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Positively charged oligo(poly(ethylene glycol) fumarate) (OPF+) hydrogel scaffolds, implanted into a complete transection spinal cord injury (SCI), facilitate a permissive regenerative environment and provide a platform for controlled observation of repair mechanisms. Axonal regeneration after SCI is critically dependent upon nutrients and oxygen from a newly formed blood supply. Our objective was to investigate fundamental characteristics of revascularization in association with the ingrowth of axons into hydrogel scaffolds, thereby defining spatial relationships between axons and the neovasculature. A novel combination of stereologic estimates and precision image analysis techniques quantitate neurovascular regeneration in rats. Multichannel hydrogel scaffolds containing Matrigel-only (MG), Schwann cells (SCs), or SCs with rapamycin-eluting poly(lactic co-glycolic acid) microspheres (RAPA) were implanted for 6 weeks following complete spinal cord transection. Image analysis of 72 scaffold channels identified a total of 2494 myelinated and 4173 unmyelinated axons at 10 μm circumferential intervals centered around 708 individual blood vessel profiles. Blood vessel number, density, volume, diameter, intervessel distances, total vessel surface and cross-sectional areas, and radial diffusion distances were compared. Axon number and density, blood vessel surface area, and vessel cross-sectional areas in the SC group exceeded that in the MG and RAPA groups. Individual axons were concentrated within a concentric radius of 200–250 μm from blood vessel walls, in Gaussian distributions, which identified a peak axonal number (Mean Peak Amplitude) corresponding to defined distances (Mean Peak Distance) from each vessel, the highest concentrations of axons were relatively excluded from a 25–30 μm zone immediately adjacent to the vessel, and from vessel distances >150 μm. Higher axonal densities correlated with smaller vessel cross-sectional areas. A statistical spatial algorithm was used to generate cumulative distribution F- and G-functions of axonal distribution in the reference channel space. Axons located around blood vessels were definitively organized as clusters and were not randomly distributed. A scoring system stratifies 5 direct measurements and 12 derivative parameters influencing regeneration outcomes. By providing methods to quantify the axonal-vessel relationships, these results may refine spinal cord tissue engineering strategies to optimize the regeneration of complete neurovascular bundles in their relevant spatial relationships after SCI. IMPACT STATEMENT: Vascular disruption and impaired neovascularization contribute critically to the poor regenerative capacity of the spinal cord after injury. In this study, hydrogel scaffolds provide a detailed model system to investigate the regeneration of spinal cord axons as they directly associate with individual blood vessels, using novel methods to define their spatial relationships and the physiologic implications of that organization. These results refine future tissue engineering strategies for spinal cord repair to optimize the re-development of complete neurovascular bundles in their relevant spatial architectures.

Animal study. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have recently been shown to hold great therapeutic potential for spinal cord injury (SCI). However, majority of the studies have been done using human cells transplanted into the rat with immunosuppression; this may not represent the outcomes that occur in humans. Herein, we present the therapeutic effect of using rat UC-MSCs (rUC-MSC) without immunosuppression in a rat model of SCI. Mayo Clinic, Rochester, MN, USA. Twelve female rats were randomly divided into two groups, control, and rUC-MSC group, and then subjected to a T9 moderate contusion SCI. Next, 2 × 106 rUC-MSCs or ringer-lactate solution were injected through the tail vein at 7 days post injury. Rats were assessed for 14 weeks by an open-field Basso, Beattie, and Bresnahan (BBB) motor score as well as postmortem quantification of axonal sparing/regeneration, cavity volume, and glial scar. Animals treated with rUC-MSCs were found to have early and sustained motor improvement (BBB score of 14.6 ± 1.9 compared to 10.1 ± 1.7 in the control group) at 14 weeks post injury (mean difference: 4.55, 95% CI: 2.04 to 7.06; p value

