Common radiographic imaging modalities fail to accurately predict capitate morphology.

BACKGROUND: There are three morphologies of the capitate based on its lunate and scaphoid articulations: flat, spherical, and V-shaped. Following a proximal row carpectomy (PRC), the capitate articulates with the lunate facet of the radius, altering contact biomechanics at the radiocarpal joint. Therefore, capitate morphology may influence contact pressures at the capitolunate articulation and influence clinical outcomes after PRC. However, it remains unclear which diagnostic imaging technique most reliably distinguishes between capitate morphologies. METHODS: We evaluated the ability of plain radiographs, two-dimensional computed tomography (2D-CT), three-dimensional (3D)-CT reconstruction, and magnetic resonance imaging (MRI) to predict capitate type in 47 fresh frozen cadaver wrists. Two attending hand surgeons and one hand surgery fellow characterized capitate type based on each imaging modality. True capitate type was determined after gross dissection. We determined the reliability of each modality to predict capitate morphology. RESULTS: We found all four imaging modalities to have a low sensitivity and specificity for predicting capitate morphology. Plain radiographs, 2D-CT, 3D-CT, and MRI had sensitivities/specificities of 0.46/0.57, 0.54/0.72, 0.54/0.52, and 0.56/0.65, respectively. All modalities had high negative predictive values for detecting the more rare V-shaped capitate subtype (range 91-94 %). Inter-rater reliability was poor for all modalities. CONCLUSION: These data suggest that plain radiographs, CT, 3D-CT, and MRI are not helpful in preoperative determination of true capitate morphology. Plain radiographs are as effective as more cost-intensive modalities in ruling out V-shaped capitates.

Clinical outcomes of zone II flexor tendon repair depending on mechanism of injury.

PURPOSE: To determine whether mechanism of injury affects outcomes of Zone II flexor tendon repairs. METHODS: We retrospectively analyzed patients who underwent Zone II flexor tendon repair between 2001 and 2010 with a minimum of 12-month follow-up. Exclusion criteria included fingers with fracture, pulley reconstruction, or flexor tendon bowstringing. The saw group injuries were from saws or from tearing mechanisms; the sharp group had clean transection injuries from knives or glass. At final evaluation, primary outcomes were total passive motion (TPM) and total active motion (TAM) at the proximal interphalangeal and distal interphalangeal joints. Secondary comparisons included strength, Disabilities of the Shoulder, Arm, and Hand (DASH) score, percentage of postoperative tendon rupture, and percentage of patients requiring secondary surgery. The saw group had 13 patients with 17 fingers studied. The sharp group had 21 patients with 24 fingers studied. All patients had primary flexor digitorum profundus repairs in Zone II. Operative records review confirmed for all but 1 patient that flexor digitorum profundus injuries were repaired with a minimum of a 4-strand core suture technique. In the saw group, 9 of 14 fingers with a 50% or greater laceration of flexor digitorum superficialis were repaired; in the sharp group, 15 of 18 such flexor digitorum superficialis injuries were repaired. Average follow-up was 4 years (range, 1-9 y). RESULTS: The saw group had significantly less TAM and TPM compared with the sharp group. There was no significant difference in DASH scores, strength measurements, or tendon rupture rates. The rate of secondary surgery was significantly higher in the saw group. CONCLUSIONS: Tearing types of injury, such as those caused by saws, led to poorer outcomes for Zone II flexor tendon injuries compared with sharp injuries at an average follow-up of 4 years. Our results can be useful when discussing expected outcomes. Mechanism of injury in Zone II flexor tendon lacerations may eventually help define optimal treatment.

Injectable thermogelling chitosan for the local delivery of bone morphogenetic protein.

The aim of the present study was to evaluate the in vivo biocompatibility of injectable thermo gelling chitosan-ammonium hydrogen phosphate solution (chitosan-AHP) and its efficacy to deliver recombinant human bone morphogenetic protein-2 (rhBMP-2) in a bioactive form. The thermogel showed a typical foreign body response upon subcutaneous implantation surrounded by a fibrous capsule. Even at 4 and 8 weeks post implantation, significant neutrophil infiltration was observed within the gel. Chitosan-AHP gel retained most of the loaded rhBMP-2 after a small initial release. The bioactivity of the released protein was demonstrated in vitro by the increase in alkaline phosphatase activity of mouse pre osteoblast cells (MC3T3-E1). Histological and micro-computed tomography (µCT) evaluation showed evidence of ectopic bone formation upon 4 µg/mL rhBMP-2 loaded chitosan-AHP injection. The study demonstrated a neutrophil mediated local tissue response to chitosan-AHP gel and its ability to encapsulate and maintain the bioactivity of rhBMP-2.

