Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive weakness and spasticity of the lower limbs. Dominant mutations in the human SPG4 gene, encoding spastin, are responsible for the most frequent form of HSP. Spastin is an ATPase that binds microtubules and localizes to the spindle pole and distal axon in mammalian cell lines. Furthermore, its Drosophila homolog, Drosophila spastin (Dspastin), has been recently shown to regulate microtubule stability and synaptic function at the Drosophila larval neuromuscular junction. Here we report the generation of a spastin-linked HSP animal model and show that in Drosophila, neural knockdown of Dspastin and, conversely, neural overexpression of Dspastin containing a conserved pathogenic mutation both recapitulate some phenotypic aspects of the human disease, including adult onset, locomotor impairment, and neurodegeneration. At the subcellular level, neuronal expression of both Dspastin RNA interference and mutant Dspastin cause an excessive stabilization of microtubules in the neuromuscular junction synapse. In addition, we provide evidence that administration of the microtubule targeting drug vinblastine significantly attenuates these phenotypes in vivo. Our findings demonstrate that loss of spastin function elicits HSP-like phenotypes in Drosophila, provide novel insights into the molecular mechanism of spastin mutations, and raise the possibility that therapy with Vinca alkaloids may be efficacious in spastin-associated HSP and other disorders related to microtubule dysfunction.     

Fibromyalgia syndrome and depressive symptoms: Comorbidity and clinical correlates

ObjectiveFibromyalgia is characterized by chronic widespread musculoskeletal pain and higher pain perception in specific anatomic sites called tender points. Fibromyalgia is frequently associated with psychiatric symptoms, like depression and anxiety; indeed some authors have argued about the possibility to classify this syndrome into affective spectrum disorder. Few studies have analyzed the impact of depressive symptoms on pain threshold. This research is aimed at evaluating the prevalence and the clinical correlates of depressive symptoms in fibromyalgic patients, and investigating their impact on pain perception and quality of life.MethodsOutpatients between 18 and 75 years with diagnosis of fibromyalgia according to the criteria of the American College of Rheumatology have been included. All subjects have been evaluated with the following rating scales: HAM-D; VAS (to quantify pain); a visual analogical scale to evaluate quality of life; and Paykel's List of Recent Life Events.ResultsThirty subjects have been recruited. Most patients (83.3%) had clinically significant depressive symptoms as indicated by a HAM-D score > 7. Depressive symptoms are associated with higher pain perception, worse quality of life and more severe life events.ConclusionThe presence of depressive symptoms is associated with a great impairment in patients with fibromyalgia syndrome: indeed the psychiatric comorbidity lowers pain threshold and worsens the quality of life of our patients. Future studies should be conducted in order to identify the individual factors, e.g. stress or inflammatory processes, which drive the association between depression and higher severity of fibromyalgia syndrome.     

Neuromuscular paralysis and recovery in mice injected with botulinum neurotoxins A and C

Botulinum neurotoxin type A (BoNT/A) is commonly used in human therapy. This treatment may induce immunoresistance and preliminary evaluation of other botulinum neurotoxin serotypes suggested botulinum neurotoxin type C (BoNT/C) to be a good alternative to BoNT/A. Here, we have further characterized the biological activities of BoNT/C using a variety of experimental approaches. Muscle paralysis and time of recovery of mouse hind limb injected with BoNT/A or BoNT/C were assayed with the Digit Abduction Scoring assay. The extent and duration of paralysis were similar with the two toxin serotypes. Extensor digitorum longus or tibialis anterior muscles were dissected at times of complete paralysis and of complete recovery. Muscle weight and force were significantly reduced in mice injected with BoNT/A and BoNT/C, and some atrophy persisted for a long time. In BoNT/C-treated junctions, nerve terminal sprouting was prominent, indicating that the capacity to extend the field of innervation is not hampered by BoNT/C. BoNT/C induced a marked decrease in the frequency of miniature endplate potentials and in the amplitude of endplate potentials. 3,4-diaminopyridine reversed the effect of BoNT/C by increasing the amplitude of synchronized endplate potentials. The present study shows an extensive similarity in the biological activities of BoNT/A and BoNT/C, further supporting the suggestion that BoNT/C is a valid alternative to BoNT/A.     

