Respiratory Dysfunction Research Articles

Revisiting Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM) and Portsmouth-POSSUM (P-POSSUM) Scores: Are They Valid in Cases of Ileal Perforation?

Introduction Ileal perforation due to typhoid is common in tropical countries, and the ensuing secondary peritonitis is treated by resuscitation and surgery. The Physiological and Operative Severity Scorefor the Enumeration of Mortality and Morbidity (POSSUM) was developed to predict postoperative outcomes to overcome systemic obstacles in any healthcare setupand is considered fairly accurate. The Portsmouth-POSSUM (P-POSSUM) score was developed as a corrective scoring system for overestimations made by the POSSUM score vis-à-vis mortality. Our study aimed to examine the validity of these two scores in the postoperative prediction of surgical outcomes in patients with ileal perforation. Materials and methods An observational study involving 40 patients diagnosed with ileal perforations was undertaken over 18 months. The postoperative outcome for each patient was calculated as per the POSSUM and P-POSSUM parameters. Statistical analysis was done using SPSS(IBM Corp., Armonk, NY) and the results were tabulated. Results We found that age, gender, respiratory dysfunction, propensity for multiple surgeries, duration of surgery, co-morbidities, underlying malignancy, and systolic blood pressure played a significant role in determining postoperative outcomes. Haemoglobin, potassium, and urea levels were also found to be significantly associated with outcome. Cardiac signs, pulse, white blood cell count, Glasgow Coma Scale score, sodium, and electrocardiography, part of the physiological score parameters, were found to be insignificant in the prediction of postoperative outcomes. Among the intraoperative parameters, peritoneal soiling was found to be insignificant. Conclusion Some parameters inherent to POSSUM and P-POSSUM calculations appear to bear no statistical significance to the final score, highlighting that these need to be revisited and perhaps modified to further simplify the calculation.The POSSUM score is an excellent predictor of postoperative morbidity and mortality in ileal perforation patients but is of questionable reliability due to its tendency to overestimate them. P-POSSUM has a better predictive power of postoperative mortality by correcting POSSUM mortality overestimation.

Pulsatile Right Ventricle to Pulmonary Artery Extracorporeal Membrane Oxygenation in a Pigs

Background: We investigated the impact of right ventricle to pulmonary artery extracorporeal membrane oxygenation in acute respiratory dysfunction with or without pulsatile flow. Methods: We used bronchoalveolar lavage with intrapulmonary administration of warm saline to establish a severe acute respiratory distress syndrome model (ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration ratio <200) in eight piglets (mean body weight: 8.45±1.24 kg). The piglets were categorized into the pulsatile (N=4) and non-pulsatile extracorporeal membrane oxygenation groups (N=4). We started right ventricle to pulmonary artery extracorporeal membrane oxygenation with a 60 mL/kg/min flow to support the animals for 6 hours. We monitored hemodynamic data and blood gas levels for assessing base excess, and performed arterial blood sampling and electrocardiogram. Interleukin-6 and endotherlin-1 concentrations in blood plasma were evaluated before and after right ventricle to pulmonary artery extracorporeal membrane oxygenation. We compared the lung wet/dry weight ratio as a measure of pulmonary edema and collected lung tissue samples for the pathologically evaluating pneumocytes before and after right ventricle to pulmonary artery extracorporeal membrane oxygenation. Results: We maintained stable hemodynamics and extracorporeal membrane oxygenation flow above an arterial oxygen saturation of 85% in both groups. Pneumocyte evaluation showed clearly less pulmonary edema, pulmonary fibrosis, and inflammation. Interleukin-6 concentration was less in the pulsatile group than in the non-pulsatile group. Conclusions: Pulsatile right ventricle to pulmonary artery extracorporeal membrane oxygenation was less vasoconstrictive and maintained more effective oxygenated pulmonary flow. It ameliorates pulmonary circulation and facilitates recovery from acute respiratory failure.

