Altered ventilatory responses to hypercapnia-hypoxia challenges in a preclinical SUDEP model involve orexin neurons.

Failure to recover from repeated hypercapnia and hypoxemia (HH) challenges caused by severe GCS and postictal apneas may contribute to sudden unexpected death in epilepsy (SUDEP). Our previous studies found orexinergic dysfunction contributes to respiratory abnormalities in a preclinical model of SUDEP, Kcna1-/- mice. Here, we developed two gas challenges consisting of repeated HH exposures and used whole body plethysmography to determine whether Kcna1-/- mice have detrimental ventilatory responses. Kcna1-/- mice exhibited an elevated ventilatory response to a mild repeated hypercapnia-hypoxia (HH) challenge compared to WT. Moreover, 71% of Kcna1-/- mice failed to survive a severe repeated HH challenge, whereas all WT mice recovered. We next determined whether orexin was involved in these differences. Pretreating Kcna1-/- mice with a dual orexin receptor antagonist rescued the ventilatory response during the mild challenge and all subjects survived the severe challenge. In ex vivo extracellular recordings in the lateral hypothalamus of coronal brain slices, we found reducing pH either inhibits or stimulates putative orexin neurons similar to other chemosensitive neurons; however, a significantly greater percentage of putative orexin neurons from Kcna1-/-mice were stimulated and the magnitude of stimulation was increased resulting in augmentation of the calculated chemosensitivity index relative to WT. Collectively, our data suggest that increased chemosensitive activity of orexin neurons may be pathologic in the Kcna1-/- mouse model of SUDEP, and contribute to elevated ventilatory responses. Our preclinical data suggest that those at high risk for SUDEP may be more sensitive to HH challenges, whether induced by seizures or other means; and the depth and length of the HH exposure could dictate the probability of survival.

Effect of nutritional status on occurrence of pneumonia after traumatic cervical spinal cord injury.

Pneumonia after cervical spinal cord injury (CSCI) is a common and serious complication; however, its nutrition-related etiology has not yet been elucidated. This study aimed to elucidate the effects of nutritional factors on pneumonia after CSCI. Patients with acute traumatic CSCI who were admitted within 3 days after injury and followed up for at least 3 months were retrospectively examined. Occurrence of pneumonia, nutritional status, severity of dysphagia, vital capacity, use of respirators, and motor scores for paralysis were evaluated. Of 182 patients included in this study, 33 (18%) developed pneumonia. Multiple logistic regression analysis revealed that low nutritional status, severe paralysis, and low vital capacity were significant risk factors for pneumonia. The severity of paralysis, respiratory dysfunction, and poor nutritional status can affect the occurrence of pneumonia after CSCI. In addition to respiratory management, nutritional assessment and intervention may play key roles in preventing pneumonia associated with spinal cord injury-induced immune depression. Nutritional care should be provided as soon as possible when the nutritional status of a patient worsens after an injury.

[A case of high cervical cord infarction presenting with cardiopulmonary arrest due to respiratory dysfunction].

A 46-year-old man with neck pain and impaired physical mobility called for emergency medical services. The patient was able to communicate with the emergency medical team upon their arrival. However, he went into cardiopulmonary arrest 5 minutes later. Cardiopulmonary resuscitation was immediately performed, and the patient was admitted to our hospital with a Glasgow Coma Scale score of E1V1M1. His respiratory rate was 5 breaths/minute and his partial pressure of carbon dioxide in arterial blood (PaCO2) was 127 |mmHg, necessitating intubation and ventilation. His consciousness improved as the PaCO2 level decreased. However, he was unable to be weaned off the ventilator and breathe independently. Neurological examination revealed flaccid quadriplegia, pain sensation up to the C5 level, absence of deep tendon reflexes, indifferent plantar responses, and absence of the rectoanal inhibitory reflex. Magnetic resonance imaging showed a hyperintense lesion with slight enlargement of the anterior two-thirds of the spinal cord at the C2-C4 level on both T2-weighted and diffusion-weighted images, consistent with a diagnosis of spinal cord infarction. Although the quadriplegia and sensory loss partially improved, the patient was unable to be weaned from the ventilator. Cervical cord infarction of the anterior spinal artery can cause rapid respiratory failure leading to cardiopulmonary arrest. Therefore, cervical cord infarction should be included as a differential diagnosis when examining patients after cardiopulmonary resuscitation.

