Role of SARS-CoV-2 neurotropism and neuroinvasion in COVID-19 patients disease severity / Papel del neurotropismo y neuroinvasión de SARS-CoV-2 en la gravedad de los pacientes con COVID-19

Abstract The disease caused by the new SARS-CoV-2 coronavirus (COVID-19) spread rapidly from China to the entire world. Approximately one third of SARS-CoV-2-infected patients have neurological disorders, especially those classified as severe cases and that require mechanical ventilation. On the other hand, almost nine out of 10 patients admitted to an Intensive Care Unit could not breathe spontaneously, thus requiring invasive and non-invasive ventilatory support. So far, whether early neurological disorders such as hyposmia or anosmia, dysgeusia or ageusia, headache and vertigo are significant in the progression to the severe form of the disease or whether they are related to entry to the central nervous system via peripheral nerves has not been determined. Considering the great similarity between SARS-CoV and SARS-CoV-2, and that the severity of the condition that leads to death cannot be explained solely by lung involvement, it is important to determine whether SARS-CoV-2 potential invasion to the central nervous system is partially responsible for the severe respiratory component observed in patients with COVID-19.

Resumen La enfermedad (COVID-19) producida por el nuevo coronavirus SARS-CoV-2 se extendió rápidamente desde China a todo el mundo. Aproximadamente una tercera parte de los pacientes infectados de SARS-CoV-2 presenta alteraciones neurológicas, con mayor frecuencia los clasificados como graves que requirieron ventilación mecánica. Por otro lado, casi nueve de cada 10 pacientes admitidos en una unidad de cuidados intensivos no podían respirar espontáneamente, por lo que ameritaron apoyo ventilatorio invasivo y no invasivo. Hasta el momento no se ha determinado si las alteraciones neurológicas tempranas como la hiposmia o anosmia, disgeusia o ageusia, cefalea y vértigo son significativas en la progresión a la forma grave de la enfermedad y se relacionan con la entrada al sistema nervioso central a través de los nervios periféricos. Considerando la gran similitud entre SARS-CoV y SARS-CoV-2 y que la severidad del cuadro que conduce a la muerte no puede ser explicado únicamente por la afección pulmonar, es importante determinar si la invasión potencial del SARS-CoV-2 al sistema nervioso central es parcialmente responsable del componente respiratorio severo que presentan los pacientes con COVID-19.

The protective effects of cyclosporin A on vascular permeability in sepsis rats / 药学学报

The protective effects of cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPTP), on vascular permeability in sepsis rats were investigated. Cecal ligation and puncture (CLP)-induced sepsis rats were used for in vivo studies, and the effects of CsA (1 and 5 mg·kg-1) on vascular permeability of lung, kidney, and intestine, mitochondrial respiratory control ratio, and the survival of the sepsis rats were observed. Lipopolysaccharide (LPS) was used for stimulating vascular endothelial cells (VECs) in vitro, and the effects of CsA on leakage of microvascular, immunofluorescence of zonula occludes-1 (ZO-1), and transendothelial electrical resistance (TER) were observed. All the animal welfare and experimental procedures are in accordance with the regulations of the Animal Ethics Committee of the Army Medical University. Compared with sham-operated group, the vascular permeability of lung, kidney, and intestine in sepsis rats increased significantly (P<0.05). Compared with conventional treatment group, CsA could significantly decrease the vascular permeability of lung, kidney, and intestine (P<0.05 or P<0.01), and prolong the survival period. The results of microcirculation also showed that CsA could significantly reduce the permeability of mesenteric venules in sepsis rats. At the cellular level, LPS stimulation significantly increased the permeability of vascular endothelial cells, including the decrease of transmembrane resistance and protein expression of ZO-1 (P<0.05). CsA can significantly reduce the increase of permeability of vascular endothelial cells induced by LPS stimulation (P<0.01). The function of mitochondria in the kidneys and intestines of sepsis rats was obviously impaired, and the respiratory control ratio of mitochondria was decreased. LPS significantly increased MPTP opening of VECs, while CsA significantly inhibited MPTP opening and improved mitochondrial function. CsA may protect mitochondrial function by inhibiting the opening of MPTP and play a protective role in the vascular permeability of sepsis rats. This study will provide an insight for the treatment of sepsis vascular leakage.

