Impact of Pericervical Dentin on Fracture Resistance of Endodontically Treated Posterior Permanent Teeth: A Systematic Review and Meta-analysis.

OBJECTIVE: The main aim of this present systematic review is to evaluate if the preservation of pericervical dentin (PCD) increases the fracture resistance of endodontically treated permanent posterior teeth. MATERIALS AND METHODS: Two independent reviewers conducted a comprehensive review of all published studies from 2007 (1/1/2007) to 2023 (31/5/23) since the concept of PCD first appeared in the literature in 2007. Searches were conducted in multiple electronic database engines: PubMed, Scopus, EBSCO (Dentistry and oral health sciences), Web of Sciences (WOS), Cochrane, Google Scholar and Open Grey, Ovid and Shodhganga, in addition to cross-references and hand search. Articles were chosen according to a certain inclusion and exclusion criteria, which, in brief, are laboratory-based studies published in English that assess the impact of PCD on fracture resistance of endodontically treated permanent posterior teeth. Using domains, such as sample size, sample dimensions, and control group as quality assessment criteria, evaluated the selected articles and classified them according to their risk of bias into low, moderate, and high. A meta-analysis was conducted using random effects modeling at a significance level of p < 0.05. RESULTS: A total of studies 6,043 were retrieved from 10 different electronic search databases and hand searches, but only 12 laboratory-based studies were selected after removing duplicates and applying the eligibility criteria. Of the included 12 studies, nine studies showed low risk of bias and three studies showed moderate risk of bias. Two studies showed related data for meta-analysis, the difference observed between the two studies is statistically non-significant. CONCLUSION: Based on the results of the study, there is evidence to support that PCD preservation offers fracture resistance to the endodontically treated posterior teeth. CLINICAL SIGNIFICANCE: The practice of conservative cavity preparation and avoiding the usage of instruments with high taper increases the fracture resistance of the tooth by retaining the PCD. How to cite this article: Haridoss S, Rajendran M, Swaminathan K, et al. Impact of Pericervical Dentin on Fracture Resistance of Endodontically Treated Posterior Permanent Teeth: A Systematic Review and Meta-analysis. J Contemp Dent Pract 2024;25(4):372-385.

Cerebrolysin Attenuates Exacerbation of Neuropathic Pain, Blood-spinal Cord Barrier Breakdown and Cord Pathology Following Chronic Intoxication of Engineered Ag, Cu or Al (50-60 nm) Nanoparticles.

Neuropathic pain is associated with abnormal sensations and/or pain induced by non-painful stimuli, i.e., allodynia causing burning or cold sensation, pinching of pins and needles like feeling, numbness, aching or itching. However, no suitable therapy exists to treat these pain syndromes. Our laboratory explored novel potential therapeutic strategies using a suitable composition of neurotrophic factors and active peptide fragments-Cerebrolysin (Ever Neuro Pharma, Austria) in alleviating neuropathic pain induced spinal cord pathology in a rat model. Neuropathic pain was produced by constrictions of L-5 spinal sensory nerves for 2-10 weeks period. In one group of rats cerebrolysin (2.5 or 5 ml/kg, i.v.) was administered once daily after 2 weeks until sacrifice (4, 8 and 10 weeks). Ag, Cu and Al NPs (50 mg/kg, i.p.) were delivered once daily for 1 week. Pain assessment using mechanical (Von Frey) or thermal (Hot-Plate) nociceptive showed hyperalgesia from 2 weeks until 10 weeks progressively that was exacerbated following Ag, Cu and Al NPs intoxication in nerve lesioned groups. Leakage of Evans blue and radioiodine across the blood-spinal cord barrier (BSCB) is seen from 4 to 10 weeks in the rostral and caudal cord segments associated with edema formation and cell injury. Immunohistochemistry of albumin and GFAP exhibited a close parallelism with BSCB leakage that was aggravated by NPs following nerve lesion. Light microscopy using Nissl stain exhibited profound neuronal damages in the cord. Transmission electron microcopy (TEM) show myelin vesiculation and synaptic damages in the cord that were exacerbated following NPs intoxication. Using ELISA spinal tissue exhibited increased albumin, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and heat shock protein (HSP 72kD) upregulation together with cytokines TNF-α, IL-4, IL-6, IL-10 levels in nerve lesion that was exacerbated following NPs intoxication. Cerebrolysin treatment significantly reduced hyperalgesia and attenuated BSCB disruption, edema formation and cellular changes in nerve lesioned group. The levels of cytokines were also restored near normal levels with cerebrolysin treatment. Albumin, GFAP, MABP and HSP were also reduced in cerebrolysin treated group and thwarted neuronal damages, myelin vesiculation and cell injuries. These neuroprotective effects of cerebrolysin with higher doses were also effective in nerve lesioned rats with NPs intoxication. These observations suggest that cerebrolysin actively protects spinal cord pathology and hyperalgesia following nerve lesion and its exacerbation with metal NPs, not reported earlier.

