The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected at China in December 2019 and rapid worldwide spread, causing the coronavirus disease 2019 (COVID-19). In this pandemic situation, the importance of structural-functional relationships between virus and host cell should be considered. In this work, we investigated the molecular interactions of seven drugs used in clinical therapy by in silico analysis with specific protein target of SARS-CoV-2 – RBD domain of the Brazilian S protein genome sequence – in docking models. Initially, a three-dimensional structure of SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) model was obtained by homology. Then, a prediction analysis of cavities in the RBD structure was performed to detect a possible active site in the S protein fragment. Our molecular docking study demonstrated that only 2 ligands showed considerably acceptable values in relation to the seven drugs (Umifenovir, Darunavir, Lopinavir, Ritonavir, Remdesivir, Pirfenidone, Oseltamivir) used to screen. The interaction between Lopinavir and RBD revealed binding affinity of -9.8 kcal/mol and interactions with residues PHE168, GLY167, SER176, GLN175, GLU166, LEU134, LEU137, TYR171, PHE138, LEU174, PHE172. Ritonavir demonstrated binding affinity of -8.9 kcal/mol and interactions with residues ARG148, ASN130, VAL23, SER81, ASN33, PHE29, TYR33, SER31, ASN132, ALA26, ALA30, ALA34, TYR133. Molecular dynamics simulations were performed to evaluate the stability of the complexes formed. The present study shows that protease inhibitors Lopinavir and Ritonavir have best binding at the active site (the RBD of S protein) through molecular docking.
Background: Hypothyroidism is an endocrine disease that leads to a reduction in the hormones thyroxine (T3) and triiodothyronine (T4), which therapy with levothyroxine restores the clinical signs related to the metabolic rate. Due to the influence of thyroid hormones on the heart, which is under the constant influence of the autonomic nervous system (ANS), dogs with hypothyroidism can develop bradycardia, arrhythmia, and dysautonomia. Heart rate variability (HRV) assesses autonomic modulation by the Holter method, which is scarce in dogs. We aimed to report the cardiac and autonomic effects of the primary hypothyroidism untreated and treated with levothyroxine in a canine case by Holter monitoring.Case: A 7-year-old female Dalmatian, weighing 36 kg, was referred for clinical evaluation due to apathy, weight gain, low hair quality, and lethargy. On physical examination, alopecic lesions on the hind limbs and tail, as well as bradycardia with a heart rate (HR) of 40-50 beats per minute (bpm) were observed, in addition to a 3/6 mitral murmur and 2/6 tricuspid murmur. Given the suspicion of thyroid gland disorder, the blood hormonal measurement revealed an increase in thyroid-stimulating hormone (TSH; 0.65 ng/mL) and a decrease in free T4 (0.11 ng/mL) and total T4 (0.44 ng/mL), confirming primary hypothyroidism. Therapy was started with a minimum dose of levothyroxine (0.913 mg, every 12 h), which clinical signs were restored in five months of treatment, with weight loss, hair growth, and active behavior. To assess the impact of untreated and treated hypothyroidism on the patient’s ANS, a Holter monitoring exam was performed for 24 h before and after therapy. Before treatment, the average HR was 75 bpm, and the HR<50 bpm occurred during 05 h 20 min 36 s. Still, 320 pause events (>2.0s), 1st-degree atrioventricular blocks (AVB), six ventricular ectopias events, and 2nd-degree sinoatrial block (SAB) were also observed. The ANS parasympathetic tone was significantly stimulated, highlighting bradycardia, arrhythmia, and dysautonomia. After five months of treatment with levothyroxine, the average HR was 89 bpm, and the HR<50 bpm occurred during 02 h 06 min 13 s. No ventricular pauses, blocks, or ectopias were observed, showing the stimulation of sympathetic tonus, which restored HR and ANS balance. Still, it was observed that the minimum levothyroxine dose corrected cardiac changes by increasing the low frequency (LF), decreasing the high frequency (HF), and, consequently, increasing the LF/HF ratio, normalizing the frequency conditions in HRV.Discussion: In the frequency index, HF indicates the vagal activity, whereas LF indicates both systems with parasympathetic predominance. Before treatment, the dog had a low LF/HF ratio (0.46), indicating dysautonomia with parasympathetic stimulation. After therapy, the conditions of bradycardia and functional cardiac capacity were corrected, restoring ANS, due to the serum recovery of thyroid hormones. This study reported the cardiac and autonomic effects of primary hypothyroidism untreated and treated with levothyroxine on a dog, that had intense bradycardia and abnormal stimulation of the parasympathetic tone, associated with episodes of 1st-degree AVB, ventricular ectopias, and 2nd-degree SAB. After therapy with a minimum dose of levothyroxine, there was a decrease in parasympathetic activity and an increase in sympathetic stimulus, correcting cardiac changes, and restoring the balance of ANS. As it is a simple, non-invasive, and safe tool that helps the clinician to understand cardiac autonomic modulation, it is recommended to adopt the Holter monitoring exam in cases of hypothyroidism cases to assess sympathetic-vagal balance and check potential cardiac risks.
