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Timothy Syndrome 1 (TS1) is a multiorgan form of Long QT Syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. Here, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C, known to impair CaV1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using reentry vulnerability index, which we further demonstrate can be used as a benchmark for predicting treatment efficacy, as shown by pharmacological shortening of action potential using HERG channel agonist ICA-105574. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca2+ overload and decreased peak INa current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.

Anti-thymocyte or anti-lymphocyte globulins (ATGs/ALGs) are immunosuppressive drugs used in induction therapies to prevent acute rejection in solid organ transplantation. Because animal-derived, ATGs/ALGs contain highly immunogenic carbohydrate xenoantigens eliciting antibodies that are associated with subclinical inflammatory events, possibly impacting long-term graft survival. Their strong and long-lasting lymphodepleting activity also increases the risk for infections. We investigated here the in vitro and in vivo activity of LIS1, a glyco-humanized ALG (GH-ALG) produced in pigs knocked out for the two major xeno-antigens αGal and Neu5Gc. It differs from other ATGs/ALGs by its mechanism of action excluding antibody-dependent cell-mediated cytotoxicity and being restricted to complement-mediated cytotoxicity, phagocyte-mediated cytotoxicity, apoptosis and antigen masking, resulting in profound inhibition of T-cell alloreactivity in mixed leucocyte reactions. Preclinical evaluation in non-human primates showed that GH-ALG dramatically reduced CD4+ (p=0.0005,***), CD8+ effector T cells (p=0.0002,***) or myeloid cells (p=0.0007,***) but not T-reg (p=0.65, ns) or B cells (p=0.65, ns). Compared with rabbit ATG, GH-ALG induced transient depletion (less than one week) of target T cells in the peripheral blood (

This study was conducted to determine first local diagnostic reference levels (DRLs) and achievable doses (ADs) for pediatric patients during the most common computed tomography (CT) procedures in Yazd province. The DRL was obtained based on volume CT dose index (CTDIvol) and dose length product (DLP) for four various age groups of children. Data were collected from the most commonly performed pediatric CT scans, including abdomen–pelvis, chest, brain and sinus examinations, at six high-loaded institutes. The patients’ data (766 no.) in terms of CTDIvol and DLP were obtained from four age groups: ≤1-, 1–5-, 5–10- and 10–15-y-old. The 75th percentiles of CTDIvol and DLP were considered as DRL values and the 50th percentiles were described as ADs for those parameters. Consequently, the acquired DRLs were compared with other national and international published values. The DRLs in terms of CTDIvol for abdomen–pelvis, chest, brain and sinus examinations were 3, 8, 9 and 10 mGy; 4, 5, 5 and 5 mGy; 25, 28, 29 and 38 mGy; and 23, 24, 26 and 27 mGy for four different age groups of ≤1-, 1–5-, 5–10- and 10–15-y-old, respectively. The DRL values in terms of DLP were 75, 302, 321 and 342 mGy.cm; 109, 112, 135 and 170 mGy.cm, 352, 355, 360 and 481 mGy.cm; and 206, 211, 228 and 245 mGy.cm, respectively, for the mentioned age groups. In this study, the DRL and AD values in the brain examination were greater among the other studied regions. The DRL plays a critical role in the optimization of radiation doses delivered to patients and in improving their protection. This study provides the local DRLs and ADs for the most common pediatric CT scanning in Yazd province to create optimum situation for the clinical practice.

Amyotrophic Lateral Sclerosis is still a poorly understood neurological syndrome showing muscle impairment and leading to death because of respiratory failure. Recently, a new, transgenic swine model overexpressing the human superoxide-dismutase 1 gene, promised the chance to investigate animals before disease onset, and we planned to investigate vascular alterations that we recently learned to quantify. In order to address for feasibility, we checked angioarchitectures in spinal cord samples of at least one animal for each of three health conditions: healthy, asymptomatic, clear motor symptoms. Furthermore, analyses were carried out in three different regions: cervical, thoracic and lumbar districts.

