Bridging larger gaps in peripheral nerves using neural prosthetics and physical therapeutic agents Muhammad Sana Ullah Sahar, Matthew Barton, Geoffrey Douglas Tansley Neural Regeneration Research 2019 14(7):1109-1115 Peripheral nerve injuries are relatively common and can be caused by a variety of traumatic events such as motor vehicle accidents. They can lead to long-term disability, pain, and financial burden, and contribute to poor quality of life. In this review, we systematically analyze the contemporary literature on peripheral nerve gap management using nerve prostheses in conjunction with physical therapeutic agents. The use of nerve prostheses to assist nerve regeneration across large gaps (> 30 mm) has revolutionized neural surgery. The materials used for nerve prostheses have been greatly refined, making them suitable for repairing large nerve gaps. However, research on peripheral nerve gap management using nerve prostheses reports inconsistent functional outcomes, especially when prostheses are integrated with physical therapeutic agents, and thus warrants careful investigation. This review explores the effectiveness of nerve prostheses for bridging large nerve gaps and then addresses their use in combination with physical therapeutic agents. |
Magnesium: Pathophysiological mechanisms and potential therapeutic roles in intracerebral hemorrhage Jason J Chang, Rocco Armonda, Nitin Goyal, Adam S Arthur Neural Regeneration Research 2019 14(7):1116-1121 Intracerebral hemorrhage (ICH) remains the second-most common form of stroke with high morbidity and mortality. ICH can be divided into two pathophysiological stages: an acute primary phase, including hematoma volume expansion, and a subacute secondary phase consisting of blood-brain barrier disruption and perihematomal edema expansion. To date, all major trials for ICH have targeted the primary phase with therapies designed to reduce hematoma expansion through blood pressure control, surgical evacuation, and hemostasis. However, none of these trials has resulted in improved clinical outcomes. Magnesium is a ubiquitous element that also plays roles in vasodilation, hemostasis, and blood-brain barrier preservation. Animal models have highlighted potential therapeutic roles for magnesium in neurological diseases specifically targeting these pathophysiological mechanisms. Retrospective studies have also demonstrated inverse associations between admission magnesium levels and hematoma volume, hematoma expansion, and clinical outcome in patients with ICH. These associations, coupled with the multifactorial role of magnesium that targets both primary and secondary phases of ICH, suggest that magnesium may be a viable target of study in future ICH studies. |
Network-centric medicine for peripheral nerve injury: Treating the whole to boost endogenous mechanisms of neuroprotection and regeneration David Romeo-Guitart, Caty Casas Neural Regeneration Research 2019 14(7):1122-1128 Peripheral nerve injuries caused by accidents may lead to paralysis, sensory disturbances, anaesthesia, and lack of autonomic functions. Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors: motoneuronal soma viability, proper axonal sprouting across inhibitory zones and elongation toward specific muscle, effective synapse contact rebuilding, and prevention of muscle atrophy. Therapies, such as adjuvant drugs with pleiotropic effects, that promote functional recovery after peripheral nerve injury are needed. Toward this aim, we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools. Our focus is on boosting intrinsic capabilities of neurons for neuroprotection; this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition. Using our workflow, we discovered neuroheal, a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection, is anti-inflammatory, enhances axonal regeneration after axotomy, and reduces muscle atrophy. This drug discovery workflow has thus yielded a therapy that is close to its clinical application. |
Exogenous neural stem cell transplantation for cerebral ischemia Ling-Yi Liao, Benson Wui-Man Lau, Dalinda Isabel Sánchez-Vidaña, Qiang Gao Neural Regeneration Research 2019 14(7):1129-1137 Cerebral ischemic injury is the main manifestation of stroke, and its incidence in stroke patients is 70–80%. Although ischemic stroke can be treated with tissue-type plasminogen activator, its time window of effectiveness is narrow. Therefore, the incidence of paralysis, hypoesthesia, aphasia, dysphagia, and cognitive impairment caused by cerebral ischemia is high. Nerve tissue regeneration can promote the recovery of the aforementioned dysfunction. Neural stem cells can participate in the reconstruction of the damaged nervous system and promote the recovery of nervous function during self-repair of damaged brain tissue. Neural stem cell transplantation for ischemic stroke has been a hot topic for more than 10 years. This review discusses the treatment of ischemic stroke with neural stem cells, as well as the mechanisms of their involvement in stroke treatment. |
Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage Hideki Kanamaru, Hidenori Suzuki Neural Regeneration Research 2019 14(7):1138-1143 Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities. Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure, followed by global cerebral ischemia. Post-subarachnoid hemorrhage ischemia, tissue injuries as well as extravasated blood components and the breakdown products activate microglia, astrocytes and Toll-like receptor 4, and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades. Once blood-brain barrier is disrupted, brain tissues are directly exposed to harmful blood contents and immune cells, which aggravate brain injuries furthermore. Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins. Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage, but the exact mechanisms remain unclear. Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage. This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage. |
