- Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia. [Journal Article]
- CNClin Neurophysiol 2018 Aug 31; 129(11):2290-2295
- CONCLUSIONS: We found abnormal sudomotor but normal heart rate variability in FRDA. Small cholinergic post-ganglionic fibers are affected in the disease.Quantification of sudomotor function might be a biomarker for FRDA.
- Rotundic acid enhances the impact of radiological toxicity on MCF-7 cells through the ATM/p53 pathway. [Journal Article]
- IJInt J Oncol 2018 Aug 29
- Although radiation therapy is a powerful anticancer modality, radiation- induced stress response and gene expression with adaptive resistance may severely compromise the effectiveness of radiation. T...
Although radiation therapy is a powerful anticancer modality, radiation- induced stress response and gene expression with adaptive resistance may severely compromise the effectiveness of radiation. The function of rotundic acid (RA) on inducing apoptosis in the human breast cancer cell line MCF-7 has been investigated in a previous study. In the present study, the combined effect of chemotherapy and radiotherapy on reducing side effects was examined. The results of an MTT assay revealed that radiation (0.5, 2 and 10 Gy) effectively inhibit MCF-7 cell viability in a dose-dependent manner, consistent with the effects of RA (2, 5 and 12.5 µM). Interestingly, a lower dose of radiation (1 Gy) combined with RA (5 µM) exhibited a greater inhibition efficiency compared with a high dose of radiation alone. Flow cytometry revealed that radiation combined with RA induced the apoptosis of MCF-7 cells. Using western blotting, it was demonstrated that radiation induced the expression of ataxia-telangiectasia mutated (ATM) and p53 protein, and that RA enhanced this effect. On examining the potential underlying mechanism, it was revealed that radiation and RA combined induce Bcl-2-associated X protein expression and cell apoptosis in MCF-7 cells. An ATM inhibitor was able to restore the effect of radiation and RA on inducing MCF-7 cell apoptosis. These results suggest that the ATM/p53 pathway directly participates in radiation and RA-induced apoptosis in MCF-7 cells. RA has the potential for development as a novel drug for the treatment of human breast cancer combined with radiation therapy, given that the combined side effects are reduced.
- Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype. [Journal Article]
- JNJ Neurochem 2018 Sep 17
- Purkinje cell degeneration (pcd) was first identified in a spontaneous mouse mutant showing cerebellar ataxia. In addition to cerebellar Purkinje cells (PCs), retinal photoreceptors, mitral cells in ...
Purkinje cell degeneration (pcd) was first identified in a spontaneous mouse mutant showing cerebellar ataxia. In addition to cerebellar Purkinje cells (PCs), retinal photoreceptors, mitral cells in the olfactory bulb, and a discrete subpopulation of thalamic neurons also degenerate in the mutant brains. The gene responsible for the pcd mutant is Nna1, also known as ATP/GTP binding protein 1 or cytosolic carboxypeptidase like 1, which encodes a zinc carboxypeptidase protein. To investigate pathogenesis of the pcd mutation in detail, we generated a conditional Nna1 allele targeting the carboxypeptidase domain at C-terminus. After Cre recombination and heterozygous crossing, we generated Nna1 knockout (KO) mice and found that the Nna1 KO mice began to show cerebellar ataxia at postnatal day 20 (P20). Most PCs degenerated until 4-week-old, except lobule X. Activated microglia and astrocytes were also observed in the Nna1 KO cerebellum. In the mutant brain, the Nna1 mRNA level was dramatically reduced, suggesting that nonsense-mediated mRNA decay occurs in it. Since the Nna1 protein acts as a de-glutamatase on the C-terminus of α-tubulin and β-tubulin, increased polyglutamated tubulin was detected in the Nna1 KO cerebellum. Additionally, the endoplasmic reticulum stress marker, CHOP, was upregulated in the mutant PCs. We report the generation of a functional Nna1 conditional allele and possible mechanisms of PC death in the Nna1 KO in the cerebellum. This article is protected by copyright. All rights reserved.