Study of the therapeutic strategy to improve survival outcomes from the perspective of perioperative conditions in elderly gastric cancer patients: a propensity score-matched analysis

BackgroundElderly gastric cancer patients (EGCPs) require treatment according to not just the stage of their cancer, but also to their general condition and organ function, and rather than full treatment, the appropriate amount of treatment is necessary.MethodsA total of 425 patients who underwent gastrectomy for primary gastric cancer in our institution between April 2013 and March 2020 were classified by age into two groups: elderly patients (EP, age ≥ 80 years, n = 89); and younger patients (YP, age < 80 years, n = 336). The preoperative, intraoperative, and postoperative conditions of the two groups were then compared. Propensity score matching (PSM) was performed, and factors affecting complications and survival outcomes were examined in detail. In addition, the necessary treatment strategy for EGCPs in the preoperative, intraoperative, and postoperative periods was investigated.ResultsOf the preoperative factors, American Society of Anesthesiologists physical status (ASA-PS) was significantly higher, and respiratory function was significantly lower in the EP group than in the YP group, and the prognostic nutritional index (PNI) also tended to be lower. Of the intraoperative factors, there was no difference in the level of lymph node dissection. However, the EP group had significantly higher rates of postoperative pneumonia and anastomotic leakage. Of the postoperative factors, on simple comparison, postoperative long-term outcomes of the EP group were significantly worse (63.8% vs. 85.4%, p < 0.001), but there was no significant difference in disease-specific survival (DSS), and the DSS survival curves after PSM were almost identical, indicating that the survival rate in the EP group was decreased by death from other disease. Though the survival rate of laparoscopic surgery was significantly better than that of open surgery in the YP group, there was a significantly lower rate of postoperative complications in the EP group after PSM.ConclusionsIn EGCPs, one needs to be aware of short-term complications such as pneumonia and anastomotic leakage due to respiratory dysfunction and malnutrition that are present before surgery. Furthermore, to suppress deaths from other diseases that reduce postoperative survival rates, prevention of postoperative complications (particularly pneumonia) through minimally invasive surgery can be effective.

The Clinical Approach to Interstitial Lung Disease in Childhood: A Narrative Review Article.

Interstitial lung disease (ILD) comprises a group of respiratory diseases affecting the interstitium of the lungs, which occur when a lung injury triggers an abnormal healing response, and an inflammatory process leads to altered diffusion and restrictive respiratory dysfunction. The term "interstitial" may be misleading, as other components of the lungs are usually also involved (epithelium, airways, endothelium, and so on). Pediatric conditions (childhood interstitial lung disease, chILD) are different from adult forms, as growing and developing lungs are affected and more diverse and less prevalent diseases are seen in childhood. Diffuse parenchymal lung disease (DPLD) and diffuse lung disease (DLD) can be used interchangeably with ILD. Known etiologies of chILD include chronic infections, bronchopulmonary dysplasia, aspiration, genetic mutations leading to surfactant dysfunction, and hypersensitivity pneumonitis due to drugs or environmental exposures. Many forms are seen in disorders with pulmonary involvement (connective tissue disorders, storage diseases, malignancies, and so on), but several conditions have unknown origins (desquamative pneumonitis, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia in infancy, and so on). Currently, there is no consensus on pediatric classification; however, age grouping is proposed as some specific forms are more prevalent in infancy (developmental and growth abnormalities, surfactant dysfunction mutations, etc.) and others are usually seen in older cohorts (disorders in normal or immunocompromised hosts, systemic diseases, etc.). Clinical manifestations vary from mild nonspecific symptoms (recurrent respiratory infections, exercise intolerance, failure to thrive, dry cough, etc.) to a severe clinical picture (respiratory distress) and presentation related to the child's age. The diagnostic approach relies on imaging techniques (CT), but further investigations including genetic tests, BAL, and lung biopsy (VATS) are needed in uncertain cases. Pharmacological treatment is mostly empiric and based on anti-inflammatory and immunomodulatory drugs. Lung transplantation for selected cases in a pediatric transplantation center could be an option; however, limited data and evidence are available regarding long-term survival. International collaboration is warranted to understand chILD entities better and improve the outcomes of these patients.

