Platelet Concentrate Treatments for Temporomandibular Disorders: A Systematic Review and Meta-analysis

Objectives: This systematic review compared platelet concentrates (PCs) versus hyaluronic acid (HA) or saline/Ringer?s solution injections as treatments of temporomandibular osteoarthritis and disc displacement in terms of pain and maximum mouth opening (MMO). Methods: PubMed, Cochrane, and Scopus were searched up to March 6, 2020. Inclusion criteria were randomized clinical trials (RCTs). Exclusion criteria were case series, observational studies, animal studies, and reviews. The Effective Public Health Practice Project (EPHPP) quality assessment tool was used to assess the risk of bias in the included studies. The weighted mean difference was used to compare the results. Results: Nine RCTs were included with a total of 407 patients. The numbers of joints treated were 262, 112, and 112 in the PC, HA, and saline groups, respectively. The quality of studies was rated as strong in 4 studies, moderate in 4 studies, and weak in 1 study. The meta-analysis revealed that PCs decreased pain visual analogue scale (VAS) scores compared to HA by an average of ?1.11 (CI, ?1.62 to ?0.60; P < 0.0001) and ?0.57 (CI, ?1.55 to 0.41; P = 0.26) at 3 and 12 mo follow-up respectively. Also, the average decrease in pain scores with PC compared to saline was ?1.33 (CI, ?2.61 to ?0.06; P = 0.04), ?2.07 (CI, ?3.46 to ?0.69; P = 0.003), and ?2.71 (CI, ?4.69 to ?0.72; P = 0.008) at 3, 6, and 12 mo, respectively. Regarding MMO measurements, PC was comparable to HA, but it was significantly better than saline after 3 and 6 mo [2.9 mm (CI,1.47 to 4.3; P < 0.0001), and 1.69 mm (CI, 0.13 to 3.25; P = 0.03) respectively]. Conclusion: PC reduces pain VAS scores compared to HA during the first 3 m after treatment, and when compared to saline, it reduces pain and increases MMO for longer durations. However, due to differences between groups regarding PC preparation protocols and study heterogeneity, further standardized RCTs are required. Knowledge Transfer Statement: This study provides researchers and clinicians with quantitative and qualitative analyses of the current evidence regarding the clinical outcomes of platelet concentrate injections in the treatment of temporomandibular joint osteoarthritis and disc displacement in terms of pain control and maximum mouth opening.Scopu

Ranitidine Impairs Bone Healing and Implant Osseointegration in Rats' Tibiae

Purpose: Ranitidine has been found to have an impact on bone metabolism by suppressing osteoclastogenesis. We hypothesized that the use of ranitidine would impair bone healing and implant osseointegration. This study investigated the effect of postoperative administration of ranitidine on bone healing and osseointegration in rats. Materials and Methods: Twenty-two Sprague-Dawley rats underwent surgery to create a unicortical bone defect in each tibia. A titanium implant was placed on the right tibial defect, whereas the contralateral defect was left unfilled. After surgery, the rats were randomly divided into 2 groups receiving a daily dose of ranitidine or saline solution for 14 days and then euthanized for assessment of bone healing and osseointegration using micro?computed tomography (CT) and histomorphometry. Results: Micro-CT analysis of the bone defect showed a larger bone defect volume in the ranitidine group (0.82 � 0.13 ?L vs 0.66 � 0.16 ?L, P = .034), thinner cortical thickness (0.54 � 0.07 mm vs 0.63 � 0.11 mm, P = .026), and less bone regeneration at the defect site (40% � 12% vs 57% � 11%, P = .003). Implant-site micro-CT analysis showed less osseointegration in the ranitidine group (34.1% � 2.7% vs 43.5% � 2.1%, P = .014), and implant-site histologic analysis showed less medullary (P = .021), cortical (P = .001), and total (P = .003) bone-implant contact and less peri-implant bone volume?tissue volume (P = .002) in the ranitidine group. Histologic analysis for osteoclastic activity showed a lower number of osteoclasts in the ranitidine group (4.8 � 2.4 mm?2 vs 9.1 � 2.1 mm?2, P = .026). Conclusions: The postoperative use of ranitidine impaired bone healing and osseointegration. ? 2020 American Association of Oral and Maxillofacial SurgeonsScopu

