bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships between Objective Assessment of Ligament Stability and Subjective Assessment of Symptoms and Function after Anterior Cruciate Ligament Reconstruction
Authors: Kocher Mininder S. , Steadman J. Richard , Briggs Karen K. , Sterett William I. , Hawkins Richard J.
Published: March 2004

Background

Relationships between objective assessment of ligament stability and subjective assessment of symptoms and function after anterior cruciate ligament reconstruction have not been established.

Hypothesis

Relationships exist between objective and subjective assessments after anterior cruciate ligament reconstruction.

Study Design

Case series.

Methods

Patients (N = 202) undergoing anterior cruciate ligament reconstruction with 2-year minimum follow-up were studied. Objective variables of ligament stability at follow-up included instrumented laxity, Lachman examination, and pivot-shift examination. Subjective variables of symptoms at follow-up included pain, swelling, giving way, locking, crepitus, stiffness, and limping. Subjective function at follow-up included walking, squatting, stair climbing, running, cutting, jumping, twisting, activity limitation, sports level, activities of daily living level, work level, knee function, sports participation, Lysholm score, and satisfaction withoutcome.

Results

Instrumented knee laxity and Lachman examination had no significant (P> .05) relationships with any subjective variables of symptoms and function. Pivot-shift examination had significant associations with satisfaction (P= .03), partial giving way (P= .01), full giving way (P= .01), difficulty cutting (P= .01), difficulty twisting (P= .01), activity limitation (P= .01), overall knee function (P= .03), sports participation (P= .02), and Lysholm score (P= .01).

Conclusions

The pivot-shift examination may be a better measure of “functional instability” than instrumented knee laxity or Lachman examination after anterior cruciate ligament reconstruction.
Diagnostic Value of Physical Tests for Isolated Chronic Acromioclavicular Lesions
Authors: Chronopoulos Efstathios , Kim Tae Kyun , Park Hyung Bin , Ashenbrenner Diane , McFarland Edward G.
Published: March 2004

Purpose

Chronic acromioclavicular joint lesions are a common source of pain and disability in the shoulder. The goal of this study was to evaluate diagnostic values of physical tests for isolated, chronic acromioclavicular joint lesions.

Study Design

A retrospective case-control study.

Methods

Between 1994 and 2002, 35 patients underwent a distal clavicle excision for isolated acromioclavicular joint lesions. The results of 3 commonly used examinations for acromioclavicular joint lesions were calculated for sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy.

Results

The cross body adduction stress test showed the greatest sensitivity (77%), followed by the acromioclavicular resisted extension test (72%) and active compression test (41%). The active compression test had the greatest specificity (95%). All tests had a negative predictive value of greater than 94%, but the positive predictive value was less than 30% for all tests. The active compression test had the highest overall accuracy (92%), followed by the acromioclavicular resisted extension test (84%) and the cross arm adduction stress test (79%). Combinations of the tests increased the diagnostic values for chronic acromioclavicular joint lesions.

Conclusions

These tests have utility in evaluating patients with acromioclavicular joint pathologic lesions, and a combination of these physical tests is more helpful than isolated tests.
A New Device to Detect Early Cartilage Degeneration
Authors: Duda Georg N. , Kleemann Ralf U. , Bluecher Uwe , Weiler Andreas
Published: March 2004

Background

Currently available arthroscopic techniques do not allow the quantification of cartilage stiffness without direct mechanical indentation or penetration of the tissue.

Purpose

A novel device, capable of quantifying cartilage stiffness during arthroscopy, is believed to detect degenerated cartilage.

Study Design

Controlled laboratory study.

Methods

The stiffness of biological materials was measured arthroscopically without contact between the instrument and the examined object. Object deformation was produced by a flow of sodium chloride and measured optically. Eight ovine femoral condyles and tibial plateaus were tested in a native and degenerated (0.1% trypsin solution) state. Cartilage stiffness was nondestructively determined by using the new device and by indentation methods. In addition, a standard probe was measured by 5 independent users.

Results

The trypsin caused cartilage degeneration and consequently stiffness reduction, measured at 30.8% by the new device and 33.0% by indentation. A good correlation (r = 0.69) between the new device and the standard indentation procedure was observed. Intraindividual and interindividual variability of the new device were low (<10%).

Conclusions

The developed device has demonstrated the ability to quantify the mechanical quality of cartilage by means of mechanical stiffness measurements.

Clinical Relevance

The findings suggest that this device has the capability to detect cartilage degeneration at an early stage.
Plantar Fascia Ruptures in Athletes
Authors: Saxena Amol , Fullem Brian
Published: March 2004

Objective

To educate sports medicine practitioners as to length of time for an athlete to return to activity after sustaining a rupture of the plantar fascia.

Methods

Athletic patients sustaining plantar fascia ruptures and subsequent treatment were reviewed. Diagnosis was based on clinical findings, although radiographic studies were done. Patients were treated for 2 to 3 weeks with a below-knee or high- top boot, nonweightbearing, with an additional 2 to 3 weeks of weightbearing in the boot. Patients used physical therapy.

Results

Eighteen athletes, including 6 elite athletes, were evaluated. Mean age was 40.9 ± 13.2 years. There were 12 males and 6 females. Mean postinjury follow-up was 42 months. Duration of prior plantar fascia symptoms ranged from 0 to 52 weeks. All but 2 ruptures were of the medial portion. Four patients had injections prior to rupture. Five patients wore orthoses preinjury; 14 wore orthoses postinjury. All patients returned to activity after 2 to 26 weeks (mean, 9.1 ± 6.0 weeks). Running athletes predominantly composed the cohort; others played tennis, volleyball, and basketball.