Comparison of myocardial injures between asphyxia and ventricular fibrillation models of cardiac arrests / 中华急诊医学杂志

Objective To compare the difference in cardiac injuries between asphyxia and ventricular fibrillation modes in different periods after cardiac arrest (CA).Methods The model was established in Cardiopulmonary Resuscitation Lab,Sun Yat-sen University.A total of 35 male SD rats were used to produce the asphyxia or ventricular fibrillation (VF) cardiac arrest models randomly.Both of the two modes were induced 8 minutes cardiac arrest.The myocardial HE stains,mitochondrial respiratory control ratio (RCR),and echocardiography were observed at 4 h,24 h and 72 h after ROSC (restoration of spontaneous circulation).The results were expressed as (-x ± s),t test was performed to compare between two groups,and one way analysis of variance was used to compare multiple groups.P ＜ 0.05 was considered as significant difference.Results HE stains showed damages were more serious in the VF mode than in asphyxia mode at 4 h,and both of them had a disorderly-arranged myocardium at 72 h.RCR in VF mode became worse at 4 h,and RCR resumed at 24 h in both modes without significant difference compared with the sham operated rats.The echocardiography showed VF mode had a lower left ventricular ejection fraction (LVEF) than asphyxia mode at 4 h (29.68％ vs.42.16％,P =0.03),and there was no difference in LVEF between VF mode and the sham operated rats at 24 h,however no difference in LVEF between the asphyxia and sham operated rats at 72 h.Both of them had a thicker left ventricular anterior wall than the sham operated rats at 72 h (2.41 mm vs.1.72 mm,P=0.013; 2.61 mmvs.1.72 mm,P=0.007),and there was no significant difference between them.Conclusions The ventricular fibrillation mode has a more severe injuries in early period,but it recovers sooner than asphyxia one.Both of two groups get compensatory left ventricular hypertrophy in later period of ROSC.

Expression of 5-HT2A receptor in brainstem affects the occurrence of central sleep apnea in Sprague-Dawley rat / 实用医学杂志

Objective To investigate the correlationship of 5-HT2A receptor expression in the brainstem and sleep apnea in Sprague-Dawley (SD)rat. Method PSG monitoring for sleep and sleep apneas scoring was performed in freely moving SD rats. The level of 5-HT2A protein in rat brainstem was detected by Western blot and the relationship of 5-HT2A level with sleep apneas was analyzed. Results Two types sleep apnea model were obtained in rats, one was post-sigh sleep apnea (PS) and the other was spontaneous apnea (SP). The sleep apnea index was negatively correlated with the amount of 5-HT2A receptor level in brainstem (r=0.672,P 0.05). Conclusion The expression of 5-HT2A receptor in brainstem was negatively correlated with the severity of post-sigh sleep apnea. This association implies that 5-HT 2A receptor plays a critical role in the respiratory network and is closely correlated with the occurrence of central sleep apneas.

Un modelo anfibio para el estudio evolutivo del control respiratorio / Anphibian model study for evolutionary respiratory control