The effect of aging on the bone healing properties of blood plasma

Objectives: Age-related changes in blood composition have been found to affect overall health. Thus, this study aimed to understand the effect of these changes on bone healing by assessing how plasma derived from young and old rats affect bone healing using a rat model. Methods:. Blood plasma was collected from 6-month and 24-month old rats. Differences in elemental composition and metabolome were assessed using optical emission spectrometry and liquid mass spectrometry, respectively. Bilateral tibial bone defects were created in eight rats. Young plasma was randomly applied to one defect, while aged plasma was applied to the contralateral one. Rats were euthanized after two weeks, and their tibiae were analyzed using micro-CT and histology. The proteome of bone marrow was analyzed in an additional group of three rats. Results: Bone-defects treated with aged-plasma were significantly bigger in size and presented lower bone volume/tissue volume compared to defects treated with young-plasma. Histomorphometric analysis showed fewer mast cells, macrophages, and lymphocytes in defects treated with old versus young plasma. The proteome analysis showed that young plasma upregulated pathways required for bone healing (e.g. RUNX2, platelet signaling, and crosslinking of collagen fibrils) whereas old plasma upregulated pathways, involved in disease and inflammation (e.g. IL-7, IL-15, IL-20, and GM-CSF signaling). Plasma derived from old rats presented higher concentrations of iron, phosphorous, and nucleotide metabolites as well as lower concentrations of platelets, citric acid cycle, and pentose phosphate pathway metabolites compared to plasma derived from young rats. Conclusion: bone defects treated with plasma-derived from young rats showed better healing compared to defects treated with plasma-derived from old rats. The application of young and old plasmas has different effects on the proteome of bone defects.Scopu

Acetylcholinesterase inhibitors and risk of bleeding and acute ischemic events in non-hypertensive Alzheimer's patients

Introduction: Acetylcholinesterase inhibitors (AChEIs) are commonly used to treat mild to moderate cases of Alzheimer disease (AD). To the best of our knowledge, there has been no study estimating the risk of bleeding and cardiovascular events in patients with non-hypertensive AD. Therefore, this study aimed to estimate the association between AChEIs and the risk of bleeding and cardiovascular ischemic events in patients with non-hypertensive AD. Methods: A nested case-control study was conducted to estimate the risk of bleeding and ischemic events (angina, myocardial infarction [MI], and stroke) in patients with AD. This study was conducted using the UK Clinical Practice Research Datalink and Hospital Episode Statistics (HES) databases. The study cohort consisted of AD patients �65 years of age. The case groups included all AD subjects in the database who had a bleeding or ischemic event during the cohort follow-up. Four controls were selected for each case. Patients were classified as current users or past users based on a 60-day threshold of consuming the drug. Simple and multivariable conditional logistic regression analyses were used to calculate the adjusted odds ratio for bleeding events and cardiovascular events. Results: We identified 507 cases and selected 2028 controls for the bleeding event cohort and 555 cases and 2220 controls for the ischemic event cohort. The adjusted odds ratio (OR) (95% confidence interval [CI]) for the association of AChEI use was 0.93 (0.75 to 1.16) for bleeding events, 2.58 (1.01 to 6.59) for angina, and 1.89 (1.07 to 3.33) for MI. Past users of AChEIs were also at increased risk of stroke (1.51 [1.00 to 2.27]). Discussion: This is the first study assessing the risk of bleeding and cardiovascular events in patients with non-hypertensive AD. Our findings could be of great interest for clinicians and researchers working on AD.Scopu