Conclusion

Using the treatment protocol, patients sustaining plantar fascia rupture can achieve favorable results with complete return to activity. None of the 18 patients sustained reinjury, had postinjury sequelae, or necessitated surgery, contrary to other studies.
Porcine Tibia is a Poor Substitute for Human Cadaver Tibia for Evaluating Interference Screw Fixation
Authors: Nurmi Janne T. , Sievänen Harri , Kannus Pekka , Järvinen Markku , Järvinen Teppo L. N.
Published: March 2004

Background

Animal tissues are commonly used in anterior cruciate ligament graft fixation studies.

Hypothesis

Porcine bones and tendons provide good surrogates for human cadaver tissues in the biomechanical evaluation of anterior cruciate ligament reconstruction.

Study Design

Randomized experimental study.

Method

Three different tissue models—pure porcine (porcine graft fixed in porcine tibia, group 1), combination (human hamstring graft and porcine tibia, group 2), and pure human (human graft and tibia, group 3)—were compared using both cyclicloading and subsequent single-cycle load-to-failure tests to assess the effect of graft and bone tissue source (porcine vs human) on the fixation strength of anterior cruciate ligament reconstruction.

Results

In the cyclic-loading test, the displacement (slippage) after 1500 cycles was 2.0 mm ± 0.7 mm, 1.6 mm ± 0.4 mm, and 4.4 mm ± 1.9 mm for groups 1, 2, and 3, respectively (P< .001 between 1 and 2 vs 3). In the subsequent single-cycle load-tofailure test, the corresponding average yield loads were 668 N ± 157 N, 962 N ± 238 N, and 448 N ± 98 N, all differences being statistically significant.

Conclusions

In comparison to young human cadaver tibia, porcine tibia underestimate graft slippage and overestimate the failure load of the soft tissue graft in anterior cruciate ligament reconstruction.

Clinical Relevance

Porcine tibia does not provide a reasonable surrogate for human cadaver tibia for evaluating ACL reconstructions.
Acute Quadriceps Muscle Strains
Authors: Cross Thomas M. , Gibbs Nathan , Houang Michael T. , Cameron Matthew
Published: March 2004

Background

There has been no research examining the magnetic resonance imaging findings, and in turn the prognosis, for a series of acute quadriceps muscle strains.

Hypothesis

The magnetic resonance imaging findings of acute quadriceps muscle strain injuries are helpful in predicting their prognosis.

Study Design

Causal-comparative study.

Method

Forty professional players of Australian Rules football were followed over 3 years. Magnetic resonance imaging examinations were performed within 24 to 72 hours of muscle-strain injury. Imaging features of muscle strain injury included the anatomical location, size (cross-sectional area and length), and site (proximal, middle, or distal). The time from injury to return to full training was termed the rehabilitation interval.

Results

25 clinical quadriceps muscle strain injuries occurred, with 15 cases involving the rectus femoris. The rectus femoris injuries could be further categorized into cases with straining about the central tendon (n = 7, mean rehabilitation interval = 26.9 days) or cases with straining in the periphery (n = 8, mean rehabilitation interval = 9.2 days). Six cases involved one of the vastus muscles (mean rehabilitation interval = 4.4 days). Three players had normal magnetic resonance imaging examinations (mean rehabilitation interval = 5.7 days).

Conclusions

The rectus femoris–central tendon injury is the red flag diagnosis associated with a significantly longer rehabilitation interval.

Clinical Relevance

Magnetic resonance imaging is helpful in predicting the prognosis for acute quadriceps strains.
Mechanical Properties of Bioabsorbable Meniscal Arrows as a Function of Tear Location
Authors: Jani Mihir M. , Silva Matthew J. , Gregush Ron V. , Matava Matthew J.
Published: March 2004

Background

Ex vivo studies have established that arrow fixation of meniscal tears is inferior to vertical sutures and is dependent on arrow length, although the influence of tear location is not known.

Hypothesis

Arrow length and tear location influence the mechanical properties of meniscal arrows.

Study Design

Controlled laboratory study.

Methods

A longitudinal incision was created either 2 mm or 7 mm from the periphery in 70 bovine medial menisci. Each was repaired with a meniscal arrow (10, 13, or 16 mm) or a single vertical suture and subjected to load-to-failure testing and video- graphic analysis.

Results

Mode of failure (P < .0001), maximum force (P < .0001), stiffness (P < .01), 2-mm gap force (P < .03), and ultimate gap formation (P < .002) were all directly related to arrow length. Sixteen-mm arrows and suture exhibited similar, superior mechanical properties. Tear location significantly influenced properties of 10-mm and 16-mm but not 13-mm arrows. Ten-millimeter arrows displayed the worst performance.

Conclusions

Mechanical properties of meniscal arrows depend on tear location and arrow length.

Clinical Relevance

Sixteen-millimeter arrows are a possible alternative to suture for repair of central tears. Thirteen-millimeter arrows may be effective for central and peripheral tears. Ten-millimeter arrows should not be used.
Arthroscopic Microscopy of Articular Cartilage Using Optical Coherence Tomography
Authors: Chu Constance R. , Lin Diana , Geisler Jessica L. , Chu Charleen T. , Fu Freddie H. , Pan Yingtian
Published: March 2004

Background

Optical coherence tomography is an echograph of infrared light that can yield microscopic cross-sectional images of articular cartilage without removing or damaging the tissue.

Hypothesis

To determine whether optical coherence tomography images of human cartilage can be acquired arthroscopically and whether the resulting images have high correlation with histopathology.

