An Updated Canvas of the RFC1-mediated CANVAS (Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome).

Proliferation of specific nucleotide sequences within the coding and non-coding regions of numerous genes has been implicated in approximately 40 neurodegenerative disorders. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a neurodegenerative disorder, is distinguished by a pathological triad of sensory neuropathy, bilateral vestibular areflexia and cerebellar impairments. It manifests in adults gradually and is autosomal recessive and multi-system ataxia. Predominantly, CANVAS is associated with biallelic AAGGG repeat expansions in intron 2 of the RFC1 gene. Although various motifs have been identified, only a subset induces pathological consequences, by forming stable secondary structures that disrupt gene functions both in vitro and in vivo. The pathogenesis of CANVAS remains a subject of intensive research, yet its precise mechanisms remain elusive. Herein, we aim to comprehensively review the epidemiology, clinical ramifications, molecular mechanisms, genetics, and potential therapeutics in light of the current findings, extending an overview of the most significant research on CANVAS.

Getting Neurosurgery Services Back on Its Feet: "Learning to Live" with COVID-19.

BACKGROUND: Cancellation/postponement of "non-emergent" surgeries during coronavirus disease of 2019 (COVID-19) pandemic has created a huge backlog of patients waiting for surgery and has put them at risk of disease progression. We share our institute's policy and our department's attempt to resume "non-emergent" surgeries. MATERIALS AND METHODS: We collected details of all patients operated under department of neurosurgery since the onset of COVID-19 pandemic in India and categorized them into "lockdown" and "unlock" groups for comparison. COVID-19 tests done in these patients were also analyzed. We also compared our surgical volume with the number of COVID-19 cases in the state. RESULTS: One hundred and forty-eight patients (97 males, 51 females) with mean age of 37.8 years (range-2 months-82 years) underwent surgery in our department during the study period. The operative volume per week increased by 37% during the "unlock" period as compared to "lockdown" period. The proportion of elective/"non-emergent" surgeries increased from 11.3% during "lockdown" to 34.7% during the "unlock" period (P = 0.0037). During "lockdown" period, number of surgeries declined steadily as the number of COVID-19 cases rose in the state (rs(8) = -0.914, P = 0.000). Whereas there was a trend toward increased number of cases done per week despite increase in the number of cases in the state during the "unlock" period. During the "unlocking" process, in-patient department admissions and surgeries performed per month increased (P = 0.0000) and this increase was uniform across all specialties. COVID-19 test was done (preoperatively or postoperatively) for all surgeries during "unlock" period compared to 12 (22.6%) surgeries during "lockdown" period. Three neurosurgery patients who underwent surgery during the "unlock" period tested positive for COVID-19. CONCLUSIONS: Our experience shows that proper evidence-based protocols, setting up of adequate COVID-19 testing facilities and provision of ample personal protective equipments are instrumental in re-starting "nonemergent" surgeries.

"Locked up inside home" - Head injury patterns during coronavirus disease of 2019 pandemic.

BACKGROUND: As citizens have been forced to stay home during coronavirus disease of 2019 (COVID-19) pandemic, the crisis created unique trends in the neurotrauma patterns with changes in mode, severity, and outcome of head injured patients. METHODS: Details of neurotrauma admissions under the neurosurgery department at our institute since the onset of COVID-19 pandemic in the country were collected retrospectively and compared to the same period last year in terms of demographic profile, mode of injury, GCS at admission, severity of head injury, radiological diagnosis, management (surgical/conservative), and outcome. The patients were studied according to which phase of pandemic they were admitted in - "lockdown" period (March 25 to May 31, 2020) or "unlock" period (June 1 to September 15, 2020). RESULTS: The number of head injuries decreased by 16.8% during the COVID-19 pandemic. Furthermore, during the lockdown period, the number of admissions was 2.7/week while it was 6.8/week during the "unlock" period. RTA was the mode of injury in 29.6% patients during the lockdown, while during the unlock period, it was 56.9% (P = 0.000). Mild and moderate head injuries decreased by 41% and severe head injuries increased by 156.25% during the COVID-19 pandemic (P = 0.000). The mortality among neurotrauma patients increased from 12.4% to 22.5% during the COVID-19 era (P = 0.009). CONCLUSION: We observed a decline in the number of head injury admissions during the pandemic, especially during the lockdown. At the same time, there was increase in the severity of head injuries and associated injuries, resulting in significantly higher mortality in our patients during the ongoing COVID-19 pandemic.

Quizartinib (AC220) reverses ABCG2-mediated multidrug resistance: In vitro and in vivo studies.