Los enormes progresos de la medicina perinatal han permitido la sobrevivencia de recién nacidos prematuros en estadios de desarrollo cada vez más precoces. Estos pequeños pacientes requieren de medios muy sofisticados y costosos para paliar su inmadurez respiratoria. Además de las complicaciones asociadas al desarrollo pulmonar, la inestabilidad respiratoria y las apneas asociadas a la inmadurez de los circuitos nerviosos productores del control respiratorio, contribuyendo éstos últimas, como factor principal de morbilidad, a las prolongadas hospitalizaciones que presenta esta tan vulnerable población. Éstos imperativos médicos combinados a la curiosidad fisiológica han contribuido al desenvolvimiento de novedosas investigaciones en neurobiología respiratoria. Si bien la mayoría de los trabajos realizados en éste campo utilizan a los múridos como modelos experimentales, las investigaciones recientes efectuadas a partir del tronco cerebral aislado de anfibios (Rana catesbeiana) han revelado las ventajas técnicas de este modelo animal, para mostrar los principales fenómenos que rigen el funcionamiento y el desarrollo del sistema de control respiratorio entre los vertebrados. El presente artículo se propone repasar los avances más recientes realizados en la investigación de la neurobiología evolutiva del control respiratorio, prestando una atención particular a la respiración episódica, así como al rol que desempeñan la modulación serotoninérgica y Gabaérgica de la actividad respiratoria en el curso del desarrollo.

Recent perinal advances have made possible that premature newborns survive increasingtly in earlier developmental stages. This babies requires sophisticated and costly critical intensive care to address the problems associated with inmadurity of the respiratory system. In addition respiratory instability and apnea reflecting inmaturity of the respiratory control system are major causes of morbidity and prolonged hospitalization in this highly vulnerable group of patients. These concerns have contributed to the development of research in respiratoy evolutionary neurobiology. While the majority of researchers working in this field use rodents as an animal model, recent research using in vitro brainstem preparations from bullfrog (Rana catesbeiana) have reveled the technical advantages of this model to study the basic principles underlying respiratory control and its ontogeny between vertebrates. The present article review the recent advances in the area of research with special interest on episodic breathing and the role of serotoninergic and GABAergic modulation of respiratory control during development.

Efeitos do pré-condicionamento hepático em ratos cirróticos, submetidos à isquemia e reperfusão hepática resultados preliminares

We studied the influence of ischemic preconditioning in rat liver cirrhosis.The cirrhosis were induced in wistar rat with occlusion of biliary duct before 30 days operation and divided into group A, ischemic preconditioning and ischemic/reperfusion, and group B, only ischemic/reperfusion. In group A the preconditioning consisted of 5 min ischemic and 10 min reperfusion. The ischemic/reperfusion consisted of 20 min ischemic and 120 min reperfusion for both groups. The level of respiratory control reason (RCR) in the liver tissue 120 min after reperfusion was not difference significantly in the groups. Therefore it suggests that the preconditioning cam be viability and another object of studies must be rated in future this work.

Baseando-se nos efeitos estimuladores do metabolismo energético pelo pré-condicionamento isquêmico (PCI) no tecido hepático, estudou-se dois grupos de ratos cirróticos submetidos a isquemia de 20 min e reperfusão de 120 min, após o PCI ou não respectivamente, determinando assim o valor do seu uso no prolongamento da manobra de Pringle e na regeneração hepática na hepatectomia.

Mechanisms of hepatocytic mitochondria damage following septic shock / 中国病理生理杂志

AIM: To study mechanism of hepatocytic mitochondria damage following septic shock. METHODS: 30 SD rats were randomly divided into three groups: sham operation group, 12 h cecal ligation and puncture (CLP) group and 16 h CLP group. The model of septic shock was made by cecal ligation and puncture. The liver mitochondria respiratory control rate (RCR), phosphate/oxygen (P/O) and ATPase activities were assayed. RESULTS: In 12 h CLP group mean artery pressure (MAP) [(9.54?1.26) kPa] was significantly lower than sham operation group [(14.58?1.32) kPa, P

Correlative study on changes of liver mitochondria calcium content and respiratory function in obstructive jaundice and biliary drainage / 中华肝胆外科杂志