Methods

Optical coherence tomography was configured into an arthroscope and used to image 2 human cadaver knees and 45 cores harvested from 9 osteoarthritic knees. The imaged cartilage was then processed for histological analysis. Optical coherence tomography images and histology were graded using a modified Mankin structural score. Agreement was determined using weighted kappa statistics. Morphometric analysis performed on optical coherence tomography images was correlated with histomorphometric analysis using linear regression.

Results

Imaging of the medial and lateral femoral condyles and trochlea was readily accomplished using the optical coherence tomography arthroscope. Modified Mankin surface scores for specimens with the earliest structural changes (grades 0-3) had high agreement with scores assigned to histology ([.kappa] = 0.87). Fibrillation indices calculated from optical coherence tomography had near-perfect correlation to that of histology (R = 0.98)

Clinical Relevance

Arthroscopic optical coherence tomography may be clinically useful for early detection of articular cartilage injury and nondestructive assessment of articular cartilage repair.
Arthroscopic Capsulolabroplasty for Posteroinferior Multidirectional Instability of the Shoulder
Authors: Kim Seung-Ho , Kim Hyo-Kon , Sun Jong-Il , Park Jun-Sic , Oh Irvin
Published: March 2004

Background

Arthroscopic treatment of posteroinferior multidirectional instability of the shoulder is not well documented.

Purpose

To evaluate pathologic lesions of posteroinferior multidirectional instability and the results of arthroscopic capsulolabroplasty.

Study Design

Prospective nonrandomized clinical trial.

Methods

Thirty-one patients with posteroinferior multidirectional instability were prospectively evaluated after arthroscopic capsulolabroplasty (mean follow-up, 51 months). Labral lesion and height were measured in the MRI arthrogram and arthroscopic examination.

Results

All patients had a labral lesion and variable capsular stretching in the posteroinferior aspect. There were 11 type I labral lesions (incomplete detachment), 12 type II (the Kim's lesion: incomplete and concealed avulsion), 6 type III (chondrolabral erosion), and 2 type IV (flap tear). All patients with type II and III lesions had chondrolabral retroversion, with lost labral height in the MRI arthrogram and arthroscopic examination. Twenty-one patients had an excellent Rowe score, nine had good scores, and one had a fair score. Thirty patients had stable shoulders, and one had recurrent instability. All patients had improved shoulder scores and function and pain scores.

Conclusions

Symptomatic patients with posteroinferior multidirectional instability had posteroinferior labral lesions, including retroversion of the posteroinferior labrum, which were previously unrecognized. Restoration of the labral buttress and capsular tension by arthroscopic capsulolabroplasty successfully stabilized shoulders with posteroinferior multidirectional instability.
Injuries in Intercollegiate Women's Lacrosse
Authors: Matz Samuel O. , Nibbelink Gregg
Published: March 2004

Background

Historically, the sport of women's lacrosse has required little or no protective equipment. Recently, there has been increasing concern over trauma to the face and head incurred during play. A rule change passed in spring 2003, during the course of this study, mandates goggles in 2005.

Purpose

To survey injuries in women's lacrosse over multiple seasons and institutions and to categorize injury rates and patterns.

Study Design

A prospective survey.

Methods

A standard report-of-injury form was sent to participating institutions. Injuries were defined by athletic training staff as any event resulting in the athlete missing one or more games or practices.

Results

The overall injury rate for women's lacrosse for the 2001-2002 and 2002-2003 seasons from participating schools was 3.8 per 1000 athlete exposures. The rate of head and face injuries was 1.4 per 1000 athlete exposures, representing 38.5% of all injuries incurred. The rate of eye injuries was 0.43 per 1000 athlete exposures, accounting for 11.5% of the total injuries. The practice injury rate was 2.7 per 1000 athlete exposures, and the competition injury rate was 8.8 per 1000 athlete exposures.

Conclusion

Data support the future requirements for protective eyewear. There is significant and increasing exposure for head and face trauma. Further investigation is needed to monitor injury patterns in women's lacrosse as rules for protective gear evolve.
Lyophilization Does Not Inactivate Infectious Retrovirus in Systemically Infected Bone and Tendon Allografts
Authors: Crawford Matthew J. , Swenson Cheryl L. , Arnoczky Steven P. , O'shea Jeremy , Ross Herbert
Published: March 2004

Background

A review of multiple transplantations of human immunodeficiency virus–infected musculoskeletal allografts found that recipients of lyophilized (freeze-dried) bone or tendon from an infected donor all tested negative for human immunodeficiency virus. The finding that 75% of the recipients of fresh-frozen bone from the same donor contracted human immunodeficiency virus has led to speculation that freeze-drying may render retroviral-infected musculoskeletal allografts noninfectious.

Hypothesis

Lyophilization does not inactivate retrovirus in systemically infected bone and tendon.

Study Design

Controlled laboratory study.

Methods

Tendons and cortical bone segments from cats systemically infected with feline leukemia virus were used in this study. Feline embryonic fibroblast cells were cultured in the presence of fresh-frozen or freeze-dried cortical bone or tendon segments. At each passage, feline leukemia virus p27 antigen was measured in media by enzyme-linked immunosorbent assay, and feline leukemia virus (pro)viral nucleic acids were quantified by real-time quantitative polymerase chain reaction in the DNA extracted from cells.

Results

Enzyme-linked immunosorbent assay results and quantitative polymerase chain reaction results demonstrated retroviral antigen and proviral DNA in all cultured cell replicates after exposure to fresh-frozen or freeze-dried bones or tendons.