Large phenotypic diversity by genotype in patients with GNE myopathy: 10 years after the establishment of a national registry in Japan.

BACKGROUND: GNE myopathy is an ultra-rare autosomal recessive distal myopathy caused by pathogenic variants of the GNE gene, which encodes a key enzyme in sialic acid biosynthesis. The present study aimed to examine the long-term progression of GNE myopathy, genotype-phenotype correlations, and complications to provide useful information for predicting patient progression and designing clinical trials using a large collection of registry data over a 10-year period. METHODS: We analyzed 220 Japanese patients with GNE myopathy from a national registry in Japan. Diagnoses were confirmed by genetic curators based on genetic analysis reports. We analyzed registration sheets and annually updated items completed by attending physicians. RESULTS: In total, 197 of 220 participants (89.5%) carried p.D207V or p.V603L in at least one allele. The median disease duration to loss of ambulation was estimated to be 10 years in p.V603L homozygotes (n = 48), whereas more than 90% of p.D207V/p.V603L compound heterozygotes were estimated to be ambulatory even 20 years after disease onset according to Kaplan-Meier analysis (p < 0.001). Moreover, participants with a younger age of onset lost ambulation earlier regardless of genotype. A decline in respiratory function was observed as the disease progressed, particularly in p.V603L homozygotes, whereas none of the p.D207V/p.V603L compound heterozygotes showed a decline. CONCLUSIONS: The present study demonstrated large differences in disease progression and respiratory function between genotypes. Moreover, age of onset was found to be an indicator of disease severity regardless of genotype in GNE myopathy patients. These results may help stratify patients in clinical trials and predict disease progression.

Office-based respiratory assessment in patients with generalized myasthenia gravis.

Patients with myasthenia gravis (MG) can present with respiratory dysfunction, ranging from exercise intolerance to overt respiratory failure, increased fatigue, or sleep-disordered breathing. To investigate the value of multiple respiratory tests in MG, we performed clinical and respiratory assessments in patients with mild to moderate generalized disease. One-hundred and thirty-six patients completed the myasthenia gravis quality-of-life score(MG-QOL-15), myasthenia gravis impairment index(MGII), Epworth sleepiness scale(ESS), University of California-San Diego Shortness of Breath Questionnaire(UCSD-SOB), Modified Medical Research Council Dyspnea Scales(MRC-DS), supine and upright forced vital capacity(FVC), maximal inspiratory pressures(MIPs) and sniff nasal inspiratory pressures(SNIP). Seventy-three (54 %) had respiratory and/or bulbar symptoms and 45 (33 %) had baseline abnormal FVC, with no significant postural changes (p = 0.89); 55 (40.4 %) had abnormal MIPs and 50 (37 %) had abnormal SNIPs. Overall, there were low scores on respiratory and disability scales. Females had increased odds of presenting with abnormal FVC (OR 2.89, p = 0.01) and MIPs (OR 2.48, p = 0.022). There were significant correlations between MIPs, FVC and SNIPs; between MGII/MG-QOL15 and UCSD-SOB/MRC-DS and between ESS and respiratory scales in the whole group. Our data suggests that office-based respiratory measurements are a useful screening method for stable MG patients, even when presenting with minimal respiratory symptoms and no significant disability.

Autonomic dysfunction in dementia with Lewy bodies: Focusing on cardiovascular and respiratory dysfunction.