Choroid plexus tumor necrosis factor receptor 1: A new neuroinflammatory piece of the complex Alzheimer's disease puzzle Sophie Steeland, Roosmarijn E Vandenbroucke Neural Regeneration Research 2019 14(7):1144-1147 Due to the aging of the population and despite the enormous scientific effort, Alzheimer’s disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer’s disease. Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer’s disease led to inconclusive results, partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1, but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer’s disease patients, signaling via tumor necrosis factor receptor 1. In agreement with this, choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer’s disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer’s disease-associated inflammation, choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in (early) Alzheimer’s disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer’s disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer’s disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer’s disease and prevent the irreversible neurodegeneration and resulting memory decline. |
Transcriptional dysregulation in neurodegenerative diseases: Who tipped the balance of Yin Yang 1 in the brain? Zhefan Stephen Chen, Ho Yin Edwin Chan Neural Regeneration Research 2019 14(7):1148-1151 Yin Yang 1 (YY1) is a multi-functional transcription factor that regulates gene expression in a range of cell types, including neurons. It controls neuronal differentiation, as well as neuronal specification and migration during the development of the mammalian nervous system. Besides, YY1 also mediates the transcription of genes that are required for neuronal survival. An impairment of the transcriptional function of YY1 causes neuronal death. This review summarizes recent research findings that unveil the dysfunction of YY1 in multiple neurodegenerative disorders. The expression of disease proteins perturbs the function of YY1 via distinct molecular mechanisms, including recruitment to protein aggregates, protein degradation and aberrant nuclear/cytoplasmic shuttling. Understanding the pathogenic roles of YY1 will further broaden our knowledge of the disease mechanisms in distinct neurodegenerative disorders. |
Effects of Ginkgo biloba extract EGb761 on neural differentiation of stem cells offer new hope for neurological disease treatment Chao Ren, Yong-Qiang Ji, Hong Liu, Zhe Wang, Jia-Hui Wang, Cai-Yi Zhang, Li-Na Guan, Pei-Yuan Yin Neural Regeneration Research 2019 14(7):1152-1157 Stem cell transplantation has brought new hope for the treatment of neurological diseases. The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells. Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors, the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located. Accordingly, the optimal microenvironment for inducing stem cell differentiation is a hot topic. EGb761 is extracted from the leaves of the Ginkgo biloba tree. It is used worldwide and is becoming one of the focuses of stem cell research. Studies have shown that EGb761 can antagonize oxygen free radicals, stabilize cell membranes, promote neurogenesis and synaptogenesis, increase the level of brain-derived neurotrophic factors, and replicate the environment required during the differentiation of stem cells into nerve cells. This offers the possibility of using EGb761 to induce the differentiation of stem cells, facilitating stem cell transplantation. To provide a comprehensive reference for the future application of EGb761 in stem cell therapy, we reviewed studies investigating the influence of EGb761 on stem cells. These started with the composition and neuropharmacology of EGb761, and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation. |
Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease Bridget Martinez, Philip V Peplow Neural Regeneration Research 2019 14(7):1158-1176 The most common age-related neurodegenerative disease is Alzheimer’s disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation. |
Precision medicine in pantothenate kinase-associated neurodegeneration Mónica Alvarez-Cordoba, Marina Villanueva-Paz, Irene Villalón-García, Suleva Povea-Cabello, Juan M Suárez-Rivero, Marta Talaverón-Rey, Javier Abril-Jaramillo, Ana Belén Vintimilla-Tosi, José A Sánchez-Alcázar Neural Regeneration Research 2019 14(7):1177-1185 Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson’s disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate. The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available, and monitoring its effect on the pathophysiological changes, can help for a better therapeutic strategy. In addition, these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future. |
Δευτέρα 25 Φεβρουαρίου 2019
Neural Regeneration Research (Neural Regen Res)
Mediterranean diet, alkaline water may be as effective as PPIs for laryngopharyngeal reflux
Sitagliptin and Simvastatin Interaction Causing Rhabdomyolysis and AKI
We report a case of rhabdomyolysis and severe acute kidney injury (AKI) requiring dialysis in a 69-year-old male who was recently started on sitagliptin while on chronic simvastatin therapy. This potential interaction is not included in the package insert for sitagliptin. A comprehensive literature review revealed six previous reports of rhabdomyolysis due to drug interaction between sitagliptin and statins including simvastatin, lovastatin, and atorvastatin. Of these six cases, only two had developed rhabdomyolysis-associated AKI, none of which were severe enough to require dialysis. As patients are commonly prescribed statins and sitagliptin for treatment of dyslipidemia and diabetes, health care professionals should be aware of this potential drug interaction and closely monitor their patients for signs and symptoms of rhabdomyolysis and AKI. This case highlights the importance of conducting further studies on the risk of muscular toxicity of sitagliptin especially when administered concurrently with statins.