Conclusion

Freeze-drying (lyophilization) of retroviral-infected cortical bone and tendon does not inactivate retrovirus.

Clinical Relevance

These results conclusively demonstrate that freeze-drying should not be relied on to inactivate infectious retrovirus in systemically infected musculoskeletal allografts.
Myogenic fusion of human bone marrow stromal cells, but not hematopoietic cells
Authors: Shi Daqing , Reinecke Hans , Murry Charles E. , Torok-Storb Beverly
Published: March 2004

Following marrow transplantation in both patients and animals, cells containing donor nuclei have been detected in a variety of nonhematopoietic tissue. Whether this phenomenon represents transdifferentiation of marrow-derived cells, infiltration of blood cells, or cell fusion is still controversial. In muscle, where cell fusion occurs during normal myogenesis, fusion of marrow-derived cells with resident myotubes is a likely explanation. We tested 8 subpopulations of human bone marrow for their ability to fuse with mouse C2C12 myoblast cells. Relatively high fusion efficiency was observed with marrow stromal cells whereas hematopoietic cells, including populations enriched for stem cells, progenitor cells, and monocytes were refractory to fusion. Mouse myotubes containing human nuclei also contained transcripts for human muscle–specific genes. Injection in vivo of human stromal cells expressing green fluorescent protein (GFP) into the regenerating tibialis anterior muscle of nonobese diabetic–severe combined immunodeficient (NOD/SCID) β2m–/– mice resulted in regenerating mouse muscle fibers expressing GFP. These data suggest that marrow-derived cells contribute to myogenesis through fusion and that stromal cells are better fusion partners than hematopoietic cells.
Characterization of hematopoietic progenitor mobilization in protease-deficient mice
Authors: Levesque Jean-Pierre , Liu Fulu , Simmons Paul J. , Betsuyaku Tomoko , Senior Robert M. , Pham Christine , Link Daniel C.
Published: March 2004

Recent evidence suggests that protease release by neutrophils in the bone marrow may contribute to hematopoietic progenitor cell (HPC) mobilization. Matrix metalloproteinase-9 (MMP-9), neutrophil elastase (NE), and cathepsin G (CG) accumulate in the bone marrow during granulocyte colony-stimulating factor (G-CSF) treatment, where they are thought to degrade key substrates including vascular cell adhesion molecule-1 (VCAM-1) and CXCL12. To test this hypothesis, HPC mobilization was characterized in transgenic mice deficient in one or more hematopoietic proteases. Surprisingly, HPC mobilization by G-CSF was normal in MMP-9–deficient mice, NE × CG-deficient mice, or mice lacking dipeptidyl peptidase I, an enzyme required for the functional activation of many hematopoietic serine proteases. Moreover, combined inhibition of neutrophil serine proteases and metalloproteinases had no significant effect on HPC mobilization. VCAM-1 expression on bone marrow stromal cells decreased during G-CSF treatment of wild-type mice but not NE × CG-deficient mice, indicating that VCAM-1 cleavage is not required for efficient HPC mobilization. G-CSF induced a significant decrease in CXCL12α protein expression in the bone marrow of Ne × CG-deficient mice, indicating that these proteases are not required to down-regulate CXCL12 expression. Collectively, these data suggest a complex model in which both protease-dependent and -independent pathways may contribute to HPC mobilization.
Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia
Authors: Suliman Hagir B. , Ali Mervat , Piantadosi Claude A.
Published: March 2004

Extracellular superoxide dismutase (SOD3) is the primary extracellular enzymatic scavenger of superoxide (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(^{{\cdot}}\mathrm{O}_{2}^{-}\) \end{document}). SOD3's expression is highest in the kidney, but its distribution and biologic functions there are unknown. To investigate the function of renal SOD3, we colocalized it with erythropoietin (EPO) to proximal tubules using in situ hybridization and immunohistochemistry. We then exposed wild-type (Wt) and SOD3 knock-out (KO) mice to hypoxia and found a late hematocrit response in the KO strain. EPO mRNA expression was attenuated in KO mice during the first 6 hours of hypoxia preceded at 2 hours by less accumulation of nuclear hypoxia-inducible transcription factor 1 α (HIF-1α) protein. Meanwhile KO mice exposed to hypoxia showed increases in renal mRNA for superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4) and early significant increases in glutathione disulfide (GSSG)/glutathione (GSH), a marker of oxidative stress, compared with Wt mice. Plasma nitrite/nitrate and renal 3-nitrotyrosine (3-NTyr), indicating peroxynitrite formation, increased later in hypoxia, and renal endothelial nitric oxide synthase protein induction was similar in both strains. These data show that hypoxic activation of HIF-1α and its target gene EPO in mouse kidney is regulated closely by the oxidant/antioxidant equilibrium involving SOD3, thus identifying renal SOD3 as a regulatory element in the body's innate adaptation to hypoxia.
Reconstitution dynamics of plasmacytoid and myeloid dendritic cell precursors after allogeneic myeloablative hematopoietic stem cell transplantation
Authors: Fagnoni Francesco F. , Oliviero Barbara , Giorgiani Giovanna , De Stefano Piero , Dehò Anna , Zibera Carlo , Gibelli Nadia , Maccario Rita , Da Prada GianAntonio , Zecca Marco , Locatelli Franco
Published: March 2004

