The potential effect of anatomic relationship between the femur and the tibia on medial meniscus tears

Background

The anatomic and the kinematical relationships between the femur and the tibia have been previously examined in both normal and diseased knees. However, less attention has been directed to the effect of these relationships on the meniscal diseases. Therefore, we aimed to investigate the impact of femorotibial incongruence on both lateral and medial meniscal tears.

Materials and methods

A total of 100 images obtained from MRI of 100 patients (39 males and 61 females) were included in the study. Diameters of the medial and the lateral femoral condyles, thicknesses of the menisci, and diameters of the medial and the lateral tibial articular surfaces were measured.

Results

The medial meniscus tear was detected in 40 (40 %) patients. However, no lateral meniscus tear was found. Significant relationships were found between the diameters of the posterior medial femoral condyle and the medial tibial superior articular surface and between the diameters of the posterior lateral femoral condyle and the lateral tibial superior articular surface. The mean values for the diameter of the medial condyle of the femur, the lateral condyle of the femur, the medial superior articular surface of the tibia, and the lateral superior articular surface of the tibia were found to be significantly higher in cases with meniscus tear compared to cases without meniscus tear. However, no significant difference was present regarding the thicknesses of the medial and the lateral menisci. A positive relationship between the diameter of the posterior medial femoral condyle and the tibial medial superior articular surface was found in cases with (n = 40) (r ² = 0.208, p = 0.003) and without tear (n = 60) (r ² = 0.182, p = 0.001). In addition, a significant positive relationship was found between the diameter of the posterior medial femoral condyle and the medial tibial superior articular surface in cases with and without tear.

Conclusion

The impact of femorotibial incongruence on the medial meniscus tear is important for the understanding of the lesions.     

FIH-1 Disrupts an LRRK1/EGFR Complex to Positively Regulate Keratinocyte Migration

Factor inhibiting hypoxia-inducible factor 1 (FIH-1; official symbol HIF1AN) is a hydroxylase that negatively regulates hypoxia-inducible factor 1α but also targets other ankyrin repeat domain–containing proteins such as Notch receptor to limit epithelial differentiation. We show that FIH-1 null mutant mice exhibit delayed wound healing. Importantly, in vitro scratch wound assays demonstrate that the positive role of FIH-1 in migration is independent of Notch signaling, suggesting that this hydroxylase targets another ankyrin repeat domain–containing protein to positively regulate motogenic signaling pathways. Accordingly, FIH-1 increases epidermal growth factor receptor (EGFR) signaling, which in turn enhances keratinocyte migration via mitogen-activated protein kinase pathway, leading to extracellular signal–regulated kinase 1/2 activation. Our studies identify leucine-rich repeat kinase 1 (LRRK1), a key regulator of the EGFR endosomal trafficking and signaling, as an FIH-1 binding partner. Such an interaction prevents the formation of an EGFR/LRRK1 complex, necessary for proper EGFR turnover. The identification of LRRK1 as a novel target for FIH-1 provides new insight into how FIH-1 functions as a positive regulator of epithelial migration.CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.The asparaginyl hydroxylase factor-inhibiting hypoxia-inducible factor 1α (FIH-1; official symbol HIF1AN) was originally identified as a protein that interacts with and inhibits the activity of hypoxia-inducible factor 1α (HIF-1α) in the C-terminal transactivation domain^1,2 by coupling the oxidative decarboxylation of 2-oxoglutarate to the hydroxylation of HIF-1α.³ Significantly, proteins containing the ankyrin repeat domain, such as Notch, are other substrates for FIH-1.³ Only recently has FIH-1 been recognized to have pleiotropic roles in maintaining epithelial homeostasis.^4,5 For example, FIH-1 negatively regulates glycogen metabolism in corneal epithelium in a HIF-1α–independent manner via the direct involvement of the Akt/glycogen synthase kinase 3β signaling pathway.⁴ Furthermore, in epidermal and corneal epithelial keratinocytes, FIH-1 was shown to act as a negative regulator of differentiation via a coordinate decrease in Notch signaling.⁵ What is not clear in these studies is whether FIH-1 affects other signaling pathways known to influence keratinocyte growth, differentiation, and migration. For example, the regulation of Notch 1 activity by FIH-1⁵ raises the possibility of cross-talk with the epidermal growth factor receptor (EGFR)-signaling pathway, since EGFR signaling has been shown to be a negative regulator of Notch 1 gene expression and activity in keratinocytes.⁶Once EGF binds to the EGFR, numerous signaling pathways are activated that impact on cell proliferation, migration, differentiation, and survival.^7–9 With respect to the skin, EGFR impacts on epidermal and hair follicle development, keratinocyte proliferation, survival, cancer, and immune homeostasis.¹⁰ EGFR signaling also plays a prominent role in epidermal and corneal epithelial migration and wound repair. For example, in the epidermis, EGFR signaling has been shown to promote keratinocyte migration and wound repair.¹¹ Likewise, corneal perturbations activate the EGFR and downstream Ras-Raf-Mek-Erk1/2 (Ras, Raf, mitogen-activated protein kinase kinase, extracellular signal–regulated kinase 1/2) and phosphoinositide 3 kinase–Akt signaling cascades, which are required for efficient wound healing and are attenuated in patients with diabetic keratopathies.^12–14The activation of EGFR also commences endocytic trafficking, whereby the receptor is either packaged in lysosomes for degradation or recycled to the cell surface.^15,16 Endosomal trafficking is essential for establishing the extensiveness of the EGF-mediated signal, and thus much attention has been directed toward understanding the steps involved in the movement of the EGFR from the cell surface to cytoplasmic vesicles, such as the endosome, multivesicular body, and lysosome.^16–18 Recently, leucine-rich repeat kinase 1 (LRRK1) was recognized as a key regulator of EGFR endosomal trafficking.^19,20 Specifically, it is believed that LRRK1 forms a complex with activated EGFR through an interaction with growth factor receptor–bound protein 2 and that this complex is internalized in early endosomes.¹⁹ The mechanism by which LRRK1 regulates EGFR transport is from early to late endosomes.¹⁹LRRK1 protein kinase is one of the ROCO proteins, which contain a GTPase-like domain [Ras of complex proteins (Roc)] and a C-terminal of Roc (COR) domain.²¹ ROCO proteins have a series of leucine-rich repeats and/or ankyrin repeats, with LRRK1 containing six N-terminal ankyrin repeats.²² This latter aspect of LRRK1 is noteworthy since, as mentioned above, proteins with ankyrin repeat domains are potential substrates for FIH-1.³ Thus, FIH-1 has the potential to directly interact with LRRK1, which could impact on EGFR signaling.Here we show that ectopic expression of FIH-1 in keratinocytes increases phosphorylation of the EGFR, which positively affects keratinocyte migration via stimulation of the mitogen-activated protein kinase pathway, resulting in an increase in phosphorylated ERK1/2. Such enhanced migration is independent of Notch signaling. Moreover, our studies reveal that FIH-1 interacts with LRRK1 and prevents the formation of an EGFR/LRRK1 complex necessary for proper EGFR turnover.¹⁹ The identification of LRRK1 as a substrate for FIH-1 provides new insight into how FIH-1 functions as a positive regulator of epithelial migration. Thus, the breadth of FIH-1 epithelial biology is considerably larger than previously realized.     

The effect of healing phenotype-inducing cytokine formulations within soft hydrogels on encapsulated monocytes and incoming immune cells

The adverse immune responses to implantable biomedical devices is a general problem with important consequences for the functionality of implants. Immunomodulatory soft hydrogel-based interfaces between the implant and the host can attenuate these reactions. Moreover, encapsulation of the patient''s own immune cells into these interfaces can lead to the personalisation of implants from the immune reaction point of view. Herein, we described a co-crosslinkable composite hydrogel (composed of gelatin and hyaluronic acid), which could be used for the encapsulation of macrophages in the presence of an anti-inflammatory phenotype-fixing cytokine cocktail. To mimick the incoming immune cells on the coating surface in vivo, peripheral blood mononuclear cells were seeded on the hydrogels. The encapsulation of monocytic cells into the composite hydrogels in the presence of cytokine cocktails at 5× or 10× concentrations led to the spreading of the encapsulated cells instead of the formation of clusters. Moreover, the secretion of the anti-inflammatory cytokines IL-1RA and CCL-18 was significantly increased. The attachment of PBMC to the surface of the hydrogel is dependent on the hydrogel composition and also significantly increased in the presence of the cytokine cocktail together with the number of CD68+ cells on the hydrogel surface. Our study demonstrates that the delivery of a polarisation cocktail with biocompatible hydrogels can control the initial response by the incoming immune cells. This effect can be improved by the encapsulation of autologous monocytes that are also polarised by the cytokine cocktail and secrete additional anti-inflammatory cytokines. This interface can fine tune the initial immune response to an implanted biomaterial in a personalised manner.

Hydrogels made from the derivatives of gelatin and hyaluronic acid were used as coatings to control the immune responses.     

Melanotic neuroectodermal tumor of infancy: a histopathological and immunohistochemical study

Melanotic neuroectodermal tumor of infancy is an uncommon neoplasm that normally occurs in the anterior maxilla of children less than 1 year of age. This is a tumor with controversial origin, although neural crest origin is proposed. This case report presents an analysis of histopathological and immunohistochemical findings in this rare tumor.     

Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice

STAT5 proteins are constitutively activated in malignant cells from many patients with leukemia, including the myeloproliferative neoplasms (MPNs) chronic myeloid leukemia (CML) and polycythemia vera (PV), but whether STAT5 is essential for the pathogenesis of these diseases is not known. In the present study, we used mice with a conditional null mutation in the Stat5a/b gene locus to determine the requirement for STAT5 in MPNs induced by BCR-ABL1 and JAK2(V617F) in retroviral transplantation models of CML and PV. Loss of one Stat5a/b allele resulted in a decrease in BCR-ABL1-induced CML-like MPN and the appearance of B-cell acute lymphoblastic leukemia, whereas complete deletion of Stat5a/b prevented the development of leukemia in primary recipients. However, BCR-ABL1 was expressed and active in Stat5-null leukemic stem cells, and Stat5 deletion did not prevent progression to lymphoid blast crisis or abolish established B-cell acute lymphoblastic leukemia. JAK2(V617F) failed to induce polycythemia in recipients after deletion of Stat5a/b, although the loss of STAT5 did not prevent the development of myelofibrosis. These results demonstrate that STAT5a/b is essential for the induction of CML-like leukemia by BCR-ABL1 and of polycythemia by JAK2(V617F), and validate STAT5a/b and the genes they regulate as targets for therapy in these MPNs.     

Spontaneous Pneumothorax in Children with Osteosarcoma: Report of Three Cases and Review of the Literature

Spontaneous pneumothorax is a rare manifestation of primary lung cancer or metastasis. It is estimated that < 1% of all cases of spontaneous pneumothorax are tumor-associated and metastatic osteogenic or soft-tissue sarcomas are associated most commonly with pneumothorax especially in the setting of cytotoxic chemotherapy or radiotherapy. In this article, we report three pediatric cases with osteosarcoma that developed spontaneous pneumothorax during chemotherapy with a review of the literature. Two of them had lung metastasis at the time of the detection of pneumothorax and the remaining patient was found to have a bronchopleural fistula.

SPx is an emergency situation and early diagnosis and management can improve prognosis and quality of life of the patient however the optimal management has yet to be determined.     

Gingival crevicular fluid and serum levels of APRIL,BAFF and TNF-alpha in rheumatoid arthritis and osteoporosis patients with periodontal disease

Background

This study was performed to evaluate gingival crevicular fluid (GCF) and serum levels of a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF) and compare this to differences between TNF-alpha levels in rheumatoid arthritis (RA), osteoporosis (OPR) and systemically healthy women with periodontal disease (SH).

Design

Gingival crevicular fluid (GCF) and serum samples were obtained before any periodontal intervention from 17 RA, 19 OPR patients and 13 SH women with periodontitis. Full-mouth clinical periodontal measurements were recorded. APRIL, BAFF and TNF-α levels were determined by ELISA. Statistical analysis was performed using multivariate analysis, ANOVA and Spearman correlation.

Results

Pocket depths differed in site-specific comparisons, but otherwise clinical measurements were similar in the three study groups. Multivariate least squares regression ANOVA adjusted for age and for plaque index indicated that total amounts of TNF-α and concentrations of TNF-α, BAFF and APRIL were significantly greater in the RA patients than in the SH group (p < 0.05), and GCF concentrations of BAFF were greater in OPR patients than in SH. Serum TNF-α and BAFF were significantly higher in the RA group compared to SH (p < 0.05) and serum TNF-α was greater in RA than in OPR (p < 0.05). APRIL and BAFF correlated with RANKL levels in GCF and serum (p < 0.05).

Conclusion

Despite long-term usage of anti-inflammatory drugs in the RA and OPR patients, increased TNF-family cytokines, might suggest that these patients have a propensity to overproduce these inflammatory mediators but whether this results from greater disease activity or contribute to greater disease activity remains moot.     

Gingival Crevicular Fluid,Serum Levels of Receptor Activator of Nuclear Factor‐κB Ligand,Osteoprotegerin, and Interleukin‐17 in Patients With Rheumatoid Arthritis and Osteoporosis and With Periodontal Disease

Background: This study is performed to evaluate gingival crevicular fluid (GCF) and serum levels of soluble receptor activator of nuclear factor‐κB ligand (sRANKL), interleukin (IL)‐17A, IL‐17E, IL‐17F, IL‐17A/F, and osteoprotegerin (OPG) in women with rheumatoid arthritis (RA), osteoporosis (OPR), and those who are systemically healthy (SH), all with periodontal disease. Methods: GCF and serum samples were obtained before any periodontal intervention from 17 women with RA, 19 with OPR, and 13 who were SH with periodontitis. Full‐mouth clinical periodontal measurements were recorded. sRANKL, OPG, and IL‐17 levels were determined by enzyme‐linked immunosorbent assay. Results: Clinical periodontal measurements were similar in the three study groups. Although the total amounts of GCF albumin, OPG, IL‐17A, and IL‐17A/F were similar in the study groups, there were statistically significant differences in GCF concentrations of sRANKL, OPG, IL‐17A, IL‐17E, IL‐17F, and IL‐17A/F. The sRANKL/OPG ratios were significantly higher in the RA group than in the OPR and SH groups (P <0.05). Serum sRANKL, sRANKL/OPG, and IL‐17A/IL‐17E ratios were significantly higher, whereas OPG concentrations were significantly lower in the RA group compared to other groups (P <0.05). Serum IL‐17A concentrations were significantly higher in the RA and OPR groups than in the SH group (P <0.05). Conclusion: Increased inflammatory mediator levels in patients with RA, despite the long‐term use of various anti‐inflammatory drugs, suggest that these patients may have a propensity to overproduce these inflammatory mediators.