Tissue engineering solutions for tendon repair.

Tendon injuries range from acute traumatic ruptures and lacerations to chronic overuse injuries, such as tendinosis. Even with improved nonsurgical, surgical, and rehabilitation techniques, outcomes following tendon repair are inconsistent. Primary repair remains the standard of care. However, repaired tendon tissue rarely achieves functionality equal to that of the preinjured state. Poor results have been linked to alterations in cellular organization within the tendon that occur at the time of injury and throughout the early stages of healing. Enhanced understanding of the biology of tendon healing is needed to improve management and outcomes. The use of growth factors and mesenchymal stem cells and the development of biocompatible scaffolds could result in enhanced tendon healing and regeneration. Recent advances in tendon bioengineering may lead to improved management following tendon injury.

Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: a combined gene therapy-cell transplantation approach.

One of the fundamental principles underlying tissue engineering approaches is that newly formed tissue must maintain sufficient vascularization to support its growth. Efforts to induce vascular growth into tissue-engineered scaffolds have recently been dedicated to developing novel strategies to deliver specific biological factors that direct the recruitment of endothelial cell (EC) progenitors and their differentiation. The challenge, however, lies in orchestration of the cells, appropriate biological factors, and optimal factor doses. This study reports an approach as a step forward to resolving this dilemma by combining an ex vivo gene transfer strategy and EC transplantation. The utility of this approach was evaluated by using 3D poly(lactide-co-glycolide) (PLAGA) sintered microsphere scaffolds for bone tissue engineering applications. Our goal was achieved by isolation and transfection of adipose-derived stromal cells (ADSCs) with adenovirus encoding the cDNA of VEGF. We demonstrated that the combination of VEGF releasing ADSCs and ECs results in marked vascular growth within PLAGA scaffolds. We thereby delineate the potential of ADSCs to promote vascular growth into biomaterials.

Development of injectable thermogelling chitosan-inorganic phosphate solutions for biomedical applications.

Thermosetting polymers are attractive candidates for biomedical applications as noninvasive therapeutic delivery vehicles. In the present study, the feasibility of developing a neutral physiological temperature setting injectable formulation based on chitosan and an inorganic phosphate salt have been demonstrated. The in situ gelling system was developed by adding different concentrations of ammonium hydrogen phosphate (AHP) to chitosan solution. The resulting solutions have pH in the range of approximately 7-7.2. The gelling time of the chitosan-AHP solution was determined by incubating the solutions at 37 degrees C. Depending on the concentrations of AHP added, the gelling time varied from 5 min to 30 h at 37 degrees C. Addition of various diluents to chitosan-AHP solution did not significantly change the gelling time of the solutions. The gels were found to be cytocompatible as evidenced from in vitro cytocompatibility evaluation using MC3T3-E1 mouse osteoblast like cells. The feasibility of using the gels as a stem cell carrier vehicle as well as a macromolecular delivery vehicle has been demonstrated.

The chemokine CXCL14 (BRAK) stimulates activated NK cell migration: implications for the downregulation of CXCL14 in malignancy.

OBJECTIVE: The primary function of chemokines is the regulation of leukocyte trafficking by stimulating directional chemotaxis. The chemokine CXCL14 (BRAK) is highly expressed in all normal tissues, but is not expressed in most malignant tissues. The chemotactic activity of CXCL14 has been difficult to characterize. Recently it was reported that CXCL14 is a chemoattractant for activated monocytes and immature dendritic cells. Given that CXCL14 is downregulated upon transition to malignancy, we sought to characterize whether CXCL14 might play a role in NK cell chemotaxis. METHODS: Human natural killer (NK) cells were isolated from buffy coats obtained from normal volunteers and were activated with lymphocyte conditioned media, IL-2, and ionomycin. Standard transwell chemotaxis assays, proliferation assays, and chromium release cell cytotoxicity assays were performed. RESULTS: CXCL14 was found to stimulate migration of activated human NK cells in transwell chemotaxis assays by 1.4-fold. Similarly, it increased migration of an IL-2-dependent natural killer leukemia (NKL) cell line by 1.9-fold. Antisera against CXCL14 or pertussis toxin blocked this chemotactic effect. However, CXCL14 did not affect the proliferation or cytotoxic activity of normal human NK cells. CXCL14 also stimulated the chemotaxis of immature monocyte-derived dendritic cells. CONCLUSIONS: CXCL14 may play a role in the trafficking of NK cells to sites of inflammation or malignancy. In addition, the downregulation of the expression of CXCL14 might be an important step in successful oncogenesis to prevent NK immune surveillance of the malignancy.