Case 1. Female, 27 years old, with migraine with aura. Use of combined contraceptive therapy. She presented visual and cutaneous complaints for eight months, using prednisone 60mg/day due to the hypothesis of systemic vasculitis. On examination, right temporal hemianopsia, normal fundus of the eye, Raynaud ‘s phenomenon with necrosis stitches in fingers and livedo were noted. Brain MRI with diffusion restriction in the left occipital lobe, hypersignal foci in the parietal lobe, and head of the left caudate nucleus. Reticular Livedo (RL) compatible biopsy. Anticardiolipin IgM (13.3 U/mL), ESR (47mm/h in the 1st hour and 52mm/h in the 2nd hour), and VDRL 1:8 reagents. Normal CSF. Initially treated with warfarin, she has been using rivaroxaban for two years, remaining asymptomatic. Case 2. Female, 39 years old, with a report of sudden dysarthria and right hemiparesis, with a previous episode of vertigo. A lumbosacral spine MRI was performed, presenting no alterations. Normal CSF. Antiphospholipid antibodies: Beta-2-glycoprotein I IgM 21 UR/mL and IgG 9 UR/mL, lupus anticoagulant 0.98, anticardiolipin IgG 9.4 GPL and IgM 31 MPL. Cranial MRI showed old ischemic gaps and hyperintense areas on T2/FLAIR with diffusion restriction affecting the left paramedian portion of the pons, related to acute stroke. Presence of livedo in the distal region of the limbs. In current use of warfarin 7.5mg/day, presenting remission of symptoms. Discussion: Sneddon Syndrome (SS) is a non-inflammatory thrombotic vasculopathy characterized by the concomitant presence of livedo reticularis and stroke. Neurological manifestations are present in up to 77% of cases. It is more prevalent in women between 20 and 42 years old. Treatment is aimed at preventing potentially serious, disabling, and even fatal new vascular events. Final Comments: SS is a rare syndrome that probably results from a series of acquired or congenital hemostatic abnormalities that preferentially involve the cutaneous and cerebral vascular beds. Although it has no specific biomarker, there are reports associating SS with antiphospholipid antibodies and VDRL reactor. Clinical presentation, laboratory findings and skin biopsy associated with an excellent response to anticoagulant treatment were fundamental in the diagnostic elucidation.

Left ventricular noncompaction is a rare cardiomyopathy, of unknown etiology, characterized by a compacted epicardium, and an endocardium with prominent LV trabeculae and deep intertrabecular recesses that communicates with the ventricular cavity. It has been linked to thromboembolic complications in 5% to 38% of cases, even in young patients, due to possible thrombogenesis in the intertrabecular recesses and association with cardiovascular or coagulation abnormalities, which increase the risk of systemic embolism. Noncompaction of the Left Ventricular Myocardium is considered an underdiagnosed condition. Stroke is one of its main complications, and prophylactic anticoagulation is recommended in patients with LV EF ≤ 40%, history of embolism or transient ischemia, atrial fibrillation and intracardiac thrombi identified in imaging exams.

Background: Excessive use of computed tomography (CT) has become a worrying issue due to the potential risks corresponding to the radiation exposure. Purpose: This study was to investigate trends in CT usage in Yazd Province, Iran. Material and Methods: Patients were categorized in regard to sex and their age into two general groups, pediatrics (

1 INTRODUÇÃOOs impactos da COVID-19 e de suas medidas de contenção vêm afetando, direta e indiretamente, a faixa etária infantil, que apresenta maior vulnerabilidade aos riscos ambientais, gerando diversos efeitos nocivos ao desenvolvimento adequado. Tendo em vista que a saúde física e mental e a produtividade na vida adulta estão profundamente enraizadas nos primeiros anos de vida e que pesquisas sobre impactos de desastres sanitários anteriores indicam claras consequências adversas, é fundamental o domínio desta discussão para minimizar os resultados negativos da pandemia no desenvolvimento infantil. 2 OBJETIVOAnalisar possíveis repercussões da pandemia da COVID-19 no desenvolvimento infantil adequado. Método: Foi realizada uma revisão de literatura na base de dados MedLine, em Agosto de 2021, utilizando os descritores “COVID-19”, “child development”, “impact” e variações segundo MeSH. Adotou-se a escala PRISMA para sistematização do estudo. Foram incluídos ensaios clínicos controlados e randomizados em humanos de 0 a 18 anos e publicados originalmente na língua inglesa entre 2020 e 2021. Foram excluídos artigos não relacionados diretamente ao tema, que não possuíam metodologia clara ou que não preenchiam os critérios de inclusão. 3 RESULTADOSA pandemia em curso afeta todos os 5 domínios dos cuidados e atenção ao desenvolvimento infantil (saúde, nutrição, cuidados responsivos, segurança e proteção e aprendizagem oportuna) necessários para as crianças atingirem seu pleno potencial. O isolamento social combinado ao medo de contágio e à sobrecarga de informações causam estresse crônico, que está relacionado a maior risco de desenvolvimento de ansiedade e depressão. Transtorno de estresse pós-traumático foi identificado em 30% das crianças em quarentena. Os estudos encontraram mudanças nos comportamentos dietéticos com aumento do consumo de alimentos não saudáveis, o que, associado à restrição de atividade física, eleva a incidência de pré-diabetes, diabetes, obesidade e hipertensão, favorecendo o surgimento precoce de doenças cardiovasculares na população pediátrica. Há, também, o estresse experimentado pelos cuidadores, que prejudica a capacidade de fornecer cuidados adequados não só pelo prejuízo econômico, agravante da situação de pobreza, mas também pelo aumento de casos de violência doméstica. Ademais, o fechamento das escolas dificulta experiências concretas, interativas e lúdicas, limitando o aprendizado e intensificando o tempo de tela, o que predispõe maior dependência de internet e cyberbullying. Tal cerceamento pode ser irreparável, devido a maior neuroplasticidade durante a infância. Um estudo realizado em 2020 com 320 crianças e adolescentes demonstrou que todo esse contexto ocasionou: dependência excessiva dos pais (36%), desatenção (32%), preocupação (29%), problemas de sono (21%), falta de apetite (18%), pesadelos (14%), desconforto e agitação (13%). 4 CONCLUSÃOTodas as adversidades relatadas durante a infância são precipitadores de estresse tóxico, alterando conexões cerebrais e gerando mudanças potenciais permanentes na função cerebral, o que prejudica tanto o desenvolvimento da linguagem quanto o de habilidades cognitivas e socioemocionais, além de proporcionar hiperresponsividade ao estresse. Assim, é importante que profissionais da saúde que lidam com o meio pediátrico (como pediatras, fisioterapeutas, fonoaudiólogos, psicólogos) estejam cientes das consequências que possam surgir no período pós-pandêmico, a fim de proporcionar um acompanhamento mais adequado, atualizado e cuidadoso da saúde da criança nos próximos anos.