Dendritic cells (DCs) are fundamental for immunity. We investigated reconstitution of plasmacytoid DC (PDC) and myeloid DC (My-DC) precursors in the first 2 months after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Circulating DCs were monitored from the earliest phase of hematopoietic reconstitution in 43 children given standard therapy to prevent graft-versus-host disease (GVHD) and either treated or untreated with granulocyte colony-stimulating factor (G-CSF) after HSCT. In patients without GVHD, both My-DCs and PDCs reached consistently high absolute values during the initial phase. Time of engraftment did not differ between My-DCs and PDCs, regardless of administration of G-CSF. Treatment with G-CSF (1) accelerated early recovery of My-DC absolute numbers; (2) was associated with lower numbers of both My-DCs and PDCs in the later phase; and (3) significantly reduced the proportion of interleukin-12 (IL-12)–secreting cells. In some patients who developed acute GVHD, we found high numbers of circulating DC precursors during the early phase of this complication. However, treatment with steroids invariably induced rapid decrease of PDCs. Altogether, these data provide an evaluation of DC release after Allo-HSCT, indicate that postgrafting administration of G-CSF impairs the appearance of IL-12–producing DCs, and suggest that DC homeostasis may be disrupted at onset of GVHD.
A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia
Authors: Willmore Elaine , de Caux Sarah , Sunter Nicola J. , Tilby Michael J. , Jackson Graham H. , Austin Caroline A. , Durkacz Barbara W.
Published: March 2004

We report for the first time the use of a selective small-molecule inhibitor of DNA repair to potentiate topoisomerase II (topo II) poisons, identifying DNA-dependent protein kinase (DNA-PK) as a potential target for leukemia therapy. Topo II poisons form cleavable complexes that are processed to DNA double-strand breaks (DSBs). DNA-PK mediates nonhomologous end joining (NHEJ). Inhibition of this DSB repair pathway may sensitize cells to topo II poisons. We investigated the effects of a novel DNA-PK inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), on the response to topo II poisons using K562 leukemia cells. NU7026 (10 μM) potentiated the growth inhibition of idarubicin, daunorubicin, doxorubicin, etoposide, amsacrine (mAMSA), and mitroxantrone with potentiation factors at 50% growth inhibition ranging from approximately 19 for mAMSA to approximately 2 for idarubicin (potentiation of etoposide was confirmed by clonogenic assay). In contrast, NU7026 did not potentiate camptothecin or cytosine arabinoside (araC). NU7026 did not affect the levels of etoposide-induced topo IIα or β cleavable complexes. NU7026 alone had no effect on cell cycle distribution, but etoposide-induced accumulation in G2/M was increased by NU7026. A concentration-dependent increase in etoposide-induced DSB levels was increased by NU7026. The mechanism of NU7026 potentiation of topo II poisons involves inhibition of NHEJ and a G2/M checkpoint arrest. (Blood. 2004;103:4659-4665)
CD28 disruption exacerbates inflammation in Tgf-β1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-β1
Authors: Mamura Mizuko , Lee WoonKyu , Sullivan Timothy J. , Felici Angelina , Sowers Anastasia L. , Allison James P. , Letterio John J.
Published: March 2004

Tgf-β1-/- mice develop a progressive, lethal, inflammatory syndrome, but mechanisms leading to the spontaneous activation of Tgf-β1-/- T cells remain unclear. Here we show the disruption of CD28 gene expression accelerates disease in Tgf-β1-/- mice, and we link this increase in severity to a reduction in the number of CD4+CD25+ regulatory T cells. CD4+CD25+ T cells develop normally in Tgf-β1-/- mice and display characteristic expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), αEβ7 integrin, and Foxp3. Adoptive transfer of Tgf-β1-/- splenocytes to Tgf-β1+/+/Rag2-/- mice induced an autoimmune inflammatory disease with features similar to those of the Tgf-β1-/- phenotype, and disease transfer was accelerated by the depletion of Tgf-β1-/- CD4+CD25+ T cells from donor splenocytes. Cotransfer of Tgf- β1-/- CD4+CD25+ T cells clearly attenuated disease in Rag2-/- recipients of CD25+-depleted Tgf-β1-/- spleen and lymph node cells, but suppression was incomplete when compared with Tgf-β1+/+ CD4+CD25+ T cells. These data demonstrate that CD4+CD25+ regulatory T cells develop in complete absence of endogenous transforming growth factor-β1 (TGF-β1) expression and that autocrine TGF-β1 expression is not essential for these cells to suppress inflammation in vivo. (Blood. 2004;103:4594-4601)
Human B cells that hyperexpress a triad of costimulatory molecules via avipox-vector infection: an alternative source of efficient antigen-presenting cells
Authors: Palena Claudia , Zhu MingZhu , Schlom Jeffrey , Tsang Kwong-Yok
Published: March 2004

Dendritic cells (DCs) are the most potent of the antigen-presenting cells (APCs). Preparation of sufficient numbers of mature DCs, however, is both costly and time-consuming. We have examined here the possibility of using an alternative source of APCs that would be easier to obtain, would not require extensive culture, and thus would be more applicable to human immunotherapy protocols. We show here that freshly isolated human B cells can be efficiently infected by a replication-defective fowlpox recombinant vector, designated rF-TRICOM (TRIad of COstimulatory Molecules), to markedly increase surface expression of the human costimulatory molecule B7-1 and moderately increase expression of intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-3 (LFA-3). Peptide-pulsed rF-TRICOM–infected B cells were highly efficient in activating antigen-specific human T cells and shown to be superior to the use of CD40L in enhancing APC potency. Moreover, when infection of freshly isolated B cells with rF-TRICOM was combined with CD40L, a still further marked enhancement of the antigen-presenting potency was observed. Ex vivo–generated antigen-specific T cells activated in this manner might be applied to experimental protocols or used for adoptive transfer in immunotherapy protocols.
Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma
Authors: Ma Cynthia X. , Lacy Martha Q. , Rompala John F. , Dispenzieri Angela , Rajkumar S. Vincent , Greipp Philip R. , Fonseca Rafael , Kyle Robert A. , Gertz Morie A.
Published: March 2004

Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. We retrospectively reviewed 32 patients diagnosed with adult-acquired FS between April 1968 and June 2002 at Mayo Clinic (Rochester, MN). At diagnosis, most patients had monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), with a median creatinine level of 176.8 μM (2.0 mg/dL; range, 79.56-327.08 μM [0.9-3.7 mg/dL]) and evidence of osteomalacia. During the average 65 months (range, 2-238 months) of follow-up, 5 patients developed end-stage renal disease (ESRD) and only 1 of 14 patients with MGUS transformed to multiple myeloma (MM). Also, 14 deaths occurred, with only 1 from ESRD but 4 from alkylator-related leukemia or myelodysplastic syndrome. Chemotherapy offered little benefit on renal functions of MGUS or SMM patients. In conclusion, FS associated with monoclonal gammopathy does not appear to confer an additional risk of subsequent evolution to MM. ESRD occurs late in the disease process.
Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome
Authors: Nurden Paquita , Jandrot-Perrus Martine , Combrié Robert , Winckler Joelle , Arocas Veronique , Lecut Christelle , Pasquet Jean-Max , Kunicki Thomas J. , Nurden Alan T.
Published: March 2004

We report a novel case of gray platelet syndrome (GPS) where a severe deficiency of the platelet collagen receptor, glycoprotein (GP) VI, accompanies classical symptoms of a low platelet count and platelets lacking α-granules. Dense granules were normally present. Platelet aggregation with collagen was severely decreased, as was the response to convulxin (Cvx), a GPVI agonist. Quantitative analysis of GPVI using fluorescein isothiocyanate (FITC)–Cvx in flow cytometry showed its virtual absence on the patient's platelets. The GPVI deficiency was confirmed using monoclonal antibodies in Western blotting and in immunogold labeling on frozen thin sections where internal pools of GPVI were confirmed for normal platelets. The Fc receptor γ-chain, constitutively associated with GPVI in normal platelets, was present in subnormal amounts, and the phospholipase Cγ2–dependent activation pathway appeared to function normally. No autoantibodies to GPVI were found in the patient's serum using monoclonal antibody immobilization of platelet antigen (MAIPA). Sequencing of coding regions of the GPVI gene failed to show abnormalities, and mRNA for GPVI was present in the patient's platelets, pointing to a probable acquired defect in GPVI expression. Our results may provide a molecular explanation for the subgroup of patients with severely deficient collagen-induced platelet aggregation as previously described for GPS in the literature.
Gaucher disease: alendronate disodium improves bone mineral density in adults receiving enzyme therapy
Authors: Wenstrup Richard J. , Bailey Laurie , Grabowski Gregory A. , Moskovitz Jay , Oestreich Alan E. , Wu Wei , Sun Shumei
Published: March 2004

Symptomatic patients with Gaucher disease (GD) (acid β-glucosidase [Gcase] deficiency) are treated with injectable human recombinant GCase. Treatment results in significant decreases in lipid storage in liver, spleen, and bone marrow, but the generalized osteopenia and focal bone lesions present in many adult patients are refractory to treatment. A double-blind, 2-arm, placebo-controlled trial of alendronate (40 mg/d) was performed in adults with GD who had been treated with enzyme for at least 24 months. Primary therapeutic endpoints were improvements in (1) bone mineral density (BMD) and content (BMC) at the lumbar spine, and (2) focal lesions in x-rays of long bones assessed by a blinded reviewer. There were 34 patients with GD type 1 (age range, 18-50 years) receiving enzyme therapy who were randomized for this study. After 18 months, ΔBMD at the lumbar spine was 0.068 ± 0.21 and 0.015 ± 0.034 for alendronate and placebo groups, respectively (P = .001). Long-bone x-rays showed no change in focal lesions or bone deformities in any subject in either arm. Alendronate is a useful adjunctive therapy in combination with enzyme replacement therapy (ERT) for the treatment of GD-related osteopenia in adults, but it cannot be expected to improve focal lesions.
Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis
Authors: Li Aihong , Rue Montse , Zhou Jianbiao , Wang Hongjun , Goldwasser Meredith A. , Neuberg Donna , Dalton Virginia , Zuckerman David , Lyons Cheryl , Silverman Lewis B. , Sallan Stephen E. , Gribben John G. ,   for the Dana-Farber Cancer Institute ALL Consortium
Published: March 2004

Sequence analysis of the immunoglobulin heavy chain genes (IgH) has demonstrated preferential usage of specific variable (V), diversity (D), and joining (J) genes at different stages of B-cell development and in B-cell malignancies, and this has provided insight into B-cell maturation and selection. Knowledge of the association between rearrangement patterns based on updated databases and clinical characteristics of pediatric acute lymphoblastic leukemia (ALL) is limited. We analyzed 381 IgH sequences identified at presentation in 317 children with B-lineage ALL and assessed the VHDHJH gene utilization profiles. The DHJH-proximal VH segments and the DH2 gene family were significantly overrepresented. Only 21% of VH-JH joinings were potentially productive, a finding associated with a trend toward an increased risk of relapse. These results suggest that physical location at the VH locus is involved in preferential usage of DHJH-proximal VH segments whereas DH and JH segment usage is governed by position-independent molecular mechanisms. Molecular pathophysiology appears relevant to clinical outcome in patients who have only productive rearrangements, and specific rearrangement patterns are associated with differences in the tumor biology of childhood ALL. (Blood. 2004;103:4602-4609)
Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long-term follow-up of a phase 1/2 study
Authors: Gordon Leo I. , Molina Arturo , Witzig Thomas , Emmanouilides Christos , Raubtischek Andrew , Darif Mohamed , Schilder Russell J. , Wiseman Greg , White Christine A.
Published: March 2004