Atypical and typical (idiopathic) slipped capital femoral epiphysis. Reconfirmation of the age-weight test and description of the height and age-height tests.

BACKGROUND: The age-weight test was described to aid the clinician in defining demographic predictors of an atypical slipped capital femoral epiphysis. We wished to retest the accuracy and applicability of the age-weight test and height differences in children with atypical and typical slipped capital femoral epiphyses. METHODS: A retrospective review of the records for all children with slipped capital femoral epiphysis from 1998 through 2003 was performed. Gender, race, chronological age, weight, height, the duration of symptoms, and the laterality of the slip were recorded. The slip angle was classified as mild (< 30 degrees), moderate (30 to 50 degrees), or severe (> 50 degrees). Statistical analyses were performed. RESULTS: The study included 105 children (thirty-eight girls and sixty-seven boys) with 141 slipped capital femoral epiphyses; ten children had fifteen atypical slipped capital femoral epiphyses, and ninety-five children had 126 typical slipped capital femoral epiphyses. Sixty-nine children had unilateral involvement, and thirty-six had bilateral involvement. The average age at the time of presentation for the first slipped capital femoral epiphysis was 12.1 +/- 2.0 years. The average duration of symptoms was 3.7 +/- 5.5 months. In the group of 128 slipped capital femoral epiphyses for which the slip angle was known, there were ninety-three mild, twenty-seven moderate, and eight severe slips. The average slip angle was 24 degrees +/- 18 degrees. The age-weight test demonstrated a sensitivity of 50%, a specificity of 89%, a positive predictive value of 33%, and a negative predictive value of 94%. The age-height test, involving the same definition as the age-weight test except that the percentiles apply to height and not weight, demonstrated a sensitivity of 88%, a specificity of 73%, a positive predictive value of 30%, and a negative predictive value of 98%. The height test, which was defined as positive if the child's height was at or below the tenth percentile for age and as negative if it was above the tenth percentile, demonstrated a sensitivity of 75%, a specificity of 97%, a positive predictive value of 75%, and a negative predictive value of 97%. CONCLUSIONS: The present study reaffirmed the accuracy and applicability of the age-weight test for differentiating between typical and atypical slipped capital femoral epiphyses, and it further defined the age-height and height tests. If the height of a child can be obtained, the height test is likely to be most useful for differentiating between typical and atypical slipped capital femoral epiphysis. When height is not known, the age-weight test will result in a similar negative predictive value but with a lower sensitivity, specificity, and positive predictive value. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions to Authors for a complete description of levels of evidence.

The narrow window of bone age in children with slipped capital femoral epiphysis: a reassessment one decade later.

A narrow window of bone age (BA) in slipped capital femoral epiphysis (SCFE) was described a decade ago. Children now mature younger. Does the BA narrow window still exist? It is the purpose of this study to investigate this question. A retrospective review of children with idiopathic SCFE (1998-2003) was performed. The initial study data ("past") were used as a comparison. Anteroposterior pelvis radiographs were scored for BA (Oxford method) in 108 children. Only the first radiograph was used for children with sequential bilateral SCFEs. There were 67 boys and 41 girls. There were 73 children with unilateral and 35 with bilateral SCFEs. Chronological age (CA) was 12.4+/-1.8 years; Oxford score, 39+/-3 years; and Oxford BA (OXBA), 13.2+/-1.3 years. The recent children were younger (12.1 and 13.2 years; P=0.001), with lower OXBA (29.0 and 31.4; P=0.000003). When converted into years, there was no significant difference between the recent and past children (recent data, 13.1 years; past data, 13.5 years; P=0.18). Chronological age was higher in boys than in girls (12.7 and 11.6 years, respectively; P=0.0008), and so was BA (13.9+/-1.0 and 12.0 years, respectively; P<10). There were no differences in BA score between boys and girls (boys, 29.5; girls, 29.9; P=0.49). The recent data demonstrated the same narrow window of BA. The CA range for the boys' SCFE was 8.4 years, whereas the OXBA was 4.0 years. The CA range for girls was 5.3 years, whereas the OXBA was 2.3 years. Those with unilateral SCFEs were older than those with bilateral SCFEs in CA (12.7 and 11.7 years, respectively; P=0.013), but not in BA (29.8 and 29.4; P=0.51). All SCFEs are present, on average, at an OXBA of 29, regardless of sex, symptom duration, or unilateral/bilateral nature. This study has reaffirmed the narrow window of BA in SCFE, with a BA range approximating 50% of CA range.