Objective To elucidate the relationship between liver mitochondria calcium content and respi- ratory function in obstructive jaundice and biliary drainage.Methods The model of obstructive jaundice and bil- iary drainage was produced in dogs by common bile duct ligation and choledochoduodenostomy.The liver mitochon- dria were isolated and the calcium content and respiratory control rate were monitored.Results Mitochondria res- piratory control rate and calcium content significantly decreased and elevated respectively after bile duct ligation and there were varying degrees of recovery after biliary drainage,and the degree of recovery was evidently correlated with the duration of obstruction before drainage and the time after drainage.There was a strong negative correlation between the mitochondria calcium content and change of respiratory function.Conclusion The mitochondria cal- cium overload may be one of important factors for suppressed mitochondrial respiration in obstructive jaundice and early relief of the obstruction could favour the recovery of damaged liver mitochondria.

Studies on the respiratory function of platelet mitochondria in patients with Parkinson's disease / 临床神经病学杂志

Objective To investigate the respiratory function of platelet mitochondria in patients with Parkinson's disease(PD) and explore the assosiation with the pathogenesis of PD.Methods The platelet mitochondria of 35 patients with PD were extracted and the mitochondria respiratory rate and respiratory control rate were measured.Furthermore,the changes of activities of mitochondria complex Ⅰ,Ⅱ,Ⅲ and Ⅳ were observed.Results The platelet counts of patients with PD showed no changes, but the respiratory rates of respiratory state 3 were significantly decreased using the 5 mmol/L glutamate,2.5 mmol/L malate +5 mmol/L pyruvate and 5 mM succinate as substrates. Moreover, the activities of mitochondria complex Ⅰ were obviously reduced and the activites of other mitochondria complex were no changes.Conclusion Patients with PD show exactly abnormal mitochondria respiratory functions, and it might be an important mechanism in the pathogenesis of PD.

Changes of mitochondrial function and hepatic and renal ATP level after severe burn injury in dogs / 第三军医大学学报

0.05).These findings indicate that severe burns can destroy the coupled phosphorylation in the mitochondria and impair their capability to produce ATP.Immediate fluid infusion after burns can protect the mitochondrial function effectively.

Mitochondrial functions during experimentally induced cardiac hypertrophy.

When the hearts of albino rats are subjected to pressure-induced stress through constriction of ascending aorta, changes in the mitochondrial functions are observed as early as 24 h after the imposition of the stress. These include the abolition of oxidative phosphorylation, decrease in the energy dependent [45Ca]-uptake and decrease in the rate of energized swelling. A large influx of calcium ions and an increase in the fluidity of mitochondrial membranes also occur in this period. At later stages of hypertrophy (17, 28, 40%), these mitochondrial functions gradually return to normal levels.

RCR AND ADP/O RATIO CHANGES OF RAT LIVER MITOCHONDRIA DURING EARLY PHASE OF BURN INJURY / 第二军医大学学报

Using succinate as a substrate,the respiratory control ratio (RCR) of liver mito-chondria of 20 burned Sprague-Dawley rats (male, 20%of burned body surface area, III degree burn), and 32 burned Wistar rats (male), increased 30 minutes and 2 hours after burn, and ADP/O ratio increased 39 minutes after burn. But ADP/O ratio decreased and RCR was nearly normal 4 hours after burn.The observations suggest that there is an increasing mitochondria coupling during the early phase of burn injury, which has not been reported.

FUNCTIONAL CHANGES IN RAT LIVER MITOCHONDRIA DURING THE EARLY PHASE OF BURN INJURY / 第二军医大学学报

Using succinate as a substrate, the respiratory control rates (RCR's) of liver mitochondria of burned Sprague-Dawley rats (male, 20 percent of burned body surface area,III degree burn) were increased 15,30, 45, and 60 min after burn, the peak being at 30 min after burn (the sham group as control).In comparison with the sham group, the specific activity of succinic dehydro-genase was slightly decreased and the activities of cytochrome b and c + c1 were decreased significantly 30 min after burn.