Early Childhood Caries and Iron Deficiency Anaemia: A Systematic Review and Meta-Analysis.

Identification of the association between Early Childhood Caries (ECC) and Iron Deficiency Anaemia (IDA) will aid paediatricians and paediatric dentists to enhance health promotion measures to reduce the related morbidity in children. This systematic review aims to determine an evidence-based association between ECC and IDA. A systematic search was carried out from MEDLINE via PubMed, EMBASE, LILACS, Cochrane Oral Health Group's Specialized Register, CINAHL via EBSCO, Web of Science, and Scopus up to May 2020. Hand searching and grey literature screening were also conducted. Cross-sectional, case-control, and cohort studies in English language which assessed the association was included. Two reviewers independently assessed the study quality and extracted the outcome data. A total of 1,434 studies were identified. Fourteen studies qualified for qualitative review and 7 of them for a meta-analysis. In comparison with children not affected by ECC, those affected had an increased likelihood of IDA (OR = 6.07 [3.61, 10.21]). The meta-analysis showed no statistical difference when comparing blood parameters (Hb, MCV, and serum ferritin) in children with and without ECC. This systematic review demonstrates an association between ECC and increased odds of IDA rather than it being the cause for IDA. Further longitudinal studies with robust methodology are required to determine an evidence-based association.

The role of functionalized magnetic iron oxide nanoparticles in the central nervous system injury and repair: new potentials for neuroprotection with Cerebrolysin therapy.

Functionalized Magnetic Iron Oxide Nanoparticles (FMIONPs) are being explored for the development of various biomedical applications, e.g., cancer chemotherapy and/or several other radiological or diagnostic purposes. However, the effects of these NPs per se on the central nervous system (CNS) injury or repair are not well known. This review deals with different aspects of FMIONPs in relation to brain function based on the current literature as well as our own investigation in animal models of CNS injuries. It appears that FMIONPs are innocuous when administered intravenously within the CNS under normal conditions. However, abnormal reactions to FMIONPs in the brain or spinal cord could be seen if they are combined with CNS injuries e.g., hyperthermia or traumatic insults to the brain or spinal cord. Thus, administration of FMIONPs in vivo following whole body hyperthermia (WBH) or a focal spinal cord injury (SCI) exacerbates cellular damage. Since FMIONPs could help in diagnostic purposes or enhance the biological effects of radiotherapy/chemotherapy it is likely that these NPs may have some adverse reaction as well under disease condition. Thus, under such situation, adjuvant therapy e.g., Cerebrolysin (Ever NeuroPharma, Austria), a suitable combination of several neurotrophic factors and active peptide fragments are the need of the hour to contain such cellular damages caused by the FMIONPs in vivo. Our observations show that co-administration of Cerebrolysin prevents the FMIONPs induced pathologies associated with CNS injuries. These observations support the idea that FMIONPs are safe for the CNS in disease conditions when co-administered with cerebrolysin. This indicates that cerebrolysin could be used as an adjunct therapy to prevent cellular damages in disease conditions where the use of FMIONPs is required for better efficacy e.g., cancer treatment.

Genetic variations in exon 10 of ENAM and their association with early childhood caries.