We previously demonstrated that yttrium-90 (Y-90) ibritumomab tiuxetan (Zevalin) radioimmunotherapy (RIT) was safe and effective for relapsed or refractory CD20+, B-cell, non-Hodgkin lymphoma (NHL). We now provide long-term follow-up data in responding patients based on International Workshop Response Criteria. Complete (CR), CR unconfirmed (CRu), and partial response (PR) rates were 29%, 22%, and 22%, respectively (overall response rate 73%, 51% in CR/CRu). Mean time to progression (TTP) and duration of response (DR) in responders were 12.6 months and 11.7 months, respectively. At the maximum tolerated dose (0.4 mCi/kg [14.8 MBq/kg]), TTP and DR in complete responders (CR/CRu) were 28.3 and 27.5 months, respectively. Nine patients (24% of responding patients) had a TTP of more than 3 years. Long-term responders (> 5 years) have been identified. Ibritumomab tiuxetan produces durable responses in patients with indolent and diffuse large B-cell lymphoma. (Blood. 2004;103:4429-4431)
Mitochondrial DNA sequence heterogeneity in circulating normal human CD34 cells and granulocytes
Authors: Shin Myung Geun , Kajigaya Sachiko , Tarnowka Magdalena , McCoy J. Philip , Levin Barbara C. , Young Neal S.
Published: March 2004

We have reported marked mitochondrial DNA (mtDNA) sequence heterogeneity among individual CD34 clones from adult bone marrow (BM) and the age-dependent accumulation of mtDNA mutations in this mitotically active tissue. Here, we show direct evidence of clonal expansion of cells containing mtDNA mutations and that the mtDNA sequence may be easily determined by using peripheral blood (PB) as a CD34 cell source. Analysis of 594 circulating CD34 clones showed that 150 (25%) had mtDNA sequences different from the same donor's corresponding aggregate sequence. Examination of single granulocytes indicated that 103 (29%) from the same 6 individuals showed mtDNA heterogeneity, with sequences distinct from the corresponding aggregate tissue sequence and from the sequences of other single granulocytes. Circulating and BM CD34 cells showed virtually identical patterns of mtDNA heterogeneity, and the same changes were seen in progeny granulocytes as in their progenitors, indicating that blood sampling could be used in studies to determine whether mtDNA reflects an individual's cumulative or recent exposure to mutagens; as a marker of individual hematopoietic progenitors, stem cells, and their expansion; and for the detection of minimal residual disease in hematologic malignancies of CD34 cell origin. (Blood. 2004;103:4466-4477)
Identification of an HLA-A*0201–restricted CD8+ T-cell epitope SSp-1 of SARS-CoV spike protein
Authors: Wang Baomei , Chen Huabiao , Jiang Xiaodong , Zhang Minghui , Wan Tao , Li Nan , Zhou Xiangyang , Wu Yanfeng , Yang Feng , Yu Yizhi , Wang Xiaoning , Yang Ruifu , Cao Xuetao
Published: March 2004

A novel coronavirus, severe acute respiratory syndrome (SARS)–associated coronavirus (SARS-CoV), has been identified as the causal agent of SARS. Spike (S) protein is a major structural glycoprotein of the SARS virus and a potential target for SARS-specific cell-mediated immune responses. A panel of S protein–derived peptides was tested for their binding affinity to HLA-A*0201 molecules. Peptides with high affinity for HLA-A*0201 were then assessed for their capacity to elicit specific immune responses mediated by cytotoxic T lymphocytes (CTLs) both in vivo, in HLA-A2.1/Kb transgenic mice, and in vitro, from peripheral blood lymphocytes (PBLs) sourced from healthy HLA-A2.1+ donors. SARS-CoV protein-derived peptide-1 (SSp-1 RLNEVAKNL), induced peptide-specific CTLs both in vivo (transgenic mice) and in vitro (human PBLs), which specifically released interferon-γ (IFN-γ) upon stimulation with SSp-1–pulsed autologous dendritic cells (DCs) or T2 cells. SSp-1–specific CTLs also lysed major histocompatibility complex (MHC)–matched tumor cell lines engineered to express S proteins. HLA-A*0201–SSp-1 tetramer staining revealed the presence of significant populations of SSp-1–specific CTLs in SSp-1–induced CD8+ T cells. We propose that the newly identified epitope SSp-1 will help in the characterization of virus control mechanisms and immunopathology in SARS-CoV infection, and may be relevant to the development of immunotherapeutic approaches for SARS.
Platelet deposition inhibits tissue factor activity: in vitro clots are impermeable to factor Xa
Authors: Hathcock James J. , Nemerson Yale
Published: March 2004