Dementia with Lewy bodies (DLB) is the second most common cause of dementia after Alzheimer's disease. The disease is characterized by many Lewy bodies appearing in the patient's cerebrum. DLB frequently presents with a variety of autonomic symptoms from the early or prodromal stages of the disease, and these are listed as supportive features in the diagnostic criteria. As several useful assessment methods for evaluating autonomic function in DLB have been reported, this review will focus on cardiovascular and respiratory dysfunction and its assessments. Cardiovascular disorders, such as orthostatic hypotension and abnormal heart rate variability, have been reported in DLB patients. Decreased myocardial uptake by metaiodobenzylguanidine myocardial scintigraphy has been added as an indicative biomarker for DLB in the 2017 revision of the diagnostic criteria. We have reported reduced ventilatory response to hypercapnia, abnormal respiratory rhythm, and high frequency of sleep-disordered breathing as abnormalities of the respiratory regulatory system associated with DLB. Since autonomic dysfunction is highly prevalent in DLB from the early or prodromal phase of the disease and is associated with reduced activities of daily living and quality of life, the evaluation of autonomic dysfunction is also useful in the differential diagnosis of DLB from Alzheimer's disease. There are fewer studies on the respiratory regulatory system than on the cardiovascular system, thus further research is needed to explore its role in DLB.

High Sucrose Diet-Induced Subunit I Tyrosine 304 Phosphorylation of Cytochrome c Oxidase Leads to Liver Mitochondrial Respiratory Dysfunction in the Cohen Diabetic Rat Model.

The mitochondrial oxidative phosphorylation process generates most of the cellular energy and free radicals in mammalian tissues. Both factors play a critical role in numerous human diseases that could be affected by reversible phosphorylation events that regulate the function and activity of the oxidative phosphorylation complexes. In this study, we analyzed liver mitochondria of Cohen diabetes-sensitive (CDs) and Cohen diabetes-resistant (CDr) rats, using blue native gel electrophoresis (BN-PAGE) in combination with mitochondrial activity measurements and a site-specific tyrosine phosphorylation implicated in inflammation, a known driver of diabetes pathology. We uncovered the presence of a specific inhibitory phosphorylation on tyrosine 304 of catalytic subunit I of dimeric cytochrome c oxidase (CcO, complex IV). Driven by a high sucrose diet in both CDr and CDs rats, Y304 phosphorylation, which occurs close to the catalytic oxygen binding site, correlates with a decrease in CcO activity and respiratory dysfunction in rat liver tissue under hyperglycemic conditions. We propose that this phosphorylation, specifically seen in dimeric CcO and induced by high sucrose diet-mediated inflammatory signaling, triggers enzymatic activity decline of complex IV dimers and the assembly of supercomplexes in liver tissue as a molecular mechanism underlying a (pre-)diabetic phenotype.

Síndrome de infusión de propofol y COVID-19. Reporte de caso / Propofol and COVID-19 infusion syndrome. Case report

Resumen: La forma grave de neumonía por SARS-CoV-2 (COVID-19) cursa en la mayoría de los casos con un síndrome de dificultad respiratoria aguda (SDRA). Es necesario emplear sedación durante su ventilación mecánica, el propofol es el que más de utiliza por su farmacocinética y farmacodinamia. El propofol es un anestésico que se usa ampliamente en las unidades de cuidados intensivos. Su empleo puede provocar un efecto adverso poco frecuente, pero en extremo grave, conocido como síndrome por infusión de propofol (SIP), el cual se encuentra estrechamente asociado a la velocidad de infusión aunado a factores de riesgos propios del paciente. Se caracteriza principalmente por inestabilidad hemodinámica, acidosis láctica y por progresión a disfunción multiorgánica. Se presenta un caso de SIP en paciente con síndrome de dificultad respiratoria aguda (SDRA) secundario a SARS-CoV-2 que desarrolla esta complicación asociada a la sedación. Se discute fisiopatológica clínica y consideraciones que deberán tomarse en cuenta al momento de su utilización en infusión continua.