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"Fungating" tumour? No, its bacterial!
A fit and healthy 26-year-old woman presented to the general surgical team with epigastric pain and weight loss of 2 stones over 6 months. She has also a positive family history of ulcerative colitis. As her oesophagogastroduodenoscopy and colonoscopy were normal, a contrasted CT was requested, and it detected an inflammatory mass with fat streaking around her transverse colon. An intrauterine contraceptive device (IUCD) was noted. In light of the CT findings, she underwent a diagnostic laparoscopy. As the inflammatory mass was not separable from the transverse colon, a segmental transverse colectomy was proceeded. The histology revealed multiple actinomycosis abscesses in the mesentery. Subsequently, we learnt that her IUCD had been in situ for the last 7 years, and the source of actinomycosis abscesses is likely from her IUCD. The patient was recommended to have the coil removed and commenced on a 6 months course of amoxicillin.
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Phacomorphic glaucoma in a high myope with phakic intraocular lens
We report a case of a young, one-eyed woman with high myopia who presented to our emergency department with sudden onset painful diminution of vision in the right eye after undergoing laser treatment. Her right eye had a phakic intraocular lens (pIOL) implantation 4 years back and her left eye had absent light perception. She was diagnosed as right eye lens induced secondary angle closure glaucoma with pIOL touching the corneal endothelium and left eye atrophic bulbi. She was admitted under eye emergency for medical intraocular pressure control followed by pIOL explantation with lens aspiration of the cataractous lens and posterior chamber intraocular lens implantation.
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Metastatic calcinosis cutis due to refractory hypercalcaemia responsive to denosumab in a patient with multiple sclerosis
Metastatic calcinosis cutis results from abnormal calcium levels leading to the precipitation of insoluble calcium salts in the skin and subcutaneous tissue. Here, we present the case of a 67-year-old man with multiple sclerosis on chronic dexamethasone and concurrent supplementation of calcium and daily cholecalciferol presenting with painful calcified lesions. During initial presentation, corrected calcium was 13.8 mg/dL (reference range: 8.5–10.1 mg/dL), ionised calcium was 1.70 mg/dL (reference range: 1.13–1.32 mg/dL) and 25-hydroxyvitamin D was 41.6 ng/mL (reference range 30–100 ng/mL). Normocalcaemia was restored with the off-label use of denosumab, usually reserved for hypercalcaemia of malignancy and intractable osteoporosis. We discuss potential aetiologies of this patient's hypercalcaemia, calcinosis cutis diagnosis and management and the off-label use of denosumab.
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Urinary tract bleeding from a urethral caruncle mimicking genital tract bleeding
A 69-year-old Japanese woman with a post-hysterectomy status came to our primary care clinic. She presented with vaginal bleeding for the past 3 days which had developed after defecation. There was a palpable mass measuring approximately 2 cm on pelvic exam; however, heavy bleeding prevented in-depth observation. CT and MRI scans revealed that the mass was inside the urethral meatus and not in the vagina. She underwent surgical resection of the urethral tumour, and the pathological report showed no malignancy. A final diagnosis of urethral caruncle was made. Vaginal bleeding is commonly encountered in the primary care practice and is usually attributed to gynaecological diseases. However, patients and physicians may falsely regard urinary or gastrointestinal tract bleeding as one involving the genital tract. We present a case wherein vaginal bleeding was initially considered but was later identified to be due to a urethral caruncle.