Upon plaque rupture or vascular injury, tissue factor (TF) protein in the vessel wall becomes exposed to flowing blood, initiating a cascade of reactions resulting in the deposition of fibrin and platelets on the injured site. Paradoxically, the growing thrombus may act as a barrier, restricting the convective and diffusive exchange of substrates and coagulation products between the blood and reactive vessel wall, thus limiting the role TF plays in thrombus growth. In this study, various in vitro, platelet-fibrin clots were prepared on TF:VIIa-coated surfaces and the rate at which factor (F) X in the well-mixed clot supernatant permeates the clot and is converted to Xa was monitored over several hours. The apparent diffusion coefficients of FX(a) in fibrin and platelet-fibrin clots at 37°C was 2.3 × 10–7 and 5.3 × 10–10 cm2/second, respectively, indicating that the mean time required for FX(a), and likely FIX(a), to diffuse 1 mm in a fibrin clot is 4 hours, and in the presence of platelets, 3.6 months. As complete human thrombotic occlusion has been observed within 10 minutes, an alternative source of procoagulant activity that can localize to the outer surface of growing thrombi, such as platelet factor XI or blood-borne TF, appears essential for rapid thrombus growth.
Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells
Authors: Igarashi Takehito , Wynberg Jason , Srinivasan Ramprasad , Becknell Brian , McCoy J. Phillip , Takahashi Yoshiyuki , Suffredini Dante A. , Linehan W. Marston , Caligiuri Michael A. , Childs Richard W.
Published: March 2004

Cellular inactivation through killer immunoglobulin-like receptors (KIRs) may allow neoplastic cells to evade host natural killer (NK) cell–mediated immunity. Recently, alloreactive NK cells were shown to mediate antileukemic effects against acute myelogenous leukemia (AML) after mismatched transplantation, when KIR ligand incompatibility existed in the direction of graft-versus-host disease (GVHD). Therefore, we investigated whether solid tumor cells would have similar enhanced susceptibility to allogeneic KIR-incompatible NK cells compared with their KIR-matched autologous or allogeneic counterparts. NK populations enriched and cloned from the blood of cancer patients or healthy donors homozygous for HLA-C alleles in group 1 (C-G1) or group 2 (C-G2) were tested in vitro for cytotoxicity against Epstein-Barr virus–transformed lymphoblastic cell lines (EBV-LCLs), renal cell carcinoma (RCC), and melanoma (MEL) cells with or without a matching KIR-inhibitory HLA-C ligand. Allogeneic NK cells were more cytotoxic to tumor targets mismatched for KIR ligands than their KIR ligand–matched counterparts. Bulk NK populations (CD3–/CD2+/CD56+) expanded 104-fold from patients homozygous for C-G1 or C-G2 had enhanced cytotoxicity against KIR ligand–mismatched tumor cells but only minimal cytotoxicity against KIR ligand–matched targets. Further, NK cell lines from C-G1 or C-G2 homozygous cancer patients or healthy donors expanded but failed to kill autologous or KIR-matched MEL and RCC cells yet had significant cytotoxicity (more than 50% lysis at 20:1 effector-target [E/T] ratio) against allogeneic KIR-mismatched tumor lines. These data suggest immunotherapeutic strategies that use KIR-incompatible allogeneic NK cells might have superior antineoplastic effects against solid tumors compared with approaches using autologous NK cells.
Deletion of the major GATA1 enhancer HS 1 does not affect eosinophil GATA1 expression and eosinophil differentiation
Authors: Guyot Boris , Valverde-Garduno Veronica , Porcher Catherine , Vyas Paresh
Published: March 2004

Expression of the myeloid transcription factor GATA1 is required for early stages of eosinophil differentiation. Defining mechanisms regulating eosinophil GATA1 expression will be important to understand development of this lineage. However, the cis-elements required for eosinophil GATA1 expression are not fully characterized. Previous work identified HS 1 as a major GATA1 enhancer, but its role in eosinophil GATA1 expression is unclear. Here, we show that mouse HS 1 deletion leaves eosinophil GATA1 mRNA expression and eosinophil differentiation unaffected. Chromatin isolated from eosinophils and encompassing HS 1 is weakly enriched for acetylated histones H3/H4. HS 1 deletion does not alter eosinophil GATA1 locus histone acetylation. In eosinophils, GATA1 and CCAAT/enhancer binding protein ϵ (C/EBPϵ) do not bind HS 1 but bind selectively a cis-element in the first GATA1 intron. Thus, HS 1 is not required for eosinophil GATA1 expression. Instead, this study suggests a previously unsuspected role for the GATA1 intron element for this function.
Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells
Authors: Hesser Boris A. , Liang Xiao Huan , Camenisch Gieri , Yang Suya , Lewin David A. , Scheller Richard , Ferrara Napoleone , Gerber Hans-Peter
Published: March 2004

We conducted a genome-wide analysis of genes that are regulated by vascular endothelial growth factor (VEGF) in endothelial cells and identified DSCR1 to be most significantly induced. Consistent with an antagonistic function on calcineurin (CnA) signaling, expression of DSCR1 in endothelial cells blocked dephosphorylation, nuclear translocation, and activity of nuclear factor of activated T cell (NFAT), a transcription factor involved in mediating CnA signaling. DSCR1 was not only induced by VEGF, but also by other compounds activating CnA signaling, suggesting a more general role for DSCR1 in activated endothelial cells. Transient expression of DSCR1 attenuated inflammatory marker genes such as tissue factor (TF), E-selectin, and Cox-2, identifying a previously unknown regulatory role for DSCR1 in activated endothelial cells. In contrast, knock-down of endogenous DSCR1 increased NFAT activity and stimulated expression of inflammatory genes on activated endothelial cells. Thus, the negative regulatory feedback loop between DSCR1 and CnA signaling in endothelial cells identified may represent a potential molecular mechanism underlying the frequently transient expression of inflammatory genes following activation of endothelial cells.