OBJECTIVE: Enamelin is the largest enamel matrix protein encoded by the ENAM gene. The primary purpose of this study was to identify genetic variants in ENAM exon 10 that can alter susceptibility to early childhood caries (ECC). METHODS: This case-control study included 248 children aged 3-6 years, with 124 children diagnosed with ECC in the case group and 124 children without caries in the control group. Questionnaires were used to record demographic data, socioeconomic status, hygienic practices, and feeding practices, and a 24-h diet diary was kept. Seven polymorphisms (rs7671281, rs1738668322, rs3796703, rs3796704, rs759376039, rs775159311, and rs1738678483) in ENAM exon 10 were sequenced. RESULTS: The heterozygous CT genotype of rs7671281 was significantly more common in the case group compared to the control group (odds ratio [OR], 6.1765; 95% confidence interval [CI], 2.05-18.58; P = 0.0006). Under the dominant model, the TT genotype of rs7671281 was significantly more common in the control group (OR, 6.47; 95% CI, 2.15-19.39; P < 0.001). The AG genotype of rs3796704 was significantly more common in the case group than in the control group (OR, 5.705; 95% CI, 1.60-20.25; P = 0.006). Under the dominant model, the GG genotype of rs3796704 was significantly more common in children without caries than in children with caries (OR, 6.84; 95% CI, 1.96-23.90; P < 0.001). CONCLUSIONS: The C allele of rs7671281 and the A allele of rs3796704 can increase susceptibility to ECC.

New perspectives of nanoneuroprotection, nanoneuropharmacology and nanoneurotoxicity: modulatory role of amino acid neurotransmitters, stress, trauma, and co-morbidity factors in nanomedicine.

Recent advancement in nanomedicine suggests that nanodrug delivery using nanoformulation of drugs or use of nanoparticles for neurodiagnostic and/or neurotherapeutic purposes results in superior effects than the conventional drugs or parent compounds. This indicates a bright future for nanomedicine in treating neurological diseases in clinics. However, the effects of nanoparticles per se in inducing neurotoxicology by altering amino acid neurotransmitters, if any, are still being largely ignored. The main aim of nanomedicine is to enhance the drug availability within the central nervous system (CNS) for greater therapeutic successes. However, once the drug together with nanoparticles enters into the CNS compartments, the fate of nanomaterial within the brain microenvironment is largely remained unknown. Thus, to achieve greater success in nanomedicine, our knowledge in understanding nanoneurotoxicology in detail is utmost important. In addition, how co-morbidity factors associated with neurological disease, e.g., stress, trauma, hypertension or diabetes, may influence the neurotherapeutic potentials of nanomedicine are also necessary to explore the details. Recent research in our laboratory demonstrated that engineered nanoparticles from metals or titanium nanowires used for nanodrug delivery in laboratory animals markedly influenced the CNS functions and alter amino acid neurotransmitters in healthy animals. These adverse reactions of nanoparticles within the CNS are further aggravated in animals with different co-morbidity factors viz., stress, diabetes, trauma or hypertension. This effect, however, depends on the composition and dose of the nanomaterials used. On the other hand, nanodrug delivery by TiO2 nanowires enhanced the neurotherapeutic potential of the parent compounds in CNS injuries in healthy animals and do not alter amino acids balance. However, in animals with any of the above co-morbidity factors, high dose of nanodrug delivery is needed to achieve some neuroprotection. Taken together, it appears that while exploring new nanodrug formulations for neurotherapeutic purposes, co-morbidly factors and composition of nanoparticlesrequire more attention. Furthermore, neurotoxicity caused by nanoparticles per se following nanodrug delivery may be examined in greater detail with special regards to changes in amino acid balance in the CNS.

Neuromodulation and quality of life for patient with spasticity after spinal cord injury.

