Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety, and tolerability of dimethyl fumarate in Friedreich Ataxia (DMF-FA-201)

IntroductionFriedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2 in vitro and in vivo, and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients.MethodsThe aim of our study is to investigate if DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23.EndpointsThe primary endpoint will be a change in FXN gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level, cardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.ConclusionsThis is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo

Detecção de mutações no gene da anquirina eritroide em pacientes portadores de esferocitose hereditaria

Orientador: Sara Teresinha Olalla SaadDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: O presente estudo teve por objetivo a análise molecular de 28 pacientes não relacionados, atendidos no Hemocentro-UNICAMP, portadores de Esferocitose Hereditária (EsH) diagnosticada a partir de dados clínicos, esfregaço de sangue periférico e curva de fragilidade osmótica. Na maioria destes casos, a quantificação das proteínas de membrana das hemácias através da densitometria de gel de políacrilamida-SDS corado pelo azul de Coomassie, detectou deficiência de espectrina e/ou anquirina. O rastreamento de mutações foi feito através de SSCP e confirmadas por sequenciamento. Duas novas mutações foram encontradas em nossa população, ambas tratando-se de substituição de um nucleotídeo com alteração do aminoácido. A primeira no exon 9 (His -> Arg, CAC->CGC) e a segunda no exon 28 (lle->Thr ATC->ACC), totalizando uma frequência de 7.2% de mutações no gene da anquirina na população com Esferocitose Hereditária estudada. Foram também encontrados dois novos polimorfismos: no exon 6 (codon 197, CCG ->CCA) e no exon 29 (codon 1162, AGT -> AGC), além de outros polimorfismos já descritos, no exon 4 (codon 105, AAT->AAC), no exon 16 (codon 594, TCC -> TC A), e no exon 18 (codon 691, GGT -> GGC). Foi ainda realizada a análise da expressão de RNAm do gene da anquirina através de SSCP. Um paciente apresentou defeito na transcrição de um dos alelos, conforme evidenciado pela análise da repetição de nucleotídeos AC na região 3' não transcrita. Assim nossos dados indicam que, diferente da literatura, mutações no gene da anquirina podem não ser frequente em todas as populaçõesAbstract: In this study, we carried out the molecular analysis of 28 unrelated patients seen at the Hemocentro-UNICAMP with Hereditary Spherocytosis diagnosed by clinical data, peripheral blood smear and osmotic fragility test. Spectrin and/or ankyrin deficiency was detected in these patients, by densitometry of SDS-PAGE stained by Coomassie blue. By SSCP and DNA sequencing, two novel mutations were identified: In exon 9 (His ->Arg, CAC->CGC) and in exon 28 (lle-*Thr ATC->ACC) totalizing a frequency of 7,2% of ankyrin mutations in the Hereditary Spherocytosis population studied. Two novel polymorphisms were also observed: in exon 6 (codon 197,CCG ->CCA) and in exon 29 (codon 1162, AGT -" AGC), besides other polymorphisms already described in exon 4 (codon 105, AAT -> AAC), exon 16 (codon 594, TCC -> TCA), and exon 18 (codon 691, GGT -> GGC). Expression of ankyrin mRNA by SSCP-PCR of the AC repeat at the 3'ut region showed, in one patient, a defect in the transcription of one allele. Then, our data indicated that ankyrin defects might be not frequent in all populationsMestradoMestre em Ciências Médica

Un riparo nella valle dei templi di Agrigento

Il volume è l’esito di alcune riflessioni dei professori titolari delle cattedre dei corsi di Laboratorio di composizione architettonica e urbana, prof. R. Capozzi, prof.ssa P. Scala, prof.ssa V. Pezza, Prof. G. Szaniszlò, e delle relative esperienze didattiche svolte nei corsi di laboratorio al primo anno del CdL ARC5UE, a.a. 2020/2021, presso il Dip. di Architettura dell’Università degli studi di Napoli Federico II; ed infine restituisce le lectiones di docenti esterni al DiARC invitati al ciclo di seminari svolto a corsi congiunti. Il volume si suddivide in tre parti: Parte I - Il progetto didattico tra teoria e laboratori, Parte II - Le esperienze di laboratorio, Parte III - Architettura, città e archeologia. A curare il volume sono stati l’arch. Francesca Spacagna, referente del corso 1 A; l’arch. phd candidate Maria Fierro, referente del corso 1 B; l’arch. Davide Apicella, referente del corso 1 C; l’arch. Pasquale Abbagnale, referente del corso 1 D