Background Congenital heart disease (CHD) is common in patients with Down's syndrome (DS), rendering them at risk of significant mortality and morbidity. However, all patients with confirmed DS must undergo further investigation for a cardiac anomaly early in their lives. Objective To define frequency and patterns of CHD among children with DS in Northwest, Saudi Arabia (SA). Methods A five-year chart review study was conducted in Northwest SA between January 2015 and June 2019. We included all children referred to the pediatric cardiology clinic with a confirmed diagnosis of DS and CHD. Children were identified in the clinic's database, and charts were reviewed retrospectively. Results Among 851 patients with CHD, 53 were identified with DS. Male patients represented 62.3%, while female patients represented 37.7%. The median patients' age at the time of diagnosis was two days, with most patients diagnosed before 28 days old (67.9%). This study found that atrial septal defect (ASD) and patent ductus arteriosus (PDA) were the most common isolated lesions (37% of isolated cases), while the most common combined lesions were ASD, ventricular septal defect (VSD), and PDA, as well as combined ASD and VSD. Female gender was significantly associated with higher percentage of VSD (p = 0.031) more than male. While male patients had significantly higher percentages of ASD and valvular anomalies than female patients (p = 0.019 and 0.033, respectively). Conclusions The patient's gender was significantly associated with some types of CHD. Both ASD and valvular lesions were more common among males, while VSD was more common among female patients, no gender differences were detected regarding the other types of CHD.

Evidence from preclinical and clinical research suggest that neuromodulation technologies can facilitate the sublesional spinal networks, isolated from supraspinal commands after spinal cord injury (SCI), by reestablishing the levels of excitability and enabling descending motor signals via residual connections. Herein, we evaluate available evidence that sublesional and supralesional spinal circuits could form a translesional spinal network after SCI. We further discuss evidence of translesional network reorganization after SCI in the presence of sensory inputs during motor training. In this review, we evaluate potential mechanisms that underlie translesional circuitry reorganization during neuromodulation and rehabilitation in order to enable motor functions after SCI. We discuss the potential of neuromodulation technologies to engage various components that comprise the translesional network, their functional recovery after SCI, and the implications of the concept of translesional network in development of future neuromodulation, rehabilitation, and neuroprosthetics technologies.

An understanding of spinal cord functional neuroanatomy is essential for diagnosis and treatment of multiple disorders including, chronic pain, movement disorders, and spinal cord injury. Till now, no information is available on segment-specific spinal roots orientation in humans. In this study we collected neuroanatomical measurements of the dorsal and ventral roots from C2-L5, as well as spinal cord and vertebral bone measurements from adult cadavers. Spatial orientation of dorsal and ventral roots were measured and correlated to the anatomical landmarks of the spinal cord and vertebral column. The results show less variability in rostral root angles compared to the caudal angles across all segments. Dorsal and ventral rootlets were oriented mostly perpendicular to the spinal cord at the cervical level and demonstrate more parallel orientation at the thoracic and lumbar segments. The number of rootlets was the highest in dorsal cervical and lumbar segments. Spinal cord transverse diameter and size of the dorsal columns were largest at cervical and lumbar segments. The strongest correlation was found between the length of intervertebral foramen to rostral rootlet and vertebral bone length. These results could be used to locate spinal roots and spinal cord landmarks based on bone marks on CT or X-rays. These results also provide background for future correlations between anatomy of spinal cord and spinal column structures that could improve stereotactic surgical procedures and electrode positioning for spinal cord neuromodulation.One Sentence SummaryThis is the first detailed analysis of the segment-specific dorsal and ventral spinal roots spatial orientation measured and correlated to the anatomical landmarks of the spinal cord and vertebral column for human.