The metabolic role of vitamin D in children’s neurodevelopment: a network study

Neurodevelopmental disorders are rapidly increasing in prevalence and have been linked to various environmental risk factors. Mounting evidence suggests a potential role of vitamin D in child neurodevelopment, though the causal mechanisms remain largely unknown. Here, we investigate how vitamin D deficiency affects children’s communication development, particularly in relation to Autism Spectrum Disorder (ASD). We do so by developing an integrative network approach that combines metabolomic profiles, clinical traits, and neurodevelopmental data from a pediatric cohort. Our results show that low levels of vitamin D are associated with changes in the metabolic networks of tryptophan, linoleic, and fatty acid metabolism. These changes correlate with distinct ASD-related phenotypes, including delayed communication skills and respiratory dysfunctions. Additionally, our analysis suggests the kynurenine and serotonin sub-pathways may mediate the effect of vitamin D on early life communication development. Altogether, our findings provide metabolome-wide insights into the potential of vitamin D as a therapeutic option for ASD and other communication disorders.

A preclinical mice model of multiple sclerosis based on the toxin-induced double-site demyelination of callosal and cerebellar fibers

BackgroundMultiple sclerosis (MS) is an irreversible progressive CNS pathology characterized by the loss of myelin (i.e. demyelination). The lack of myelin is followed by a progressive neurodegeneration triggering symptoms as diverse as fatigue, motor, locomotor and sensory impairments and/or bladder, cardiac and respiratory dysfunction. Even though there are more than fourteen approved treatments for reducing MS progression, there are still no cure for the disease. Thus, MS research is a very active field and therefore we count with different experimental animal models for studying mechanisms of demyelination and myelin repair, however, we still lack a preclinical MS model assembling demyelination mechanisms with relevant clinical-like signs.ResultsHere, by inducing the simultaneous demyelination of both callosal and cerebellar white matter fibers by the double-site injection of lysolecithin (LPC), we were able to reproduce CNS demyelination, astrocyte recruitment and increases levels of proinflammatory cytokines levels along with motor, locomotor and urinary impairment, as well as cardiac and respiratory dysfunction, in the same animal model. Single site LPC-injections either in corpus callosum or cerebellum only, fails in to reproduce such a complete range of MS-like signs.ConclusionWe here report that the double-site LPC injections treatment evoke a complex MS-like mice model. We hope that this experimental approach will help to deepen our knowledge about the mechanisms of demyelinated diseases such as MS.

Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes

Cardiolipin (CL) is a unique, four-chain phospholipid synthesized in the inner mitochondrial membrane (IMM). The acyl chain composition of CL is regulated through a remodeling pathway, whose loss causes mitochondrial dysfunction in Barth syndrome (BTHS). Yeast has been used extensively as a model system to characterize CL metabolism, but mutants lacking its two remodeling enzymes, Cld1p and Taz1p, exhibit mild structural and respiratory phenotypes compared to mammalian cells. Here, we show an essential role for CL remodeling in the structure and function of the IMM in yeast grown under reduced oxygenation. Microaerobic fermentation, which mimics natural yeast environments, caused the accumulation of saturated fatty acids and, under these conditions, remodeling mutants showed a loss of IMM ultrastructure. We extended this observation to HEK293 cells, where phospholipase A2 inhibition by Bromoenol lactone resulted in respiratory dysfunction and cristae loss upon mild treatment with exogenous saturated fatty acids. In microaerobic yeast, remodeling mutants accumulated unremodeled, saturated CL, but also displayed reduced total CL levels, highlighting the interplay between saturation and CL biosynthesis and/or breakdown. We identified the mitochondrial phospholipase A1 Ddl1p as a regulator of CL levels, and those of its precursors phosphatidylglycerol and phosphatidic acid, under these conditions. Loss of Ddl1p partially rescued IMM structure in cells unable to initiate CL remodeling and had differing lipidomic effects depending on oxygenation. These results introduce a revised yeast model for investigating CL remodeling and suggest that its structural functions are dependent on the overall lipid environment in the mitochondrion.