RATIONALE: Spasticity develops in 80% of spinal cord injury cases and negatively affects the patents' quality of life. The most common method of surgical treatment for severe spasticity is a long-term intrathecal baclofen therapy (ITB). Long-term spinal cord stimulation is another possible treatment technique. This paper aims to evaluate the changes in quality of life for patients with spasticity who have been treated with neuromodulation (SCS or ITB) in 12 months after the surgery, as well to compare the changes in quality of life for patients who have been treated with spinal cord stimulation and those who received long-term intrathecal baclofen therapy. MATERIALS AND METHODS: The influence of spasticity, experienced by the patients with a spinal cord injury, on their quality of life was analyzed before the surgery and 12 months after it. The severity of the spinal cord damage was determined with the scale of the American Spinal Injury Association (ASIA); spasticity was evaluated with the modified Ashworth scale, Penn Spasm Frequency Scale; pain levels were determined with visual analogue scale (VAS), anxiety and depression levels - with HADS. Functional activity of the patients was evaluated with the help of the Functional Independence Measure (FIM). RESULTS: The treatment results for 33 patients (25 men and 8 women), aged from 18 to 62, are presented. After the trial stimulation, the patients were randomly assigned to either SCS or ITB group (18 and 15 people respectively). The decrease of spasticity in both experimental groups caused lower levels of pain, less functional dependency on other people, lower stress and depression rates and, as a consequence, better quality of life and social adaptation. The obtained results for SCS and ITB groups are statistically similar.

Considerations for Embedding Inclusive Research Principles in the Design and Execution of Clinical Trials.

There is a growing recognition that the clinical research enterprise has a diversity problem, given that many clinical trials recruit historically marginalized individuals or patients reflective of real-world data at a rate that is far below the incidence and prevalence of the disease for which the investigational therapy or device is targeting. This lack of diversity in clinical research participation can obscure the safety and efficacy of drug therapies and limits our collective ability to develop effective treatments for all patients, leading to even wider health disparities. This review article provides an in-depth analysis of the impact of this bias on public health, along with a description of some of the barriers that prevent historically marginalized populations from participating in clinical research. Some practical solutions that can be employed to increase diversity in clinical trial participation are also discussed, including the crucial role clinical trial sponsors, research organizations, patients, and caregivers need to play in supporting the industry to achieve this ambitious but necessary goal.

Single nucleotide polymorphisms of enamel formation genes and early childhood caries - systematic review, gene-based, gene cluster and meta-analysis.

Introduction: Genetic polymorphisms of genes regulating amelogenesis can alter susceptibility to Early Childhood Caries (ECC). This systematic review aims to analyze associations between single-nucleotide polymorphisms of enamel formation genes and ECC. Methods: Search was conducted across PUBMED, CINAHL, LILACS, SCOPUS, EMBASE, Web of Science, Genome-Wide Association Studies databases from January 2003 to September 2022. This was supplemented by hand search. Totally 7124 articles were identified and 21 articles that satisfied the inclusion criteria proceeded to data extraction. Quality assessment was done using the Q-Genie tool. Results: Quantitative synthesis revealed that homozygous genotype AA of rs12640848 was significantly higher in children with ECC with an odds ratio of 2.36. Gene-based analysis revealed significant association between six variants of AMBN, four variants of KLK4, two variants of MMP20, and a single variant of each of MMP9 and MMP13 genes and ECC. The Bonferroni corrected-log10 P value of amelogenesis gene Cluster was 2.25 (0.05/88 = 5.6 × 10-4). Search Tool for Retrieval of Interacting Genes and Proteins plot constructed to comprehend the protein-protein interaction revealed the presence of four functional clusters. Gene function prediction using Multiple Association Network Integration Algorithm revealed that physical interaction between these genes was 69.3%. Conclusion: Polymorphisms of genes regulating amelogenesis can influence the susceptibility to ECC. AA genotype of rs12640848 may increase the susceptibility to ECC. Gene-based analysis revealed a significant association between multiple polymorphisms of genes regulating amelogenesis and ECC.

Efficacy and safety of acupuncture in the treatment of post-traumatic headache secondary to mild traumatic brain injury: A systematic evaluation and meta-analysis protocol of randomized controlled trials.