Adaptive immunity is critical for controlling infections, which are a leading cause of morbidity and mortality in patients with spinal cord injury (SCI). In rats and mice, compromised peripheral adaptive immune responses, as shown by splenic atrophy and lowered frequencies of peripheral lymphocytes, were shown to result from high-level thoracic SCI. However, whether cervical SCI, which is the most common level of SCI in humans, impairs adaptive immunity remains largely unknown. In the present study, we induced cervical SCI in rats at the C7/T1 level by clip compression and looked at changes in peripheral adaptive immunity at 2-, 10- and 20-weeks post-injury. Specifically, we quantified changes in the frequencies of T- and B- lymphocytes in the blood and the mandibular and deep cervical lymph nodes, which drain the cervical spinal cord. We also assessed changes in serum IgG and IgM immunoglobulin levels, as well as spleen size. We found a significant decline in circulating T- and B- cell frequencies at 10 weeks post-SCI, which returned to normal at 20 weeks after injury. We found no effect of cervical SCI on T- and B- cell frequencies in the draining lymph nodes. Moreover, cervical SCI had no effect on net spleen size, although injured rats had a higher spleen/body weight ratio than sham controls at all time points of the study. Lastly, IgG and IgM immunoglobulin declined at 2 weeks, followed by a significant increase in IgM levels at 10 weeks of injury. These data indicate that cervical SCI causes a significant imbalance in circulating lymphocytes and immunoglobulin levels at 2 and 10 weeks. As we discuss in this article, these findings are largely in line with clinical observations, and we anticipate that this study will fuel more research on the effect of adaptive immunity on SCI recovery.

Positively charged oligo-polyethylene glycol fumarate (OPF+) hydrogel scaffolds, implanted into a complete transection spinal cord injury (SCI), facilitate a permissive regenerative environment and provide a platform for controlled observation of repair mechanisms. Axonal regeneration after SCI is critically dependent upon the availability of nutrients and oxygen from a newly formed blood supply. In this study, the objective was to investigate fundamental characteristics of revascularization in association with the ingrowth of axons into hydrogel scaffolds, and to define the spatial relationships between axons and the neovasculature. A novel combination of stereologic estimates and precision image analysis techniques are described to quantitate neurovascular regeneration in rats. Multichannel hydrogel scaffolds containing Matrigel-only (MG), Schwann cells (SCs), or SCs with rapamycin-eluting poly(lactic co-glycolic acid) (PLGA) microspheres (RAPA) were implanted for 6 weeks following complete spinal cord transection. Image analysis of 72 scaffold channels identified a total of 2,494 myelinated and 4,173 unmyelinated axons at 10 micron circumferential intervals centered around 708 individual blood vessel profiles. Blood vessel number, density, volume, diameter, inter-vessel distances, total vessel surface and cross-sectional areas, and radial diffusion distances in each group were measured. Axon number and density, blood vessel surface area, and vessel cross-sectional areas in the SC group exceeded that in the MG and RAPA groups. Axons were concentrated within a concentric radius of 200-250 microns from the blood vessel wall in Gaussian distributions which identified a peak axonal number (mean peak amplitude) corresponding to defined distances (mean peak distance) from each vessel. Axons were largely excluded from a 25 micron zone immediately adjacent to the vessel. Higher axonal densities correlated with smaller vessel cross-sectional areas. A statistical spatial algorithm was used to generate cumulative distribution F- and G-functions of axonal distribution in the reference channel space. Axons located around blood vessels were definitively organized as clusters and were not randomly distributed. By providing methods to quantify the axonal-vessel relationships, these results may refine spinal cord tissue engineering strategies to optimize the regeneration of complete neurovascular bundles in their relevant spatial relationships after SCI.Impact StatementVascular disruption and impaired neovascularization contribute critically to the poor regenerative capacity of the spinal cord after injury. In this study, hydrogel scaffolds provide a detailed model system to investigate the regeneration of spinal cord axons as they directly associate with individual blood vessels, using novel methods to define their spatial relationships and the physiologic implications of that organization. These results refine future tissue-engineering strategies for spinal cord repair to optimize the re-development of complete neurovascular bundles in their relevant spatial architectures.