- Association of Immune-Mediated Cerebellitis With Immune Checkpoint Inhibitor Therapy. [Journal Article]
- MCMayo Clin Proc Innov Qual Outcomes 2018; 2(1):74-77
- Immune-mediated encephalitis related to immune checkpoint inhibitor therapy is a rare but increasingly described condition that can cause significant morbidity. There are several reported cases in th...
Immune-mediated encephalitis related to immune checkpoint inhibitor therapy is a rare but increasingly described condition that can cause significant morbidity. There are several reported cases in the literature but no previously described cases of immune-mediated cerebellitis. We describe a case of acute cerebellitis that developed in a 20-year-old man with primary refractory Hodgkin lymphoma being treated with the immune checkpoint inhibitor nivolumab. After exposure to 3 cycles of nivolumab, the patient had acute onset of headache, ataxia, nausea, and vomiting, with imaging findings of cerebellar edema, early tonsillar herniation, and early hydrocephalus. Immune-mediated cerebellar encephalitis was suspected and high-dose dexamethasone therapy (8 mg every 6 hours) was initiated. Within 4 days of dexamethasone therapy, his symptoms greatly improved with near-complete resolution of symptoms after a 4-week taper. Differential diagnosis of his condition included viral cerebellitis and paraneoplastic cerebellar degeneration. In cerebellar encephalitis suspected to be due to immune checkpoint inhibitor therapy, prompt recognition and early initiation of high-dose corticosteroids is essential for symptom resolution and treatment success, including the prevention of hydrocephalus and tonsillar herniation. Currently, there are no evidence-based guidelines to guide the initial dose, type, or duration of corticosteroids. Further investigation is needed in the pathogenesis and treatment of cerebellar encephalitis related to immune checkpoint inhibitor therapy to effectively treat this rare, disabling condition.
- Chemical synthesis of lipophilic methylene blue analogues which increase mitochondrial biogenesis and frataxin levels. [Journal Article]
- DBData Brief 2018; 20:1105-1114
- As part of an ongoing program to develop potential therapeutic agents for the treatment of the neurodegenerative disease Friedreich׳s ataxia (FRDA), we have prepared a number of lipophilic methylene ...
As part of an ongoing program to develop potential therapeutic agents for the treatment of the neurodegenerative disease Friedreich׳s ataxia (FRDA), we have prepared a number of lipophilic methylene blue analogues. Some of these compounds significantly increase mitochondrial biogenesis and frataxin levels in cultured Friedreich's ataxia cells . This data article describes the chemical synthesis and full physicochemical characterization of the new analogues.
- Coenzyme Q10 deficiency due to a COQ4 gene defect causes childhood-onset spinocerebellar ataxia and stroke-like episodes. [Journal Article]
- MGMol Genet Metab Rep 2018; 17:19-21
- Sarcocystis calchasi Outbreak in Feral Rock Pigeons ( Columba livia) in California. [Journal Article]
- VPVet Pathol 2018 Sep 16; :300985818794262
- Twenty-two feral rock pigeons ( Columba livia) from 10 counties in California with ataxia, torticollis, and difficulty standing and flying were admitted to rehabilitation centers in late winter and s...
Twenty-two feral rock pigeons ( Columba livia) from 10 counties in California with ataxia, torticollis, and difficulty standing and flying were admitted to rehabilitation centers in late winter and spring of 2017 and died or were euthanized. Common necropsy findings included thin body condition, generalized deep red discoloration of organs, and hemorrhagic subcutaneous neck tissues. Meningoencephalitis was observed microscopically in 16 pigeons, and 3 also had protozoal schizonts in the brain. The most consistently affected regions of the brain were cerebellum and brainstem. Skeletal muscles, and less frequently the heart, contained large intrasarcoplasmic bradyzoites typically without inflammation. Fifteen of the 22 birds tested positive using pan- Sarcocystis polymerase chain reaction. The sequence of the amplicon was most closely related to S. calchasi, and the 8 subtyped sequences had 100% homology with S. calchasi. This investigation demonstrated the transcontinental and North American spread of S. calchasi causing a disease outbreak in free-ranging rock pigeons, thus warranting increased surveillance in susceptible native columbids.