INTRODUCTION: Post-traumatic headache secondary to mild traumatic brain injury in patients has become an important factor in their prognosis. Due to the lack of effective pharmacological treatments, non-pharmacological interventions such as acupuncture are considered to have greater potential. However, the efficacy and safety of acupuncture treatment have not been clearly demonstrated. The purpose of this meta-analysis protocol is to investigate the effectiveness and safety of acupuncture in the treatment of headache secondary to mild traumatic brain injury. METHODS AND ANALYSIS: Seven English and Chinese databases will be selected and searched according to their respective search methods, spanning the period from database creation to April 2022, and the languages will be limited to English and Chinese. Only randomized controlled trials will be included. Study selection, data collection, and risk of bias control will be performed by two independent investigators. Any disagreements will be referred to a third independent investigator for decision and documentation. Revman software will be used to complete our meta-analysis, and risk of bias assessment, subgroup analysis, and sensitivity analysis will be performed to correct the results. Finally we will assess the reliability of our final results using the Recommended Guidelines Development Tool for Assessment. ETHICS AND DISSEMINATION: All data for this study will be obtained from published journals, so no ethical review will be required. The completed review will be published in a peer-reviewed journal and the findings will be further disseminated through presentation at an appropriate forum or conference.

Nanowired Delivery of Cerebrolysin with Mesenchymal Stem Cells Attenuates Heat Stress-Induced Exacerbation of Neuropathology Following Brain Blast Injury.

Blast brain injury (bBI) following explosive detonations in warfare is one of the prominent causes of multidimensional insults to the central nervous and other vital organs injury. Several military personnel suffered from bBI during the Middle East conflict at hot environment. The bBI largely occurs due to pressure waves, generation of heat together with release of shrapnel and gun powders explosion with penetrating and/or impact head trauma causing multiple brain damage. As a result, bBI-induced secondary injury causes breakdown of the blood-brain barrier (BBB) and edema formation that further results in neuronal, glial and axonal injuries. Previously, we reported endocrine imbalance and influence of diabetes on bBI-induced brain pathology that was significantly attenuated by nanowired delivery of cerebrolysin in model experiments. Cerebrolysin is a balanced composition of several neurotrophic factors, and active peptide fragment is capable of neuroprotection in several neurological insults. Exposure to heat stress alone causes BBB damage, edema formation and brain pathology. Thus, it is quite likely that hot environment further exacerbates the consequences of bBI. Thus, novel therapeutic strategies using nanodelivery of stem cell and cerebrolysin may further enhance superior neuroprotection in bBI at hot environment. Our observations are the first to show that combined nanowired delivery of mesenchymal stem cells (MSCs) and cerebrolysin significantly attenuated exacerbation of bBI in hot environment and induced superior neuroprotection, not reported earlier. The possible mechanisms of neuroprotection with MSCs and cerebrolysin in bBI are discussed in the light of current literature.

Innovative emergency strategies for patients with severe traumatic brain injury: An IoT-based resource integration.

Severe traumatic brain injury patients are in critical condition, and rapid rescue is very important for prognosis. Currently, the resuscitation process is complex and it is difficult to get to the operating room quickly to target treatment. We present a new strategy based on the Internet of Things system to integrate complex first aid procedures for efficient and comprehensive rescuing of patients with severe traumatic brain injury. This system includes three modules: human sign monitoring equipment, emergency transport equipment, and a network diagnosis and treatment progress control center. The system not only supports the streamlining of rescue procedures but also transmits the patient's status and optimal treatment strategies in real-time by using an advanced Internet of Things system. After deploying the system in a hospital, we conducted a validation study to evaluate its feasibility and superiority in clinical use. The preliminary results of the study show that this system can significantly shorten the treatment time, which may help the prognosis of severe traumatic brain injury patients.

Spinal cord injury induced exacerbation of Alzheimer's disease like pathophysiology is reduced by topical application of nanowired cerebrolysin with monoclonal antibodies to amyloid beta peptide, p-tau and tumor necrosis factor alpha.

