An Organoid for Woven Bone

Bone formation (osteogenesis) is a complex process in which cellular differentiation and the generation of a mineralized organic matrix are synchronized to produce a hybrid hierarchical architecture. To study the mechanisms of osteogenesis in health and disease, there is a great need for functional model systems that capture in parallel, both cellular and matrix formation processes. Stem cell‐based organoids are promising as functional, self‐organizing 3D in vitro models for studying the physiology and pathology of various tissues. However, for human bone, no such functional model system is yet available. This study reports the in vitro differentiation of human bone marrow stromal cells into a functional 3D self‐organizing co‐culture of osteoblasts and osteocytes, creating an organoid for early stage bone (woven bone) formation. It demonstrates the formation of an organoid where osteocytes are embedded within the collagen matrix that is produced by the osteoblasts and mineralized under biological control. Alike in in vivo osteocytes, the embedded osteocytes show network formation and communication via expression of sclerostin. The current system forms the most complete 3D living in vitro model system to investigate osteogenesis, both in physiological and pathological situations, as well as under the influence of external triggers (mechanical stimulation, drug administration)

The Bilateral Pedicled Epilated Scrotal Flap: A Powerful Adjunctive for Creation of More Neovaginal Depth in Penile Inversion Vaginoplasty

Background: Penile inversion vaginoplasty is a commonly performed genital gender-affirming procedure in transgender women. The creation of an adequate functional neovaginal depth in cases of too little usable penile skin is a challenge. The bilateral pedicled epilated scrotal flap (BPES-flap) can be used as an easy adjunctive technique and may serve as a tool in the surgical armamentarium of the gender surgeon. Aim: To describe the use, dissection, design subtypes, and surgical outcomes of the BPES-flap in vaginoplasty. Methods: Perioperative considerations and different flap design subtypes were described to illustrate the possible uses of the BPES-flap in vaginoplasty. A retrospective chart study was performed on the use of this flap in 3 centers (blinded for review purposes). Outcomes: The main outcome measures are description of surgical technique, flap design possibilities, and postoperative complications. Results: A total of 42 transgender women were included (median age: 28 years (range 18–66), mean body mass index: 24.5 ± 3.5). The mean penile length and width preoperatively were 9 ± 3.1 and 2.9 ± 0.2 cm, respectively. With a mean follow up of 13 ± 10 months, total flap necrosis occurred in one case (2.4%). Partial flap necrosis occurred also in one. Neovaginal reconstruction was successful in all patients with a mean vaginal depth of 13.5 ± 1.3 cm and width of 3.3 ± 1.3 cm. Partial prolapse of the neovaginal top occurred in 3 patients (7%). Clinical Implications: The BPES-flap is a useful addition to the arsenal of surgeons performing feminizing genital reconstructive surgery. Strengths & Limitations: Strenghts comprise (1) the description of the surgical technique with clear images, (2) completeness of data, and (3) that data are from a multicenter study. A weakness is the retrospective nature with limited follow-up time. Conclusion: The BPES-flap is a vascularized scrotal flap that can be raised on the bilateral inferior superficial perineal arteries. It may be used for neovaginal depth creation during vaginoplasty and may be quicker to perform than full-thickness skin grafting. Nijhuis THJ, Özer M, van der Sluis WB, et al. The Bilateral Pedicled Epilated Scrotal Flap: A Powerful Adjunctive for Creation of More Neovaginal Depth in Penile Inversion Vaginoplasty. J Sex Med 2020;17:1033–1040

