral ligament preoperatively in all cases. The main advantage of the computed tomography arthrogram was in evaluating the partial undersurface tear.

Undersurface tear of the ulnar collateral ligament in baseball players. A newly recognized lesion.

Seven patients were diagnosed with an undersurface tear of the deep capsular layer of the anterior bundle of the ulnar collateral ligament. Preoperatively, all of the patients had tenderness over the anterior bundle of the ulnar collateral ligament and pain with valgus stressing of the elbow. Six of the seven patients had a normal magnetic resonance imaging scan, with one magnetic resonance imaging scan showing degeneration within the ligament. All of the patients had a negative computed tomography arthrogram for extracapsular contrast extravasation. A consistent finding in five of the seven patients was a leak of contrast around the edge of the humerus or ulna, although the contrast was contained within the joint. At arthroscopic evaluation, all of the patients demonstrated medial elbow instability as valgus stress was applied across the elbow joint in 70 degrees of flexion. All of the patients underwent open medial elbow surgery, where the ulnar collateral ligament was visualized and found to be intact externally. But when the anterior bundle was incised, there was a detachment of the undersurface of the ligament at the ulna or the humerus. Cadaveric dissections were performed to define the anatomy of the insertion sites and to confirm that this lesion was not an anatomic variant. A tear of the deep layer of the ulnar collateral ligament can result in symptomatic instability that is difficult to diagnose with conventional preoperative testing. This lesion of the anterior bundle of the ulnar collateral ligament has not been previously reported, and in our series it was associated with persistent medial elbow pain in throwing athletes.

Intramedullary nailing of femoral shaft fractures in adolescents.

Twenty-two femoral shaft fractures in 20 patients aged 10-14 years with open physes treated with closed reamed intramedullary nailing were studied retrospectively. Follow-up averaged 26.7 months in 18 of 20 patients. Eleven additional patients with 11 femoral shaft fractures treated with casting and traction were included for comparison of hospitalization time, cost, and time to mobilization. All of the fractures treated with an intramedullary nail healed without malunion or leg length inequality, and there was no evidence of growth plate arrest. The patients treated with an intramedullary nail had statistically significant shorter hospitalizations and shorter times to mobilization, and treatment had an estimated cost of less than half of traction treatment. Results of this study suggest that closed intramedullary nailing of femur fractures in adolescents is an effective treatment option.

A rare HLA DQB allele sequenced from patients with systemic lupus erythematosus.

Most autoimmune disorders are associated with particular alleles of the major histocompatibility complex (MHC) class II genes. However, only a minority of individuals with these alleles develop autoimmunity. The identification of alleles more closely associated with an autoimmune disorder such as lupus would facilitate screening and diagnosis and perhaps the understanding of mechanisms of disease. Analysis of sequence variation in the polymorphic first domain of the MHC genes HLA DQ beta and DQ alpha has revealed a novel DQ beta allele in two Caucasian lupus patients and no Caucasian controls. The novel DQ beta allele shares polymorphic amino acids at positions 26 to 30 and 57 with other lupus-associated DQ beta alleles. These hypervariable regions may play a role in lupus susceptibility and may provide insights into the molecular mechanism for this susceptibility.

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus.

Susceptibility to systemic lupus erythematosus is associated with major histocompatibility complex (MHC)--encoded genes. We have used nucleotide sequence analysis to better define the disease-associated MHC alleles. HLA-DR2, DQw1, and especially the rare allele DQ beta 1. AZH confer high relative risk (RR = 14) for lupus nephritis in a Caucasian population of patients. Pilot studies using historical controls suggest that these genes also confer a high risk in non-Caucasian ethnic groups (RR = 24-78). We have found that DR4 is significantly decreased in patients with lupus nephritis. Fifty percent of the patients with lupus nephritis had either the DQ beta 1.1, the DQ beta 1.AZH, or the DQ beta 1.9 alleles. These alleles share amino acid residues that have been predicted to be the contact points for antigen and the T cell receptor. These HLA alleles appear to have a direct role in the predisposition to lupus nephritis, whereas DR4 may have a "protective" effect.