High toughness resorbable brushite-gypsum fiber-reinforced cements

The ideal bone substitute material should be mechanically strong, biocompatible with a resorption rate matching the rate of new bone formation. Brushite (dicalcium phosphate dihydrate) cement is a promising bone substitute material but with limited resorbability and mechanical properties. To improve the resorbability and mechanical performance of brushite cements, we incorporated gypsum (calcium sulfate dihydrate) and diazonium-treated polyglactin fibers which are well-known for their biocompatibility and bioresorbability. Here we show that by combining brushite and gypsum, we were able to fabricate biocompatible composite cements with high fracture toughness (0.47 MPa�m1/2) and a resorption rate that matched the rate of new bone formation. Adding functionalized polyglactin fibers to this composite cement further improved the fracture toughness up to 1.00 MPa�m1/2. XPS and SEM revealed that the improvement in fracture toughness is due to the strong interfacial bonding between the functionalized fibers and the cement matrix. This study shows that adding gypsum and functionalized polyglactin fibers to brushite cements results in composite biomaterials that combine high fracture toughness, resorbability, and biocompatibility, and have great potential for bone regeneration.Scopu

Postoperative administration of the acetylcholinesterase inhibitor, donepezil, interferes with bone healing and implant osseointegration in a rat model

Donepezil is an acetylcholinesterase inhibitor commonly used to treat mild to moderate Alzheimer?s disease. Its use has been associated with increased bone mass in humans and animals. However, the effect of postoperative administration of donepezil on bone healing remains unknown. Therefore, this study aimed to assess the impact of postoperative injection of donepezil on bone healing, titanium-implant osseointegration, and soft tissue healing. Twenty-two Sprague-Dawley rats were randomly assigned to receive a daily dose of either donepezil (0.6 mg/kg) or saline as a control. In each rat, a uni-cortical defect was created in the right tibia metaphysis and a custom-made titanium implant was placed in the left tibiae. After two weeks, rats were euthanized, and their bones were analysed by Micro-CT and histology. The healing of bone defect and implant osseointegration in the rats treated with donepezil were significantly reduced compared to the saline-treated rats. Histomorphometric analysis showed lower immune cell infiltration in bone defects treated with donepezil compared to the saline-treated defects. On the other hand, the healing time of soft tissue wounds was significantly shorter in donepezil-treated rats compared to the controls. In conclusion, short-term administration of donepezil hinders bone healing whereas enhancing soft tissue healing.Scopu

Differences in platelet-rich plasma composition influence bone healing

Aim: Platelet-rich plasma (PRP) is an autologous blood-derived material that has been used to enhance bone regeneration. Clinical studies, however, reported inconsistent outcomes. This study aimed to assess the effect of changes in leucocyte and PRP (L-PRP) composition on bone defect healing. Materials and Methods: L-PRPs were prepared using different centrifugation methods and their regenerative potential was assessed in an in-vivo rat model. Bilateral critical-size tibial bone defects were created and filled with single-spin L-PRP, double-spin L-PRP, or filtered L-PRP. Empty defects and defects treated with collagen scaffolds served as controls. Rats were euthanized after 2 weeks, and their tibias were collected and analysed using micro-CT and histology. Results: Double-spin L-PRP contained higher concentrations of platelets than single-spin L-PRP and filtered L-PRP. Filtration of single-spin L-PRP resulted in lower concentrations of minerals and metabolites. In vivo, double-spin L-PRP improved bone healing by significantly reducing the size of bone defects (1.08 � 0.2 mm3) compared to single-spin L-PRP (1.42 � 0.27 mm3) or filtered L-PRP (1.38 � 0.28 mm3). There were fewer mast cells, lymphocytes, and macrophages in defects treated with double-spin L-PRP than in those treated with single-spin or filtered L-PRP. Conclusion: The preparation method of L-PRP affects their composition and potential to regenerate boneScopu

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.Paroxysmal Cerebral Disorder

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays