Hair follicle development is initiated by reciprocal molecular interactions between the placode-forming epithelium and the underlying mesenchyme. Cell fate transformation in dermal fibroblasts generates a cell niche for placode induction by activation of signaling pathways WNT, EDA, and FGF in the epithelium. These successive paracrine epithelial signals initiate dermal condensation in the underlying mesenchyme. Although epithelial signaling from the placode to mesenchyme is better described, little is known about primary mesenchymal signals resulting in placode induction. Using genetic approach in mice, we show that Meis2 expression in cells derived from the neural crest is critical for whisker formation and also for branching of trigeminal nerves. While whisker formation is independent of the trigeminal sensory innervation, MEIS2 in mesenchymal dermal cells orchestrates the initial steps of epithelial placode formation and subsequent dermal condensation. MEIS2 regulates the expression of transcription factor Foxd1, which is typical of pre-dermal condensation. However, deletion of Foxd1 does not affect whisker development. Overall, our data suggest an early role of mesenchymal MEIS2 during whisker formation and provide evidence that whiskers can normally develop in the absence of sensory innervation or Foxd1 expression.

• MeSH
• Neural Crest MeSH
• Forkhead Transcription Factors metabolism   genetics   MeSH
• Homeodomain Proteins * metabolism   genetics   MeSH
• Mesoderm * metabolism   MeSH
• Mice MeSH
• Trigeminal Nerve * MeSH
• Vibrissae * innervation   growth & development   embryology   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Fibroblasts, the most abundant cell type in the human body, play crucial roles in biological processes such as inflammation and cancer progression. They originate from the mesoderm or neural-crest-derived ectomesenchyme. Ectomesenchyme-derived fibroblasts contribute to facial formation and do not express HOX genes during development. The expression and role of the HOX genes in adult fibroblasts is not known. We investigated whether the developmental pattern persists into adulthood and under pathological conditions, such as cancer. We collected adult fibroblasts of ectomesenchymal and mesodermal origins from distinct body parts. The isolated fibroblasts were characterised by immunocytochemistry, and their transcriptome was analysed by whole genome profiling. Significant differences were observed between normal fibroblasts from the face (ectomesenchyme) and upper limb (mesoderm), particularly in genes associated with limb development, including HOX genes, e.g., HOXA9 and HOXD9. Notably, the pattern of HOX gene expression remained consistent postnatally, even in fibroblasts from pathological tissues, including inflammatory states and cancer-associated fibroblasts from primary and metastatic tumours. Therefore, the distinctive HOX gene expression pattern can serve as an indicator of the topological origin of fibroblasts. The influence of cell position and HOX gene expression in fibroblasts on disease progression warrants further investigation.

• MeSH
• Adult MeSH
• Fibroblasts * metabolism   cytology   MeSH
• Genes, Homeobox MeSH
• Homeodomain Proteins metabolism   genetics   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Mesoderm * metabolism   cytology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Iliac crest is common site for harvesting bone grafts. Morphometry of iliac crest is of vital importance in orthopedic surgery. Measurements were done on male (n=85) and female (n=85) hip bones. Length of iliac crest, thickness of iliac crest and ilium were measured. Thickness was measured at pre-defined points on crest and ilium 2 cm apart starting from anterior superior iliac spine (ASIS). Ilium was measured at a depth of 2.5 cm from crest. Statistical analysis was done. Iliac crests were longer in male bones. Ventral iliac crest was thickest at 6 cm from ASIS in both sexes. While iliac crest bore minimum thickness at 12 cm and 10 cm from ASIS in male and female bones respectively, however at 2.5 cm below iliac crest surface ilium was thickest at 4 cm from ASIS and at ASIS in male and female bones respectively. In case of male bones, dorsal part of iliac crest was thickest at 2.15 ± 1.29 cm from posterior superior iliac spine (PSIS) while in females it was at 1.78 ± 1.31 cm from PSIS. In dorsal part of ilium, it was observed at 2.31 ± 1.47 cm and 1.9 ± 1.79 cm from PSIS for male and female bones respectively. This study provided detailed variable morphometry and significant sexual dimorphism observed in iliac crest and ilium. Thickest safe zones in both sexes are a useful guide for harvesting appropriate bone grafts.

• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Tissue and Organ Harvesting methods   MeSH
• Ilium * anatomy & histology   MeSH
• Aged MeSH
• Bone Transplantation * methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The medial approach for minimally invasive harvesting of a deep circumflex iliac artery (DCIA) flap is described for reconstruction of the jaw. The associated preservation of the crest of the ilium prevents the raising of the abdominal internal oblique muscle (IO) in a standard fashion. However, reconstructive surgery of composite mandibular defects includes bone and soft tissue. To achieve this goal, we combined this technique with a new perforator-based raising of the IO for reconstruction of intraoral soft tissue. METHODS: In this study, we present eight cases of patients with composite mandibular defects who underwent the myo-osseous DCIA flap procedure with an IO perforator. Virtual surgical planning was employed to preplan the size and configuration of the graft. Cutting guides were made using CAD/CAM technology. The surgical procedure followed the described medial approach for minimally invasive harvesting, leaving the iliac crest, spine, and skin intact. In addition, we completely cut and isolated the IO with its sole attachment being the ascending branch of the DCIA. We used either a surgical guide with a slot to lead through both the transverse branch of the bone and the ascending branch of the IO or a surgical guide consisting of 2 parts. RESULTS: In all instances, the flap successfully survived with a 100% success rate. There were no signs of infection, wound opening, or bleeding in either patient. Furthermore, the patients did not exhibit permanent complications related to the donor site. The internal oblique perforator flap exhibited remarkable integration in all patients and underwent rapid transformation. Notably, the flap developed keratinized mucosa (KM) that closely resembled the attached gingiva. CONCLUSION: Our study demonstrated the effectiveness of a medial approach for harvesting a newly designed more flexible chimeric myo-osseous deep circumflex iliac artery flap. By incorporating virtual surgical planning and custom-made cutting guides for obtaining deep circumflex iliac artery flaps through the medial route along with an internal oblique perforator flap, we have established a highly promising method for the rehabilitation of patients with composite mandibular defects. This approach not only improves functional outcomes, but also enhances aesthetic results to maintain patients' quality of life.

• MeSH
• Iliac Artery surgery   MeSH
• Surgical Flaps MeSH
• Computer-Aided Design MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Mandible surgery   MeSH
• Minimally Invasive Surgical Procedures methods   MeSH
• Ilium surgery   MeSH
• Aged MeSH
• Plastic Surgery Procedures * methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Neurofibromatosis type 2 (NF-2) is a dominantly inherited genetic disorder that results from variants in the tumor suppressor gene, neurofibromin 2 (NF2). Here, we report the generation of a conditional zebrafish model of neurofibromatosis established by inducible genetic knockout of nf2a/b, the zebrafish homologs of human NF2. Analysis of nf2a and nf2b expression revealed ubiquitous expression of nf2b in the early embryo, with overlapping expression in the neural crest and its derivatives and in the cranial mesenchyme. In contrast, nf2a displayed lower expression levels. Induction of nf2a/b knockout at early stages increased the proliferation of larval Schwann cells and meningeal fibroblasts. Subsequently, in adult zebrafish, nf2a/b knockout triggered the development of a spectrum of tumors, including vestibular Schwannomas, spinal Schwannomas, meningiomas and retinal hamartomas, mirroring the tumor manifestations observed in patients with NF-2. Collectively, these findings highlight the generation of a novel zebrafish model that mimics the complexities of the human NF-2 disorder. Consequently, this model holds significant potential for facilitating therapeutic screening and elucidating key driver genes implicated in NF-2 onset.

• MeSH
• Zebrafish * genetics   embryology   MeSH
• Animals, Genetically Modified MeSH
• Gene Knockout Techniques * MeSH
• Larva metabolism   MeSH
• Humans MeSH
• Disease Models, Animal * MeSH
• Neurofibromatosis 2 genetics   pathology   metabolism   MeSH
• Neurofibromatoses genetics   pathology   metabolism   MeSH
• Neurofibromin 2 * genetics   metabolism   deficiency   MeSH
• Cell Proliferation MeSH
• Zebrafish Proteins * genetics   metabolism   deficiency   MeSH
• Schwann Cells metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Adenosine deaminase acting on RNA 1 (ADAR1) is the principal enzyme for the adenosine-to-inosine RNA editing that prevents the aberrant activation of cytosolic nucleic acid sensors by endogenous double stranded RNAs and the activation of interferon-stimulated genes. In mice, the conditional neural crest deletion of Adar1 reduces the survival of melanocytes and alters the differentiation of Schwann cells that fail to myelinate nerve fibers in the peripheral nervous system. These myelination defects are partially rescued upon the concomitant removal of the Mda5 antiviral dsRNA sensor in vitro, suggesting implication of the Mda5/Mavs pathway and downstream effectors in the genesis of Adar1 mutant phenotypes. By analyzing RNA-Seq data from the sciatic nerves of mouse pups after conditional neural crest deletion of Adar1 (Adar1cKO), we here identified the transcription factors deregulated in Adar1cKO mutants compared to the controls. Through Adar1;Mavs and Adar1cKO;Egr1 double-mutant mouse rescue analyses, we then highlighted that the aberrant activation of the Mavs adapter protein and overexpression of the early growth response 1 (EGR1) transcription factor contribute to the Adar1 deletion associated defects in Schwann cell development in vivo. In silico and in vitro gene regulation studies additionally suggested that EGR1 might mediate this inhibitory effect through the aberrant regulation of EGR2-regulated myelin genes. We thus demonstrate the role of the Mda5/Mavs pathway, but also that of the Schwann cell transcription factors in Adar1-associated peripheral myelination defects.

• MeSH
• Adenosine Deaminase * genetics   metabolism   MeSH
• Cell Differentiation * genetics   MeSH
• Neural Crest * metabolism   MeSH
• Interferon-Induced Helicase, IFIH1 genetics   metabolism   MeSH
• Myelin Sheath metabolism   MeSH
• Mice, Knockout * MeSH
• Mice MeSH
• Schwann Cells * metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Large femoral defects after trauma, femoral non-unions, fractures complicated by osteomyelitis or defects after bone tumour resection present high burden and increased morbidity for patient and are challenging for reconstructive surgeons. Defects larger than 6 cm and smaller defects after failed spongioplasty are suitable for reconstruction using a free, eventually a pedicled vascularised bone flap. The free fibular flap is preferred but an iliac crest free flap or a pedicled medial femoral condyle flap can be also used. These vascularised flaps are ideal for bridging defects of long bones and can be also used as osteocutaneous or osteomuscular flaps for coverage of soft tissue defect if present. The patients and their families were informed that data will be submitted for publication and they gave their written informed consent prior to the submission. The study was approved by the institutional ethic committee. METHODS: We analysed a group of eight patients with large diaphyseal or distal metaphyseal femoral defects. A free fibular flap was used in six patients, a pedicled medial ipsilateral femoral condyle flap was used in two patients and a defect in one patient was reconstructed using an iliac crest free flap. RESULTS: All flaps healed completely in all patients and no fracture of the flap was detected during the study period. In one patient, a locking plate broke and was replaced by a compression plate. At the last check-up all patients were able to step on the reconstructed limb with full weight. DISCUSSION: Although our study comprises a heterogeneous group of cases, they all have been successfully treated by a similar technique, adapted in each case specifically to the needs of the patient. A major limitation parameter of reconstruction by a free vascularised flap is the size of bone defect needed to be reconstructed. In case of a bone defect longer than 6 cm and a concomitant soft tissue disruption, a vascularised double-barrel fibula is the preferred. CONCLUSION: Large femoral defects can be successfully reconstructed with good long-term results using suitable free or pedicled vascularised bone flaps, especially preferring the free fibular flap.

• MeSH
• Surgical Flaps * MeSH
• Adult MeSH
• Femur * surgery   transplantation   MeSH
• Fibula transplantation   surgery   injuries   MeSH
• Femoral Fractures surgery   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Bone Transplantation * methods   MeSH
• Free Tissue Flaps transplantation   MeSH
• Treatment Outcome MeSH
• Plastic Surgery Procedures * methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Carotid stenting requires dual antiplatelet therapy to effectively prevent thromboembolic complications. However, resistance to clopidogrel, a key component of this therapy, may lead to persistent risk of these complications. The aim of this study was to determine, if the implementation of routine platelet function testing and adjusting therapy was associated with lower incidence of thromboembolic complications and death. METHODS: All consecutive patients treated with carotid artery stenting in a single institution over 8 years were enlisted in a retrospective study. Platelet function testing was performed, and efficient antiplatelet therapy was set before the procedure. Incidence of procedure-related stroke or death within periprocedural period (0-30 days) was assessed. The results were evaluated in relation to the findings of six prominent randomized control trials. RESULTS: A total of 241 patients were treated for carotid stenosis, seven patients undergo CAS on both sides over time. There was 138 symptomatic (55,6%) and 110 asymptomatic stenoses (44,4%). Five thromboembolic complications (2,01%) occurred, four of them (1,61%) was procedure-related. Two patients died because of procedure-related stroke (0,82%). Incidence of procedure-related stroke or death was significant lower compared to the results of CREST study (2,01% vs. 4,81%, P = 0,0243) in the entire cohorts, and to the results of ICSS study in the symptomatic cohorts (2,86% vs. 7,37%, P = 0,0243), respectively. CONCLUSIONS: Tailored antiplatelet therapy in carotid stenting is safe and seems to be related with lower incidence of procedure-related death or stroke rate. Larger prospective studies to assess whether platelet function testing-guided antiplatelet therapy is superior to standard dual antiplatelet should be considered.

• Publication type
• Journal Article MeSH