Spinal cord injury (SCI) is a common cause of disability and financial hardship and is currently without a cure; injuries to the cervical spine are the most severe, sometimes resulting in quadriplegia. Transplantation of neural progenitor cells (NPCs) is a promising therapeutic strategy for cervical SCI. NPCs have the ability to differentiate into both neuronal and glial lineages making them the ideal cell types for SCI therapy. However, some of the stem cell sources used to generate NPCs have associated logistical, ethical, and immune rejection challenges. NPCs derived from induced human pluripotent stem cells (hiPSCs-NPCs) represent a cell source that circumvents ethical and moral concerns while allowing for autologous transplantation. In this chapter, we describe how to generate NPCs from skin fibroblasts taken from patients and how to genetically manipulate these cells to equip them with more beneficial properties. We also explain how to generate a rodent cervical SCI model and transplant these cells for preclinical studies.

Spinal cord injury (SCI) is a devastating condition, where regenerative failure and cell loss lead to paralysis. The heterogeneous and time-sensitive pathophysiology has made it difficult to target tissue repair. Despite many medical advances, there are no effective regenerative therapies. As stem cells offer multi-targeted and environmentally responsive benefits, cell therapy is a promising treatment approach. Areas covered: This review highlights the cell therapies being investigated for SCI, including Schwann cells, olfactory ensheathing cells, mensenchymal stem/stromal cells, neural precursors, oligodendrocyte progenitors, embryonic stem cells, and induced pluripotent stem cells. Through mechanisms of cell replacement, scaffolding, trophic support and immune modulation, each approach targets unique features of SCI pathology. However, as the injury is multifaceted, it is increasingly recognized that a combinatorial approach will be necessary to treat SCI. Expert opinion: Most preclinical studies, and an increasing number of clinical trials, are finding that single cell therapies have only modest benefits after SCI. These considerations, alongside issues of therapy cost-effectiveness, need to be addressed at the bench. In addition to exploring combinatorial strategies, researchers should consider cell reproducibility and storage parameters when designing animal experiments. Equally important, clinical trials must follow strict regulatory guidelines that will enable transparency of results.

The immune system plays a critical and complex role in the pathobiology of spinal cord injury (SCI), exerting both beneficial and detrimental effects. Increasing evidence suggests that there are injury level-dependent differences in the immune response to SCI. Patients with traumatic SCI have elevated levels of circulating autoantibodies against components of the central nervous system, but the role of these antibodies in SCI outcomes remains unknown. In rodent models of mid-thoracic SCI, antibody-mediated autoimmunity appears to be detrimental to recovery. However, whether autoantibodies against the spinal cord are generated following cervical SCI (cSCI), the most common level of injury in humans, remains undetermined. To address this knowledge gap, we investigated the antibody responses following cSCI in a rat model of injury. We found increased immunoglobulin G (IgG) and IgM antibodies in the spinal cord in the subacute phase of injury (2 weeks), but not in more chronic phases (10 and 20 weeks). At 2 weeks post-cSCI, antibodies were detected at the injury epicenter and co-localized with the astroglial scar and neurons of the ventral horn. These increased levels of antibodies corresponded with enhanced activation of immune responses in the spleen. Higher counts of antibody-secreting cells were observed in the spleen of injured rats. Further, increased levels of secreted IgG antibodies and enhanced proliferation of T-cells in splenocyte cultures from injured rats were found. These findings suggest the potential development of autoantibody responses following cSCI in the rat. The impact of the post-traumatic antibody responses on functional outcomes of cSCI is a critical topic that requires further investigation.

This case report presents two female patients whose chief complaint was discoloration of teeth. On careful clinical examination it was found that the patients had features of amelogenesis imperfecta and localised aggressive periodontitis. This article will give an insight of clinical and radiographic features of amelogenesis imperfecta with localised aggressive periodontitis, which is a rare clinical entity.