Calcium overload in nerve terminals of cultured neurons intoxicated by alpha-latrotoxin and snake PLA2 neurotoxins

Snake presynaptic neurotoxins with phospholipase A2 (PLA2) activity cause degeneration of the neuromuscular junction. They induce depletion of synaptic vesicles and increase the membrane permeability to Ca²⁺ which fluxes from the outside into the nerve terminal. Moreover, several toxins were shown to enter the nerve terminals of cultured neurons, where they may display their PLA2 activity on internal membranes. The relative contribution of these different actions in nerve terminal degeneration remains to be established. To gather information on this point, we have compared the effects of β-bungarotoxin, taipoxin, notexin and textilotoxin with those of alpha-latrotoxin on the basis of the notion that this latter toxin is well known to cause massive Ca²⁺ influx and exocytosis of synaptic vesicles. All the parameters analysed here, including calcium imaging, are very similar for the two classes of neurotoxins. This indicates that Ca²⁺ overloading plays a major role in the degeneration of nerve terminals induced by the snake presynaptic neurotoxins.     

A case of Tinea nigra associated to a bite from a European rabbit (Oryctolagus cuniculus,Leporidae): the role of dermoscopy in diagnosis

We report a case of Tinea nigra in an adolescent living in Itapema,Santa Catarina, Brazil, who presented a hyperchromic macule on the palm of the lefthand, close to another erythematous macule caused by a rabbit bite. The patientreceived guidance on accidents and animal bites and evolved well treated with topicalbutenafine for the dermatomycosis. The authors also highlight the efficacy of thedermoscopic exam in diagnosing Tinea nigra with animal bite lesionsand other traumas.     

Perceived Access to Contraception via Telemedicine Among Young Adults: Inequities by Food and Housing Insecurity

BackgroundTelemedicine expanded rapidly during the COVID-19 pandemic, including for contraceptive services. Data are needed to understand whether young people can access telemedicine for contraception, especially in underserved populations.ObjectiveTo compare young people’s perceived access to telemedicine visits for contraception during the COVID-19 pandemic by food and housing insecurity.DesignSupplementary study to a cluster randomized controlled trial in 25 community colleges in California and Texas. Online surveys were administered May 2020 to April 2021. Mixed-effects logistic regression models with random effects for site were used to examine differences in access to contraception through telemedicine by food and housing insecurity status, controlling for key sociodemographic characteristics, including race/ethnicity, non-English primary language, health insurance status, and state of residence, and contraceptive method used.Participants1,414 individuals assigned female at birth aged 18–28.Main MeasuresSurvey measures were used to capture how difficult it would be for a participant to have a telemedicine visit (phone or video) for contraception.Key ResultsTwenty-nine percent of participants were food insecure, and 15% were housing insecure. Nearly a quarter (24%) stated that it would be difficult to have a phone or video visit for contraception. After accounting for sociodemographic factors and type of method used, food insecure (adjusted odds ratio [aOR], 2.17; 95% confidence interval [CI], 1.62–2.91) and housing insecure (aOR, 1.62; 95% CI, 1.13–2.33) participants were significantly more likely to report that it would be difficult to use telemedicine for contraception during the pandemic.ConclusionsUnderserved patients are those who could benefit most from the expansion of telemedicine services, yet our findings show that young people experiencing basic needs insecurity perceive the greatest difficulty accessing these services for essential reproductive care.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03519685","term_id":"NCT03519685"}}NCT03519685KEY WORDS: telemedicine, contraception, housing insecurity, food insecurity, access to care, COVID-19     

Phase II study of irinotecan and docetaxel in patients with previously treated non-small cell lung cancer: an Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 007)

This study was designed to evaluate the activity and tolerability of irinotecan and docetaxel in patients with previously treated non-small cell lung cancer (NSCLC). Eligibility included recurrent or progressive NSCLC, previous chemotherapy, age > or = 18 years, ECOG PS < or = 2. Treatment consisted of irinotecan (160 mg/m2 i.v.), followed by docetaxel (65 mg/m2 i.v.) on day 1 of a 21-day cycle, for a maximum of 6 cycles. Forty patients were enrolled. Median age was 60 years and median ECOG PS was 1. All patients were evaluable for toxicity and 31 (78%) were evaluable for response. A total of 125 cycles was administered (median, 3; range, 1-6). Most common grade 3-4 toxicities were neutropenia (62%), neutropenic fever (22%), and diarrhea (32%). Response rate was 10%; a further 40% of patients achieved stable disease. All responses were observed in patients with ECOG PS < or = 1, age <70 years, and who had received only one prior chemotherapy regimen. Median time to progression was 2.8 months and median survival was 7.4 months. Because of significant toxicity and limited activity, further investigation of irinotecan plus docetaxel in second line NSCLC is not recommended.