Abstract: The severe form of SARS-CoV-2 pneumonia (COVID-19) occurs in most cases with acute respiratory distress syndrome (ARDS), requiring the use of sedation during mechanical ventilation, with propofol being the most widely used for its pharmacokinetics and pharmacodynamics. Propofol is a widely used anesthetic in intensive care units (ICU). Its use can cause an infrequent but extremely serious adverse effect, known as propofol infusion syndrome (PRIS), which is closely associated with the speed of infusion coupled with risk factors specific to the patient, the clinical features of PRIS are hemodynamic instability, lactic acidosis and with progression to multi-organ dysfunction. We present a case of SIP in a patient with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 who develops this complication associated with sedation, discusses clinical pathophysiology and considerations that should be taken into account when using it in continuous infusion.

Tuberculose pulmonar: associação entre extensão de lesão pulmonar residual e alteração da função pulmonar / Pulmonary tuberculosis: association between extent of the residual pulmonary lesion and alteration in the lung function

OBJETIVO: Descrever as alterações nas variáveis da espirometria e seus distúrbios; estudar a existência de associação entre a extensão da lesão pulmonar residual ao final do tratamento da tuberculose e a alteração da função pulmonar aferida pela espirometria. MÉTODOS: Estudou-se uma série de 96 pacientes com diagnóstico de tuberculose pulmonar, atendidos em três unidades de saúde de Região Metropolitana do Recife, durante o período de janeiro de 2003 a novembro de 2005. Foram analisados pacientes de ambos os sexos, com idade a partir de 15 anos, cujas radiografias do tórax do final do tratamento foram classificadas pelo critério da National Tuberculosis Association (NTA). Os pacientes responderam questionário, no início da pesquisa, e foram submetidos à prova de função pulmonar, após o término do tratamento. RESULTADOS: Dos 96 pacientes estudados, concluímos que 89,6 por cento apresentavam seqüelas radiográficas; 54 por cento apresentavam seqüelas moderadas a graves. Estas alterações radiográficas correspondiam a 24,6 por cento e 73,8 por cento, respectivamente, de alterações na função pulmonar. CONCLUSÃO: Foram identificadas 89,6 por cento de lesões residuais radiográficas, enquanto 66,7 por cento das disfunções respiratórias alertam para o fato de que a assistência ao paciente com tuberculose pulmonar não deve se restringir apenas à cura baciloscópica da doença. A identificação de lesões pulmonares residuais e disfunções respiratórias em pacientes que concluem o tratamento da tuberculose permitirão instituir medidas precoces de tratamento dessas seqüelas para uma melhor qualidade de vida.

OBJECTIVE: To describe alterations in spirometric variables and its disturbances and to study the existence of a relationship between extent of the residual lung lesion at the end of treatment for tuberculosis and alteration of the lung function measured by spirometry. METHODS: Analyzed were 96 patients with diagnosis of pulmonary tuberculosis, treated in three health centers in the metropolitan area of Recife, from January, 2003 to November, 2005. Patients of both genders, 15 years of age or older were included, whose chest x-rays at end of the treatment were classified according to criteria of the National Tuberculosis Association (NTA) for extent of lung lesion. Patients replied to a questionnaire at the beginning of the survey, and were submitted to spirometry after conclusion of treatment. RESULTS: Of the 96 patients, 89.6 percent presented with radiographic sequels. About 54 percent had moderate to severe sequels. These radiographic alterations correspond to 24.6 percent and 73.8 percent respectively of alterations in the pulmonary function. CONCLUSION: The large number of residual radiographic lesionss (89.6 percent) and breathing dysfunction (66,7 percent) identified in this survey call attention to the fact that treatment of a patient with pulmonary tuberculosis must not be restricted to bacteriological healing of the disease. Identification of the residual lung lesions and of the breathing dysfunction in patients who conclude treatment will promote early actions to treat these sequels, improving the quality of life of these patients.