- Immune-mediated cerebellar ataxias: Practical guidelines and therapeutic challenges. [Journal Article]
- CNCurr Neuropharmacol 2018 Sep 16
- Immune-mediated cerebellar ataxias (IMCAs), a clinical entity reported for the first time in the 1980s, include gluten ataxia (GA), paraneoplastic cerebellar degenerations (PCDs), anti-glutamate deca...
Immune-mediated cerebellar ataxias (IMCAs), a clinical entity reported for the first time in the 1980s, include gluten ataxia (GA), paraneoplastic cerebellar degenerations (PCDs), anti-glutamate decarboxylase 65 (GAD) antibody-associated cerebellar ataxia, post-infectious cerebellitis, and opsoclonus myoclonus syndrome (OMS). These IMCAs share common features with regard to therapeutic approaches. When certain factors trigger immune processes, elimination of the antigen(s) becomes a priority: e.g., gluten-free diet in GA and surgical excision of the primary tumor in PCDs. Furthermore, various immunotherapeutic modalities (e.g., steroids, immunoglobulins, plasmapheresis, immunosuppressants, rituximab) should be considered alone or in combination to prevent the progression of the IMCAs. There is no evidence of significant differences in terms of response and prognosis among the various types of immunotherapies. Treatment introduced at an early stage, when CAs or cerebellar atrophy is mild, is associated with better prognosis. Preservation of the "cerebellar reserve" is necessary for improvement of CAs and resilience of the cerebellar networks. In this regard, we emphasize the therapeutic principle of "Time is Cerebellum" in IMCAs.
- Gene mutation and pedigree analysis of tetrahydrobiopterin deficiency in a Uygur family of China. [Journal Article]
- JCJ Clin Lab Anal 2018 Sep 17; :e22665
- CONCLUSIONS: (a) The patient was the first case of clinical diagnosis of BH4 deficiency in the Uighur. And there are two types of hyperphenylalaninemia (HPA) in the same family. (b) The mild HPA patient with severe nervous system damage should pay more attention to the BH4 deficiency. (c) Using next-generation sequencing technology can increase the mutation detection rate when the hereditary diseases are highly suspected in clinic.
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- Selective Forces Related to Spinocerebellar Ataxia Type 2. [Journal Article]
- CCerebellum 2018 Sep 15
- Spinocerebellar ataxia type 2 (SCA2) is caused by an unstable expanded CAG repeat tract (CAGexp) at ATXN2. Although prone to selective forces such as anticipation, SCA2 frequency seems to be stable i...
Spinocerebellar ataxia type 2 (SCA2) is caused by an unstable expanded CAG repeat tract (CAGexp) at ATXN2. Although prone to selective forces such as anticipation, SCA2 frequency seems to be stable in populations. Our aim was to estimate reproductive success, segregation patterns, and role of anticipation in SCA2. Adult subjects from families with molecular diagnosis provided data about all his/her relatives. Affected and unaffected sibs older than 65.7 years of age were used to estimate reproductive success and segregation patterns. Twenty-one SCA2 families were studied, including 1017 individuals (164 affected) who were born from 1840 to 2012. The median number of children of the non-carriers and carriers, among 99 subjects included in the reproductive success analysis, were 2 and 3 (p < 0.025), respectively. Therefore, the reproductive success of carriers was 1.5. There were 137 non-carriers (59.6%) and 93 carriers (40.4%) (p = 0.04), among subjects included in the segregation analysis. Age at onset across generations pointed to anticipation as a frequent phenomenon. We raised evidence in favor of increased reproductive success related to the carrier state at ATXN2, and segregation distortion favoring normal alleles. Since majority of normal alleles analyzed carried 22 repeats, we propose that this distortion segregation can be related to the high frequency of this allele in human chromosomes.