Nanodrug delivery systems are novel strategies for tumor treatment since delivery of chemotherapy drugs such as paclitaxel (PTX) is associated with substantial challenges due to its poor aqueous solubility. In addition, sonodynamic therapy (SDT) is a promising approach that can increase the uptake, accumulation, and dispersion of desirable amounts of the drugs by activating sonosensitizer and enhancing cell membrane permeability. Herein, gold-paclitaxel nanoparticles (Au-PTX NPs) were synthesized and characterized to evaluate the cytotoxicity toward C540 cancer cells in comparison of free PTX, AuNPs, and AuNPs+free PTX in the absence and presence of ultrasound radiation. Evidence shows that AuNPs have a median diameter size of 95.0 ± 15.4, while the size of Au-PTX NPs is roughly 219.7 ± 40.4 nm. Negative zeta-potential results indicate high stability and good dispersion of nanoparticles. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay results revealed that Au-PTX NPs increased the cytotoxicity compared to other treatment groups that ensure the great potential of AuNPs as a promising nano-carrier for PTX drug delivery. Moreover, the viability of C540 cells treated by Au-PTX NPs under ultrasound radiation was decreased significantly by generating more reactive oxygen species (ROS) upon STD, with representing synergism effects confirming the role of gold nanoparticles as an excellent sonosensitizer and the role of SDT as an adjunctive treatment method with chemotherapy.

SummaryThis study was performed to improve production efficiency at the level of recipient pig and donor nuclei of transgenic cloned pigs used for xenotransplantation. To generate transgenic pigs, human endothelial protein C receptor (hEPCR) and human thrombomodulin (hTM) genes were introduced using the F2A expression vector into GalT–/–/hCD55+ porcine neonatal ear fibroblasts used as donor cells and cloned embryos were transferred to the sows and gilts. Cloned fetal kidney cells were also used as donor cells for recloning to increase production efficiency. Pregnancy and parturition rates after embryo transfer and preimplantation developmental competence were compared between cloned embryos derived from adult and fetal cells. Significantly higher parturition rates were shown in the group of sows (50.0 vs. 4.1%), natural oestrus (20.8 vs. 0%), and ovulated ovary (16.7 vs. 5.6%) compared with gilt, induced and non-ovulated, respectively (P < 0.05). When using gilts as recipients, final parturitions occurred in only the fetal cell groups and significantly higher blastocyst rates (15.1% vs. 21.3%) were seen (P < 0.05). Additionally, gene expression levels related to pluripotency were significantly higher in the fetal cell group (P < 0.05). In conclusion, sows can be recommended as recipients due to their higher efficiency in the generation of transgenic cloned pigs and cloned fetal cells also can be recommended as donor cells through correct nuclear reprogramming.

Extracellular Vesicles analysis in cerebrospinal fluid of transgenic pigs: a model for biomarker discovery in Amyotrophic Lateral Sclerosis

Heterologous polyclonal antibodies might represent an alternative to the use of convalescent plasma or monoclonal antibodies (mAbs) in coronavirus disease (COVID‐19) by targeting multiple antigen epitopes. However, heterologous antibodies trigger human natural xenogeneic antibody responses particularly directed against animal‐type carbohydrates, mainly the N‐glycolyl form of the neuraminic acid (Neu5Gc) and the α1,3‐galactose, potentially leading to serum sickness or allergy. Here, we immunized cytidine monophosphate‐N‐acetylneuraminic acid hydroxylase and α1,3‐galactosyl‐transferase (GGTA1) double KO pigs with the Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike receptor binding domain to produce glyco‐humanized polyclonal neutralizing antibodies lacking Neu5Gc and α1,3‐galactose epitopes. Animals rapidly developed a hyperimmune response with anti‐SARS‐CoV‐2 end‐titers binding dilutions over one to a million and end‐titers neutralizing dilutions of 1:10 000. The IgG fraction purified and formulated following clinical Good Manufacturing Practices, named XAV‐19, neutralized spike/angiotensin converting enzyme‐2 interaction at a concentration, GGTA1/CMAH double KO pigs produced high titers of XAV‐19, an anti‐SARS‐Cov‐2 RBD glyco‐humanized polyclonal antibody. XAV‐19 is presented with a high complement activation and a high neutralization potency in vitro and in cell‐based neutralization assays. XAV‐19 does not interact with human Fc gamma receptors, preventing Fc‐dependent enhancement or immune cells skewing.