Background: Thyroid hormones have important effects on the cardiovascular system, of which the main ones are the increase in the heart response to the autonomic sympathetic nervous system. Heart rate variability is a non-invasive method of assessing autonomic heart modulation, thus being an important form of evaluation in patients with thyroid dysfunctions. This study aimed to report electrocardiographic and heart rate variability data of a dog with hypothyroidism that presented a parasympathetic dysfunction.Case: A 7-year-old female Dalmatian dog was admitted for clinical evaluation in Fortaleza, Brazil. According to the owner, she had been apathetic for a year, had gained weight, always had a sad expression, and her hair was generally brittle and opaque. On physical examination, skin lesions were observed at the end of the spine, extending to the tail region, with the latter showing total alopecia. Low T4 levels confirmed the diagnosis of primary hypothyroidism. Then, a 24-h Holter monitoring was performed, which showed that the animal had sinus arrhythmia associated with moments of second-degree sinoatrial block and rare moments of sinus tachycardia. In addition, moments of premature multifocal ventricular extrasystoles and 1st-degree atrioventricular block were observed. Based on the Holter results, heart rate variability (HRV) was calculated. Regarding the HRV in the frequency domain, 32.16 was obtained in the low frequency (LF) band, 67.84 in the high frequency (HF) band, and the LF / HF ratio was 0.46, with a total power of 5205. As for the HRV in the time domain, RMSSD was 117, pNN50 was 62.64 and SDNN was 384. This showed an increase in the parasympathetic activity of the heart and, due to this increased activity, a second-degree sinoatrial block occurred, which is a sinus function disturbance resulting from the exacerbated parasympathetic activity.Discussion: Beta-adrenergic receptors have their expression and activity altered by thyroid hormones. The sympathetic stimulation on the heart through the activation of these receptors originates a positive inotropic, lusitropic, dromotropic and chronotropic effect. Therefore, in the absence of thyroid hormones, there is a decrease in this stimulation, thus allowing a preponderant parasympathetic tone. In the present report, the increase in the parasympathetic tonus, observed in hypothyroidism, resulted in a reduction in the frequency of sinus firing, slowing of intranodal and sinoatrial conduction, and shortening of the effective refractory period, a combination of factors that led to decreased HR observed in the Holter monitoring. Previous studies have shown that thyroid hormones increase sympathetic activity, mainly in the heart, since they do not act by increasing the production or release of catecholamines, but rather increasing catecholamine response on the heart, due to a positive regulation of Ca2+-ATPase channels of the sarcoplasmic reticulum and beta1-adrenergic receptors. Thus, the observed result was already expected, because in hypothyroidism there is a decrease in these hormones that increase the sympathetic activity on the heart and so, the parasympathetic tone was very evident. The study of heart rate variability allows the simple assessment of the autonomic nervous system imbalance, and may be extremely important in the follow-up of diseases that affect this balance, such as hypothyroidism. Hence, more studies are required to verify the effect of such diseases on heart rate variability, aiming to define associations between the diseases and the alterations, as well as to define parameters of normality for such examinations.
Background: The malignant neoplasms, in general, constitute one of the main causes of death in dogs and cats. The multiple myeloma is a neoplasm characterized by the monoclonal proliferation of plasma cells in the bone marrow, causing several systemic symptoms and it is rare in pets, representing less than 1% of the malignant neoplasms in these animals. It usually occurs in older dogs. Thus, the purpose of this report was to describe a case of multiple myeloma in a 10-year-old poodle dog, occurred in the Veterinary Hospital Unit of the State University of Ceará.Case: A 10-year-old Poodle bitch was admitted in the Veterinary Hospital Unit of the State University of Ceará presenting lump erythematosus, alopecic, soft and ulcers in the region of the digits of the left front leg, pain and lameness. The blood count evidenced normocytic and normochromic anemia, presence of rouleaux, lymphopenia and monocytopenia, and the biochemical exams have demonstrated an elevated value of alanine aminotransferase (ALT). The cytology of the nodule indicated probable diagnosis of plasma cell neoplasm and radiographic examination showed the presence of bone lysis, and therefore the patient underwent amputation of the affected limb surgery. A biopsy of the nodule indicated neoplastic proliferation, with an arrange compatible to plasmacytoma of cleaved type. A follow-up consultation was realized 30 days after surgery, and 2 new nodules appeared in the superior lip region and close to the surgery site. A new blood count indicated anemia with presence of rouleaux, thrombocytopenia, leucopenia, lymphopenia and monocytopenia, and the biochemical results showed a discrete diminution of aspartate aminotransferase(AST) and a considerable increase on the alkaline phosphatase levels. The cytology of the new nodules indicated plasmacytoma, and was realized a myelogram, that showed dysplastic marrow plasma cells, with more than 20% of plasma cells.Discussion: In the present case, the patient’s lump grew rapidly with bleeding and ulcer formation. The animal presented bone involvement, which characterizes the most suggestive sign of multiple myeloma. Justified by the stimulating factor of osteoclasts, promoting bone lysis, which can cause pathological fractures and pain. The amputation was a partial treatment to attenuates the discomfort and pain presented by the patient. The appearance of new nodules stimulated a more detailed investigation for multiple myeloma. The enzyme AST presented a discrete diminution, and ALT initially was higher than normal, but then returned to normal values. So, the elevated activity of alkaline phosphatase directed the suspects to multiple myeloma, since the activity of AST and ALT was normal, the alkaline phosphatase level was ligated to bone diseases. The rouleaux was constant at the hemograms, this is justified by the excess of immunoglobulins produced in marrow. Based on the chart presented by the patient, the bone marrow was punctured for myelogram. The symptoms displayed by the animal along with the cytological analysis, histopathological, hematological, biochemical and with myelogram indicated diagnosis of multiple myeloma. Other exams could be investigated, for example, detection of Bence Jones proteinuria, serum calcium dosage and inmunoelectroforesis for determination of the type of immunoglobulin produced by the plasma cells in the bone marrow. The definitive diagnostic was established approximately three months after the first consult, emphasizing the importance of a multiple myeloma differential diagnostic in case of plasma cell neoplasm.
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