Efficacy of tulathromycin in the control of respiratory disease in buffalo calves

The aim of this study was to evaluate the efficacy of tulathromycin in the control of respiratory diseases (BRD) in buffalo calves. The trial was performed in one buffalo farm located in the South of Italy where more than 2,000 animals are bred. An outbreak of BRD was considered when the animals showed three of the following criteria: rectal temperature >39.8°C, depression score >2 on a scale of 0 (alert) to 4 (soporous), respiratory rate >60 ⁄ min), dyspnoea (abnormal lung sounds) and cough or nasal discharge. A nasal swab was performed for microbiological investigations. After the results of the latter animals were treated with a standard therapeutic regimen on D 0, which consists of 2.5 mg/kg/live weight of tulathromycin (Draxxin®, Zoetis SRL, Italy) in a single administration. Daily clinical examinations were performed on treated calves for fourteen consecutive days to evaluate: A) depression score and general health status with a score from 0 (normal) to 4 (general conditions severely impaired); B) respiratory distress with a score from 0 (no alterations) to 3 (respiratory rate >80⁄min, abdominal breath and nasal discharge) and C) rectal temperature with a score from 0 (normal; 38.8-39°C) to 3 (> 40.3°C). Data were analyzed by analysis of variance. A total of 81 calves (53 females and 28 males) were included in the study. Bacteriological cultures revealed the presence of Pasteurella M. and Moraxella spp. in 53.1 and 38.3% of the samples, respectively. The average A, B and C scores were 2.24±0.1, 1.85±0.1 and 1.78±0.1 on day 0. Treatment was effective in solving the BRD in four days (Scores A, B and C = 0) in 79/81 calves (97.5%), and, consequently, 2/81 (2.5%) mortality rate was recorded. In conclusion, treatment with tulathromycin is highly effective in the control of the BRD in buffalo calves

Influence of Days after Calving and Thermal Stress on the Efficacy of a Progesterone-Based Treatment in Acyclic Italian Mediterranean Buffalo

The aim of this study was to evaluate the efficacy of a progesterone-based treatment on anoestrus in buffaloes. Primiparous acyclic buffaloes (n = 276), were divided into three classes according to their days in milk (DIM): from 50 to 90 (Class I; n = 86), from 91 to 150 (Class II; n = 102) and from 150 to 200 (Class III; n = 88). Animals were synchronized using P4 vaginal implants, followed by timed artificial insemination (TAI). They were then allowed to enter into a larger group of buffaloes for natural mating 15 days after AI was performed, and pregnancy status was monitored from then on at 15-day intervals. Finally, the temperature–humidity index (THI) was calculated. Statistical analysis was performed by ANOVA by means and both multiple and linear regression. The total pregnancy rate (PR) was 87.7%, with no differences among DIM classes (88.0, 92.4, and 80.0% in Classes I, II, and III, respectively). However, the PR at TAI tended to be higher (p = 0.07) in buffaloes in Class II. The follicle (FL) area in Class II buffaloes was larger (p < 0.01) than that of the other classes. No influence of the THI on the total PR was recorded. The pregnancy outcome at TAI was affected by the FL area (odds ratio = 2.237; p < 0.05) and body condition score (BCS) (odds ratio = 1.256; p < 0.05). In conclusion, treatment with vaginal P4 optimizes pregnancy rates in anoestrus buffaloes, particularly when the animals are in mid-lactation and show an optimal BCS. Furthermore, the THI does not seem to affect the efficiency of the progesterone treatment

Inferring Emotional Models from Human-Machine Speech Interactions

Human-Machine Interfaces (HMIs) are getting more and more important in a hyper-connected society. Traditional HMIs are built considering cognitive features while emotional ones are often neglected, bringing sometimes such interfaces to misuse. As a part of a long run research, oriented to the definition of an HMI engineering approach, this paper concretely proposes a method to build an emotional-aware explicit model of the user starting from the behaviour of the human with a virtual agent. The paper also proposes an instance of this model inference process in voice assistants in an automatic depression context, which can constitute the core phase to realize a Human Digital Twin of a patient. The case study generated a model composed of Fluid Stochastic Petri Net sub-models, achieved after the data analysis by a Support Vector Machine