Hallmark of Alzheimer's disease include amyloid beta peptide and phosphorylated tau deposition in brain that could be aggravated following traumatic of concussive head injury. However, amyloid beta peptide or p-tau in spinal cord following injury is not well known. In this investigation we measured amyloid beta peptide and p-tau together with tumor necrosis factor-alpha (TNF-α) in spinal cord and brain following 48 h after spinal cord injury in relation to the blood-spinal cord and blood-brain barrier, edema formation, blood flow changes and cell injury in perifocal regions of the spinal cord and brain areas. A focal spinal cord injury was inflicted over the right dorsal horn of the T10-11 segment (4 mm long and 2 mm deep) and amyloid beta peptide and p-tau was measured in perifocal rostral (T9) and caudal (T12) spinal cord segments as well as in the brain areas. Our observations showed a significant increase in amyloid beta peptide in the T9 and T12 segments as well as in remote areas of brain and spinal cord after 24 and 48 h injury. This is associated with breakdown of the blood-spinal cord (BSCB) and brain barriers (BBB), edema formation, reduction in blood flow and cell injury. After 48 h of spinal cord injury elevation of amyloid beta peptide, phosphorylated tau (p-tau) and tumor necrosis factor-alpha (TNF-α) was seen in T9 and T12 segments of spinal cord in cerebral cortex, hippocampus and brain stem regions associated with microglial activation as seen by upregulation of Iba1 and CD86. Repeated nanowired delivery of cerebrolysin topically over the traumatized segment repeatedly together with monoclonal antibodies (mAb) to amyloid beta peptide (AßP), p-tau and TNF-α significantly attenuated amyloid beta peptide, p-tau deposition and reduces Iba1, CD68 and TNF-α levels in the brain and spinal cord along with blockade of BBB and BSCB, reduction in blood flow, edema formation and cell injury. These observations are the first to show that spinal cord injury induces Alzheimer's disease like symptoms in the CNS, not reported earlier.

Nanowired Delivery of Cerebrolysin Together with Antibodies to Amyloid Beta Peptide, Phosphorylated Tau, and Tumor Necrosis Factor Alpha Induces Superior Neuroprotection in Alzheimer's Disease Brain Pathology Exacerbated by Sleep Deprivation.

Sleep deprivation induces amyloid beta peptide and phosphorylated tau deposits in the brain and cerebrospinal fluid together with altered serotonin metabolism. Thus, it is likely that sleep deprivation is one of the predisposing factors in precipitating Alzheimer's disease (AD) brain pathology. Our previous studies indicate significant brain pathology following sleep deprivation or AD. Keeping these views in consideration in this review, nanodelivery of monoclonal antibodies to amyloid beta peptide (AßP), phosphorylated tau (p-tau), and tumor necrosis factor alpha (TNF-α) in sleep deprivation-induced AD is discussed based on our own investigations. Our results suggest that nanowired delivery of monoclonal antibodies to AßP with p-tau and TNF-α induces superior neuroprotection in AD caused by sleep deprivation, not reported earlier.

Nanodelivery of Histamine H3/H4 Receptor Modulators BF-2649 and Clobenpropit with Antibodies to Amyloid Beta Peptide in Combination with Alpha Synuclein Reduces Brain Pathology in Parkinson's Disease.

Parkinson's disease (PD) in military personnel engaged in combat operations is likely to develop in their later lives. In order to enhance the quality of lives of PD patients, exploration of novel therapy based on new research strategies is highly warranted. The hallmarks of PD include increased alpha synuclein (ASNC) and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) leading to brain pathology. In addition, there are evidences showing increased histaminergic nerve fibers in substantia niagra pars compacta (SNpc), striatum (STr), and caudate putamen (CP) associated with upregulation of histamine H3 receptors and downregulation of H4 receptors in human brain. Previous studies from our group showed that modulation of potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist induces neuroprotection in PD brain pathology. Recent studies show that PD also enhances amyloid beta peptide (AßP) depositions in brain. Keeping these views in consideration in this review, nanowired delivery of monoclonal antibodies to AßP together with ASNC and H3/H4 modulator drugs on PD brain pathology is discussed based on our own observations. Our investigation shows that TiO2 nanowired BF-2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of monoclonal antibodies (mAb) to AßP and ASNC induced superior neuroprotection in PD-induced brain pathology. These observations are the first to show the modulation of histaminergic receptors together with antibodies to AßP and ASNC induces superior neuroprotection in PD. These observations open new avenues for the development of novel drug therapies for clinical strategies in PD.