Demographic predictors of severity of stable slipped capital femoral epiphyses.

BACKGROUND: The outcome of stable slipped capital femoral epiphysis is directly related to the severity of the slip. If it is assumed that the slip will be less severe if it is diagnosed early, then early diagnosis should improve the prognosis. It was our purpose to determine demographic predictors of the severity of a slipped capital femoral epiphysis. METHODS: A retrospective study of 243 children with a total of 328 stable slipped capital femoral epiphyses was performed. Gender, race, age, and symptom duration were noted. Slip severity was classified as mild (<30 degrees ), moderate (30 degrees to 50 degrees ), or severe (>50 degrees ). Statistical analyses included bivariate, multivariate, linear correlation, and logistic regression techniques. RESULTS: There were 159 boys and eighty-four girls; 149 children had unilateral and ninety-four had bilateral slipped capital femoral epiphysis. Of the bilateral slips, forty-two were simultaneous and fifty-two were sequential. The mean age (and standard deviation) was 12.6 +/- 1.8 years, the mean duration of the symptoms was 5.2 +/- 7.4 months, and the mean slip angle was 29 degrees +/- 20 degrees . There were 199 mild, sixty-eight moderate, and forty-five severe slips. The mean duration of symptoms was 3.5 +/- 5.0 months for the mild slips, 7.7 +/- 9.0 months for the moderate slips, and 8.8 +/- 10.6 months for the severe slips (p < 0.0001). Older children had more severe slips: the average age was 12.3 +/- 1.8 years for the children with a mild slip, 13.0 +/- 1.6 years for those with a moderate slip, and 13.8 +/- 1.8 years for those with a severe slip (p < 0.0001). Multivariate analyses demonstrated that, among the factors studied, only the age of the patient and the duration of the symptoms were associated with the slip severity. Symptom duration and patient age were used as predictors of slip severity in a logistic regression analysis, with > or =30 degrees and <30 degrees used as the categories for slip severity, older than 12.5 years old compared with 12.5 years old or younger used as the categories for age, and more than 2.0 months compared with 2.0 months or less used as the categories for symptom duration. This model predicted the probability of a slip with confidence (p < 0.0001). The odds ratios (with 95% confidence intervals) for age and symptom duration were 2.0 (1.15 to 3.53) and 4.1 (2.34 to 7.12), respectively. Thus, a child with a stable slipped capital femoral epiphysis is 2.0 times more likely to have a moderate or severe slip if he or she is older than 12.5 years of age at the time of the diagnosis and 4.1 times more likely to have a moderate or severe slip if the duration of symptoms was longer than two months. CONCLUSIONS: The only two known significant predictors of the severity of a slipped capital femoral epiphysis are age at diagnosis and symptom duration. For any individual child, slip severity and symptom duration are unique; in a large population, there is a general correlation between slip severity and increases in patient age and increases in the duration of symptoms.

Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis.

A novel cytokine termed IL-17D was cloned using nested RACE PCR. It is a secreted cytokine with homology to the IL-17 family of proteins. IL-17D is preferentially expressed in skeletal muscle, brain, adipose tissue, heart, lung, and pancreas. Treatment of endothelial cells with purified rIL-17D protein stimulated the production of IL-6, IL-8, and GM-CSF. The increased expression of IL-8 was found to be NF-kappa B-dependent. rIL-17D also demonstrated an inhibitory effect on hemopoiesis of myeloid progenitor cells in colony formation assays.

The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression.

The POU homeodomain protein Oct-4 and the Forkhead Box protein FoxD3 (previously Genesis) are transcriptional regulators expressed in embryonic stem cells. Down-regulation of Oct-4 during gastrulation is essential for proper endoderm development. After gastrulation, FoxD3 is generally down-regulated during early endoderm formation, although it specifically remains expressed in the embryonic neural crest. In these studies, we have found that Oct-4 and FoxD3 can bind to identical regulatory DNA sequences. In addition, Oct-4 physically interacted with the FoxD3 DNA-binding domain. Cotransfection of Oct-4 and FoxD3 expression vectors activated the osteopontin enhancer, which is expressed in totipotent embryonic stem cells. FoxA1 and FoxA2 (previously HNF-3alpha and HNF-3beta) are Forkhead Box transcription factors that participate in liver and lung formation from foregut endoderm. Although FoxD3 activated the FoxA1 and FoxA2 promoters, Oct-4 inhibited FoxD3 activation of the FoxA1 and FoxA2 endodermal promoters. These data indicate that Oct-4 functions as a corepressor of FoxD3 to provide embryonic lineage-specific transcriptional regulatory activity to maintain appropriate developmental timing.