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Sentinel bruising as a presentation of metastatic melanoma
A 46-year-old man presented with a 4-week history of bruising with subcutaneous nodules and weight loss. He also had a 2-week history of progressive back and hip pain. He had been diagnosed with stage Ib cutaneous melanoma 30 months previously, which had been fully excised. A sentinel lymph node biopsy was negative. On examination, there were five skin lesions at different stages. Each had spontaneously appeared as a bruise with a central subcutaneous nodule, and the bruising then faded to leave a persistent subcutaneous nodule. Excision of one of the nodules demonstrated a 4.5 mm diameter partly necrotic melanoma deposit in the dermis. CT scan of the head, chest, abdomen and pelvis showed widespread metastases. This rare presentation of cutaneous malignant melanoma metastases has been termed 'sentinel bruising'. There are fewer than 10 cases reported in the literature.
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How does knowledge of the blood supply to an intracardiac tumour help?
Myxoma is a common benign tumour found in the heart. On reviewing literature, we found some left atrial myxomas receive blood supply from the right coronary artery. Performing a coronary angiogram in a cardiac tumour has the following uses: (1) it shows the vascularity that can be ligated by the surgeon at operation; (2) if there is a blood supply visible, it may not be an intracardiac thrombus; (3) the coronary angiogram may detect a myxoma even before an echocardiogram does so; (4) some myxomas may bleed into the right atrium or left atrium and this may be seen on coronary angiography. We show here the neovascularity of a left atrial myxoma and its blood supply from the right coronary artery. We recommend that all routine coronary angiograms be reviewed carefully for any signs of tumour vascularity or tumour blush as this would prevent missing early myxomas. Echocardiography is the gold standard for detection of myxomas but literature has a number of intracardiac tumours that were detected only by the tumour blush. Some left atrial tumours have been treated by occluding their blood supply.The absence of a blood supply on coronary angiography could rule out a benign cardiac tumour that usually has a blood supply.
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Extrapulmonary uterine lymphangioleiomyomatosis (LAM) and dysfunctional uterine bleeding: the first presentation of LAM in a tuberous sclerosis complex patient
Lymphangioleiomyomatosis (LAM) is a rare disease that typically affects women of childbearing age. It most commonly affects the lungs (P-LAM) but can occasionally occur in extra-pulmonary sites (E-LAM). There is a strong association between LAM and the tuberous sclerosis complex (TSC). We report a case of a 42-year-old female TSC sufferer who presented with dysfunctional uterine bleeding. She was not known to have LAM. An endometrial biopsy revealed a spindled-cell lesion suspicious of leiomyosarcoma, which correlated with cross-sectional imaging. She underwent a hysterectomy that showed a bizarre (symplastic) leiomyomatous endometrial polyp with background uterine LAM. We discuss the clinical and pathological implications of this unusual case of E-LAM and the importance of clinicopathological correlation in TSC sufferers. The association of uterine LAM with TSC is important and LAM should be considered as a differential of dysfunctional uterine bleeding and a benign mimic to uterine leiomyosarcoma in patients with TSC.
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Recurrent retroperitoneal abscess after biliary tract surgery in an elderly patient: a minimally invasive nonsurgical approach and its consequences: a case report
Hepatic abscess can be defined as an encapsulated collection of suppurative material within the liver parenchyma. Hepatic abscess can be distinguished as pyogenic, amebic, or fungal. Biliary tract disease rema...
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Transpedicular Endoscopic Surgery for Highly Downmigrated L5-S1 Disc Herniation
Endoscopic surgery for highly downmigrated disc herniation at level L5-S1 is a challenging technique. Most surgeons prefer the interlaminar access because of the special anatomy of the L5-S1 disc level, i.e., narrow neuroforamen and large interlaminar window. Transforaminal access to the neuroforamen L5-S1 is difficult in cases with high iliac crest. Here, the access to the highly downmigrated disc herniation with the recently reported technique of transpedicular endoscopic surgery by Krzok et al. was described. In 3 cases with highly downmigrated disc herniation of L5-S1, the sequester was removed successfully through the bone hole of S1 pedicle. This technique is demanding for experienced endoscopic surgeons.
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