Co-administration of Nanowired DL-3-n-Butylphthalide (DL-NBP) Together with Mesenchymal Stem Cells, Monoclonal Antibodies to Alpha Synuclein and TDP-43 (TAR DNA-Binding Protein 43) Enhance Superior Neuroprotection in Parkinson's Disease Following Concussive Head Injury.

dl-3-n-butylphthalide (dl-NBP) is one of the potent antioxidant compounds that induces profound neuroprotection in stroke and traumatic brain injury. Our previous studies show that dl-NBP reduces brain pathology in Parkinson's disease (PD) following its nanowired delivery together with mesenchymal stem cells (MSCs) exacerbated by concussive head injury (CHI). CHI alone elevates alpha synuclein (ASNC) in brain or cerebrospinal fluid (CSF) associated with elevated TAR DNA-binding protein 43 (TDP-43). TDP-43 protein is also responsible for the pathologies of PD. Thus, it is likely that exacerbation of brain pathology in PD following brain injury may be thwarted using nanowired delivery of monoclonal antibodies (mAb) to ASNC and/or TDP-43. In this review, the co-administration of dl-NBP with MSCs and mAb to ASNC and/or TDP-43 using nanowired delivery in PD and CHI-induced brain pathology is discussed based on our own investigations. Our observations show that co-administration of TiO2 nanowired dl-NBP with MSCs and mAb to ASNC with TDP-43 induced superior neuroprotection in CHI induced exacerbation of brain pathology in PD, not reported earlier.

Co-Administration of Nanowired Monoclonal Antibodies to Inducible Nitric Oxide Synthase and Tumor Necrosis Factor Alpha Together with Antioxidant H-290/51 Reduces SiO2 Nanoparticles-Induced Exacerbation of Pathophysiology of Spinal Cord Trauma.

Military personnel are often exposed to silica dust during combat operations across the globe. Exposure to silica dust in US military or service personnel could cause Desert Strom Pneumonitis also referred to as Al Eskan disease causing several organs damage and precipitate autoimmune dysfunction. However, the effects of microfine particles of sand inhalation-induced brain damage on the pathophysiology of traumatic brain or spinal cord injury are not explored. Previously intoxication of silica nanoparticles (50-60 nm size) is shown to exacerbates spinal cord injury induces blood-spinal cord barrier breakdown, edema formation and cellular changes. However, the mechanism of silica nanoparticles-induced cord pathology is still not well known. Spinal cord injury is well known to alter serotonin (5-hydroxytryptamine) metabolism and induce oxidative stress including upregulation of nitric oxide synthase and tumor necrosis factor alpha. This suggests that these agents are involved in the pathophysiology of spinal cord injury. In this review, we examined the effects of combined nanowired delivery of monoclonal antibodies to neuronal nitric oxide synthase (nNOS) together with tumor necrosis factor alpha (TNF-α) antibodies and a potent antioxidant H-290/51 to induce neuroprotection in spinal cord injury associated with silica nanoparticles intoxication. Our results for the first time show that co-administration of nanowired delivery of antibodies to nNOS and TNF-α with H-290/51 significantly attenuated silica nanoparticles-induced exacerbation of spinal cord pathology, not reported earlier.

Neuroprotective Effects of Nanowired Delivery of Cerebrolysin with Mesenchymal Stem Cells and Monoclonal Antibodies to Neuronal Nitric Oxide Synthase in Brain Pathology Following Alzheimer's Disease Exacerbated by Concussive Head Injury.