Previous reports have shown that some tyrosine kinase inhibitors (TKIs) could inhibit the ATP-binding cassette (ABC) transporters involved in multidrug resistance (MDR). Quizartinib (AC220), a potent class III receptor tyrosine kinase inhibitor (TKI), was synthesized to selectively inhibit FMS-like tyrosine kinase-3 (FLT3), a target in the treatment of acute myeloid leukemia (AML). Quizartinib is currently under clinical trials for FLT3 ITD and wild-type AML and is tested in combination with chemotherapy. While non-toxic to cell lines, quizartinib at 3 µM showed significant reversal effect on wild-type and mutant ABCG2 (R482T)-mediated MDR, and only a moderate reversal effect on mutant ABCG2 (R482G)-mediated MDR. Results also showed that quizartinib reversed MDR not by reducing the expression of ABCG2 protein, but by antagonizing the drug efflux function and increasing the intracellular accumulation of substrate anticancer drugs in ABCG2-overexpressing cells. Importantly, quizartinib at 30 mg/kg strongly enhanced the effect of topotecan (3 mg/kg) in ABCG2-overexpressing (H460/MX20) xenografts in athymic nude mice. These results demonstrated that quizartinib potentiates the antineoplastic activity of wild-type and R482T mutant ABCG2 substrates. These findings may be useful in clinical practice for cancer combination therapy with quizartinib.

Author's reply to 'Rickettsia retinitis cases in India: a few comments'.

Diagnosis of rickettsial retinitis remains presumptive when gold standard tests are not available or not done due to financial constrains. History of tick bite followed by fever with skin rash particularly in winter and spring season may point towards Rickettsiosis. The absence of scarring post resolution of rickettsial retinitis suggests inner retinal involvement in contrast to toxoplasmosis. Bilaterality of the disease, 2-4 weeks of latent period, and multifocal nature of retinitis lesions (cotton wool spot-like lesions) especially around the disc and posterior pole may suggest an immune response to recent systemic infection. The use of only antibiotics or only steroids or both together for treatment of rickettsial retinitis is controversial and warrants randomized controlled trials.

Rickettsial retinitis-an Indian perspective.

BACKGROUND: Though rickettsiosis is common in India, there is paucity of rickettsial retinitis (RR) reports from India. Moreover, rickettsial sub-types and their association with retinitis have not been studied. We are reporting a case series of presumed RR with their course of the disease, visual outcome, and association with rickettsial sub-type based on Weil-Felix test. FINDINGS: This is a retrospective study of 19 eyes of 10 patients presented to a single institution. Cases diagnosed with presumed RR were identified from our database from March 2006 to October 2014 and studied retrospectively for patient's demography, clinical presentation, and treatment. Patients with history of fever, retinitis, and a positive Weil-Felix test and a negative chikungunya and dengue serology were diagnosed as presumed rickettsial uveitis. One patient was diagnosed to have epidemic typhus, and four were diagnosed to have Indian tick typhus. Nine patients had bilateral presentation. One patient had history of dog tick bite, and four patients had skin rashes. All the patients presented between 2 and 4 weeks after a fever. CONCLUSIONS: Retinitis on posterior pole with recent history of fever with or without skin rash and a positive Weil-Felix test may suggest a rickettsial etiology. Its ocular manifestation could be an immune response to recent systemic rickettsial infection. Indian tick typhus and epidemic typhus could be the common sub-types seen in our population. Although it has aggressive presentation, it has a good visual prognosis.

Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.

Rapamycin extends lifespan and attenuates age-related pathologies in mice when administered through diet at 14 parts per million (PPM). Recently, we reported that daily intraperitoneal injection of rapamycin at 8 mg/kg attenuates mitochondrial disease symptoms and progression in the Ndufs4 knockout mouse model of Leigh Syndrome. Although rapamycin is a widely used pharmaceutical agent dosage has not been rigorously examined and no dose-response profile has been established. Given these observations we sought to determine if increased doses of oral rapamycin would result in more robust impact on mTOR driven parameters. To test this hypothesis, we compared the effects of dietary rapamycin at doses ranging from 14 to 378 PPM on developmental weight in control and Ndufs4 knockout mice and on health and survival in the Ndufs4 knockout model. High dose rapamycin was well tolerated, dramatically reduced weight gain during development, and overcame gender differences. The highest oral dose, approximately 27-times the dose shown to extend murine lifespan, increased survival in Ndufs4 knockout mice similarly to daily rapamycin injection without observable adverse effects. These findings have broad implications for the effective use of rapamycin in murine studies and for the translational potential of rapamycin in the treatment of mitochondrial disease. This data, further supported by a comparison of available literature, suggests that 14 PPM dietary rapamycin is a sub-optimal dose for targeting mTOR systemically in mice. Our findings suggest that the role of mTOR in mammalian biology may be broadly underestimated when determined through treatment with rapamycin at commonly used doses.