Effects of respiratory muscle training on post-stroke rehabilitation: A systematic review and meta-analysis.

Stroke often results in significant respiratory dysfunction in patients. Respiratory muscle training (RMT) has been proposed as a rehabilitative intervention to address these challenges, but its effectiveness compared to routine training remains debated. This systematic review and meta-analysis aim to evaluate the effects of RMT on exercise tolerance, muscle strength, and pulmonary function in post-stroke patients. To systematically assess the efficacy of RMT in improving exercise tolerance, respiratory muscle strength, and pulmonary function in patients recovering from a stroke, and to evaluate whether RMT offers a significant advantage over routine training modalities in enhancing these critical health outcomes in the post-stroke population. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, a comprehensive search across PubMed, Embase, Web of Science, and the Cochrane Library was conducted on October 19, 2023, without temporal restrictions. Studies were selected based on the predefined inclusion and exclusion criteria focusing on various forms of RMT, control groups, and outcome measures [including forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), maximal voluntary ventilation (MVV), peak expiratory flow (PEF), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and 6-min walking test (6MWT)]. Only randomized controlled trials (RCTs) were included. Data extraction and quality assessment were conducted independently by two reviewers using the Cochrane Collaboration's risk of bias tool. Statistical analyses, including those using the fixed-effect and random-effects models, sensitivity analysis, and publication bias assessment, were performed using Review Manager software. A total of 15 RCTs were included. Results indicated significant improvements in MIP (12.51 cmH2O increase), MEP (6.24 cmH2O increase), and various pulmonary function parameters (including FEV1, FVC, MVV, and PEF). A substantial increase in 6MWT distance (22.26 meters) was also noted. However, the heterogeneity among studies was variable, and no significant publication bias was detected. RMT significantly enhances walking ability, respiratory muscle strength (MIP and MEP), and key pulmonary function parameters (FEV1, FVC, MVV, and PEF) in post-stroke patients. These findings support the incorporation of RMT into post-stroke rehabilitative protocols.

Effect of adenosinergic manipulations on amygdala-kindled seizures in mice: Implications for sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) results in more years of potential life lost than any neurological condition with the exception of stroke. It is generally agreed that SUDEP happens due to some form of respiratory, cardiac, and electrocerebral dysfunction following a seizure; however, the mechanistic cause of these perturbations is unclear. One possible explanation lies with adenosinergic signaling. Extracellular levels of the inhibitory neuromodulator adenosine rapidly rise during seizures, a countermeasure that is necessary for seizure termination. Previous evidence has suggested that excessive adenosinergic inhibition could increase the risk of SUDEP by silencing brain areas necessary for life, such as the respiratory nuclei of the brainstem. The goal of this investigation was to further clarify the role of adenosine in seizure-induced respiratory and electrocerebral dysfunction. To determine the role of adenosine in postictal physiological dysregulation, we pharmacologically manipulated adenosine signaling prior to amygdala-kindled seizures in mice while recording electroencephalogram (EEG), electromyogram, and breathing using whole body plethysmography. The adenosinergic drugs used in this study included selective and nonselective adenosine receptor antagonists and inhibitors of adenosine metabolism. We found that high doses of adenosine receptor antagonists caused some seizures to result in seizure-induced death; however, counterintuitively, animals in these conditions that did not experience seizure-induced death had little or no postictal generalized EEG suppression. Inhibitors of adenosine metabolism had no effect on postictal breathing but did worsen some postictal electrocerebral outcomes. The unexpected effect of high doses of adenosine antagonists on seizure-induced death observed in this study may be due to the increase in seizure severity, vasoconstriction, or phosphodiesterase inhibition caused by these drugs at high doses. These findings further clarify the role of adenosine in seizure-induced death and may have implications for the consumption of caffeine in epilepsy patients and the prevention of SUDEP.