Concussive head injury (CHI) is one of the major risk factors in developing Alzheimer's disease (AD) in military personnel at later stages of life. Breakdown of the blood-brain barrier (BBB) in CHI leads to extravasation of plasma amyloid beta protein (ΑßP) into the brain fluid compartments precipitating AD brain pathology. Oxidative stress in CHI or AD is likely to enhance production of nitric oxide indicating a role of its synthesizing enzyme neuronal nitric oxide synthase (NOS) in brain pathology. Thus, exploration of the novel roles of nanomedicine in AD or CHI reducing NOS upregulation for neuroprotection are emerging. Recent research shows that stem cells and neurotrophic factors play key roles in CHI-induced aggravation of AD brain pathologies. Previous studies in our laboratory demonstrated that CHI exacerbates AD brain pathology in model experiments. Accordingly, it is quite likely that nanodelivery of NOS antibodies together with cerebrolysin and mesenchymal stem cells (MSCs) will induce superior neuroprotection in AD associated with CHI. In this review, co-administration of TiO2 nanowired cerebrolysin - a balanced composition of several neurotrophic factors and active peptide fragments, together with MSCs and monoclonal antibodies (mAb) to neuronal NOS is investigated for superior neuroprotection following exacerbation of brain pathology in AD exacerbated by CHI based on our own investigations. Our observations show that nanowired delivery of cerebrolysin, MSCs and neuronal NOS in combination induces superior neuroprotective in brain pathology in AD exacerbated by CHI, not reported earlier.

Co-administration of Nanowired Oxiracetam and Neprilysin with Monoclonal Antibodies to Amyloid Beta Peptide and p-Tau Thwarted Exacerbation of Brain Pathology in Concussive Head Injury at Hot Environment.

Environmental temperature adversely affects the outcome of concussive head injury (CHI)-induced brain pathology. Studies from our laboratory showed that animals reared at either cold environment or at hot environment exacerbate brain pathology following CHI. Our previous experiments showed that nanowired delivery of oxiracetam significantly attenuated CHI-induced brain pathology and associated neurovascular changes. Military personnel are the most susceptible to CHI caused by explosion, blasts, missile or blunt head trauma leading to lifetime functional and cognitive impairments affecting the quality of life. Severe CHI leads to instant death and/or lifetime paralysis. Military personnel engaged in combat operations are often subjected to extreme high or low environmental temperature zones across the globe. Thus, further exploration of novel therapeutic agents at cold or hot ambient temperatures following CHI are the need of the hour. CHI is also a major risk factor for developing Alzheimer's disease by enhancing amyloid beta peptide deposits in the brain. In this review, effect of hot environment on CHI-induced brain pathology is discussed. In addition, whether nanodelivery of oxiracetam together with neprilysin and monoclonal antibodies (mAb) to amyloid beta peptide and p-tau could lead to superior neuroprotection in CHI is explored. Our results show that co-administration of oxiracetam with neprilysin and mAb to AßP and p-tau significantly induced superior neuroprotection following CHI in hot environment, not reported earlier.

Nanowired Delivery of Mesenchymal Stem Cells with Antioxidant Compound H-290/51 Reduces Exacerbation of Methamphetamine Neurotoxicity in Hot Environment.

Military personnel are often exposed to hot environments either for combat operations or peacekeeping missions. Hot environment is a severe stressful situation leading to profound hyperthermia, fatigue and neurological impairments. To avoid stressful environment, some people frequently use methamphetamine (METH) or other psychostimulants to feel comfortable under adverse situations. Our studies show that heat stress alone induces breakdown of the blood-brain barrier (BBB) and edema formation associated with reduced cerebral blood flow (CBF). On the other hand, METH alone induces hyperthermia and neurotoxicity. These effects of METH are exacerbated at high ambient temperatures as seen with greater breakdown of the BBB and brain pathology. Thus, a combination of METH use at hot environment may further enhance the brain damage-associated behavioral dysfunctions. METH is well known to induce severe oxidative stress leading to brain pathology. In this investigation, METH intoxication at hot environment was examined on brain pathology and to explore suitable strategies to induce neuroprotection. Accordingly, TiO2-nanowired delivery of H-290/51 (150 mg/kg, i.p.), a potent chain-breaking antioxidant in combination with mesenchymal stem cells (MSCs), is investigated in attenuating METH-induced brain damage at hot environment in model experiments. Our results show that nanodelivery of H-290/51 with MSCs significantly enhanced CBF and reduced BBB breakdown, edema formation and brain pathology following METH exposure at hot environment. These observations are the first to point out that METH exacerbated brain pathology at hot environment probably due to enhanced oxidative stress, and MSCs attenuate these adverse effects, not reported earlier.