One of the big challenges in neuroscience that remains to be understood is why the central nervous system is not able to regenerate to the extent that the peripheral nervous system does. This is especially problematic after traumatic injuries, like spinal cord injury (SCI), since the lack of regeneration leads to lifelong deficits and paralysis. Treatment of SCI has improved during the last several decades due to standardized protocols for emergency medical response teams and improved medical, surgical, and rehabilitative treatments. However, SCI continues to result in profound impairments for the individual. There are many processes that lead to the pathophysiology of SCI, such as ischemia, vascular disruption, neuroinflammation, oxidative stress, excitotoxicity, demyelination, and cell death. Current treatments include surgical decompression, hemodynamic control, and methylprednisolone. However, these early treatments are associated with modest functional recovery. Some treatments currently being investigated for use in SCI target neuroprotective (riluzole, minocycline, G-CSF, FGF-2, and polyethylene glycol) or neuroregenerative (chondroitinase ABC, self-assembling peptides, and rho inhibition) strategies, while many cell therapies (embryonic stem cells, neural stem cells, induced pluripotent stem cells, mesenchymal stromal cells, Schwann cells, olfactory ensheathing cells, and macrophages) have also shown promise. However, since SCI has multiple factors that determine the progress of the injury, a combinatorial therapeutic approach will most likely be required for the most effective treatment of SCI.

Background: To compare treatment modalities: Open flap debridement (OFD) alone (Group I), OFD in combination with PerioGlas® (Group II), and OFD in combination with autologous platelet-rich fibrin (PRF) (Group III) for periodontal intrabony defects (IBDs). Aim: To evaluate on clinical and radiographic basis, effectiveness of PerioGlas®, and PRF in treating IBDs. Settings and Design: IBDs selected on the basis of the inclusion criteria were randomly assigned to Groups I, II, and III by coin toss method. Materials and Methods: The study was conducted on patients reporting to the department of periodontology and oral implantology. Thirty-eight patients with ninety periodontal IBDs of moderate to severe periodontitis were selected and assigned to Groups I, II, and III. In each patient, a minimum number of two sextants were present with pocket depths ≥5 mm in at least three teeth. Statistical Analysis: Statistical analysis based on mean values, standard deviation, and P values. Results: Compared to baseline, 9 months postoperatively: (1) mean probing pocket depth reduction for Group I was 3.68 mm ± 0.72, for Group II was 5.57 mm ± 1.10, and for Group III was 6.11 mm ± 0.92. (2) The mean relative attachment level gain for Group I was 4.14 mm ± 0.76, for Group II was 6.57 mm ± 1.45, and for Group III was 6.74 mm ± 1.55. (3) Mean radiographic IBD fill for Group I was 69.29% mm ± 7.73, for Group II was 74.44% mm ± 8.57, and for Group III was 75.01% mm ± 7.85. Conclusion: This study shows marked improvements in the clinical parameters and radiographic outcomes with both PerioGlas® and autologous PRF to treat periodontal IBDs as compared to OFD alone.

Background and Objectives: Aim of this randomly controlled clinical study was to evaluate the role of antibiotics to prevent postoperative complications after routine periodontal surgery and also to determine whether their administration improved the surgical outcome. Materials and Methods: Forty-five systemically healthy patients with moderate to severe chronic periodontitis requiring flap surgery were enrolled in the study. They were randomly allocated to Amoxicillin, Doxycycline, and control groups. Surgical procedures were carried out with complete asepsis as per the protocol. Postoperative assessment of patient variables like swelling, pain, temperature, infection, ulceration, necrosis, and trismus was performed at intervals of 24 h, 48 h, 1 week, and 3 months. Changes in clinical parameters such as gingival index, plaque index, probing pocket depth, and clinical attachment level were also recorded. Results: There was no incidence of postoperative infection in any of the patients. Patient variables were comparable in all the three groups. Though there was significant improvement in the periodontal parameters in all the groups, no statistically significant result was observed for any group over the others. Conclusion: Results of this study showed that when periodontal surgical procedures were performed following strict asepsis, the incidence of clinical infection was not significant among all the three groups, and also that antibiotic administration did not influence the outcome of surgery. Therefore, prophylactic antibiotics for patients who are otherwise healthy administered following routine periodontal surgery to prevent postoperative infection are unnecessary and have no demonstrable additional benefits.