Multiscale characterization of pathological bone tissue

Bone is a complex natural material with a complex hierarchical multiscale organization, crucial to perform its functions. Ultrastructural analysis of bone is crucial for our understanding of cell to cell communication, the healthy or pathological composition of bone tissue, and its three-dimensional (3D) organization. A variety of techniques has been used to analyze bone tissue. This article describes a combined approach of optical, scanning electron, and transmission electron microscopy for the ultrastructural analysis of bone from the nanoscale to the macroscale, as illustrated by two pathological bone tissues. By following a top-down approach to investigate the multiscale organization of pathological bones, quantitative estimates were made in terms of calcium content, nearest neighbor distances of osteocytes, canaliculi diameter, ordering, and D-spacing of the collagen fibrils, and the orientation of intrafibrillar minerals which enable us to observe the fine structural details. We identify and discuss a series of two-dimensional (2D) and 3D imaging techniques that can be used to characterize bone tissue. By doing so we demonstrate that, while 2D imaging techniques provide comparable information from pathological bone tissues, significantly different structural details are observed upon analyzing the pathological bone tissues in 3D. Finally, particular attention is paid to sample preparation for and quantitative processing of data from electron microscopic analysis.Biomaterials & Tissue Biomechanic

Loss of intestinal sympathetic innervation elicits an innate immune driven colitis

Abstract Background Both the parasympathetic and sympathetic nervous system exert control over innate immune responses. In inflammatory bowel disease, sympathetic innervation in intestinal mucosa is reduced. Our aim was to investigate the role of sympathetic innervation to the intestine on regulation of the innate immune responses. Methods In lipopolysaccharide (LPS)-stimulated macrophages, we evaluated the effect of adrenergic receptor activation on cytokine production and metabolic profile. In vivo, the effect of sympathetic denervation on mucosal innate immune responses using 6-hydroxydopamine (6-OHDA), or using surgical transection of the superior mesenteric nerve (sympathectomy) was tested in Rag1−/− mice that lack T- and B-lymphocytes. Results In murine macrophages, adrenergic β2 receptor activation elicited a dose-dependent reduction of LPS-induced cytokines, reduced LPS-induced glycolysis and increased maximum respiration. Sympathectomy led to a significantly decreased norepinephrine concentration in intestinal tissue. Within 14 days after sympathectomy, mice developed clinical signs of colitis, colon oedema and excess colonic cytokine production. Both 6-OHDA and sympathectomy led to prominent goblet cell depletion and histological damage of colonic mucosa. Conclusions We conclude that the sympathetic nervous system plays a regulatory role in constraining innate immune cell reactivity towards microbial challenges, likely via the adrenergic β2 receptor

Motor sequence learning in children with spina bifida

Item does not contain fulltextCognitive and motor problems are common in children with spina bifida (SB), particularly in those children with cerebral malformations (SBM). Little is known about how these conditions affect motor learning. This study examines motor sequence learning in children with SB, SBM, and healthy controls. Assessment consisted of neuropsychological tests, a simple drawing task, and a spatial motor sequence learning task. Implicit motor learning was unaffected in children with SB( M), and their sequence learning ability was also similar to that of controls. However, both groups (SB and SBM) showed impaired motor performance. The role of cerebellar malformation with SB(M) is discussed.16 p

Neural reflex pathways in intestinal inflammation: hypotheses to viable therapy

Studies in neuroscience and immunology have clarified much of the anatomical and cellular basis for bidirectional interactions between the nervous and immune systems. As with other organs, intestinal immune responses and the development of immunity seems to be modulated by neural reflexes. Sympathetic immune modulation and reflexes are well described, and in the past decade the parasympathetic efferent vagus nerve has been added to this immune-regulation network. This system, designated 'the inflammatory reflex', comprises an afferent arm that senses inflammation and an efferent arm that inhibits innate immune responses. Intervention in this system as an innovative principle is currently being tested in pioneering trials of vagus nerve stimulation using implantable devices to treat IBD. Patients benefit from this treatment, but some of the working mechanisms remain to be established, for instance, treatment is effective despite the vagus nerve not always directly innervating the inflamed tissue. In this Review, we will focus on the direct neuronal regulatory mechanisms of immunity in the intestine, taking into account current advances regarding the innervation of the spleen and lymphoid organs, with a focus on the potential for treatment in IBD and other gastrointestinal pathologies