Sarcoidosis Phenotyping: Analysis of Current Approaches (Review)

The review analyzes publications devoted to the formation of phenotypes in sarcoidosis patients. It has been noted that there is a certain difficulty in phenotyping the disease that can affect all human organs and systems. The article demonstrates the trend to shift from Scadding radiographic stages of intrathoracic sarcoidosis, based on radiography, to phenotypes based on high-resolution computed tomography. It presents phenotypes based on such parameters as organ damage, respiratory dysfunction, laboratory and genetic data, and treatment effects. The authors note that phenotypes should be applicable to clinical practice and clearly reflect differences between patients and the likelihood of clinically significant outcomes.

A new phenotype of patients with post-COVID-19 condition is characterised by a pattern of complex ventilatory dysfunction, neuromuscular disturbance and fatigue symptoms.

Patients with post-COVID-19 condition frequently suffer from chronic dyspnoea. The causes and mechanism for dyspnoea in these patients without evidence of structural lung disease are unclear. Patients treated for COVID-19 at Charité University Hospital in Berlin received pulmonary function testing including respiratory muscle strength tests and completed health-related quality-of-life questionnaires during follow-up. Patients with post-COVID-19 condition during outpatient follow-up with fatigue and exertional intolerance (PCF) were compared to patients with post-COVID-19 condition with evidence of chronic pulmonary sequelae (post-COVID-19 restriction (PCR)) as well as to patients without post-COVID-19 condition (NCF). A total of 170 patients presented for follow-up. 36 participants met criteria for PCF, 28 for PCR and 24 for NCF. PCF patients reported dyspnoea in 63.8%. % predicted value of respiratory muscle strength (median (IQR)) was reduced in PCF (55.8 (41.5-75.9)) compared to NCF and PCR (70.6 (66.3-88.9) and 76.8 (63.6-102.2), respectively; p=0.011). A pattern of reduced forced vital capacity (FVC), but normal total lung capacity (TLC), termed complex ventilatory dysfunction defined as TLC - FVC >10% predicted was observed and occurred more frequently in PCF (88.9%) compared to NCF and PCR (29.1% and 25.0%, respectively; p<0.001). Dyspnoea in PCF is characterised by reduced respiratory muscle strength and complex ventilatory dysfunction indicating neuromuscular disturbance as a distinct phenotype among patients with post-COVID-19 condition. These observations could be a starting point for developing personalised rehabilitation concepts.

Impact of minimal invasive extracorporeal circulation on systemic inflammatory response – a randomized trial

BackgroundExtracorporeal circulation causes a systemic inflammatory response, that may cause postoperative haemodynamic instability and end-organ dysfunction. This study aimed to investigate the impact of minimal invasive extracorporeal circulation (MiECC) on the systemic inflammatory response compared with conventional extracorporeal circulation (CECC).MethodsPatients undergoing coronary artery bypass grafting were randomized to MiECC (n = 30) and CECC (n = 30). Primary endpoint was tumor necrosis factor-α. Secondary endpoints were other biochemical markers of inflammation (IL1β, IL6 and IL8, C-reactive protein, leukocytes), and markers of inadequate tissue perfusion and tissue damage (lactate dehydrogenase, lactate and creatine kinase-MB). In addition, we registered signs of systemic inflammatory response syndrome, haemodynamic instability, atrial fibrillation, respiratory dysfunction, and infection.ResultsPatients treated with MiECC showed significantly lower levels of tumor necrosis factor-α than CECC during and early after extracorporeal circulation (median: MiECC 3.4 pg/mL; CI 2.2–4.5 vs. CECC 4.6 pg/mL; CI 3.4–5.6; p = 0.01). Lower levels of creatine kinase-MB and lactate dehydrogenase suggested less tissue damage. However, we detected no other significant differences in any other markers of inflammation, tissue damage or in any of the clinical outcomes.ConclusionsLower levels of TNF-α after MiECC compared with CECC may reflect reduced inflammatory response, although other biochemical markers of inflammation were comparable. Our results suggest better end-organ protection with MiECC compared with CECC. Clinical parameters related to systemic inflammatory response were comparable in this study.Clinical registration numberNCT03216720.

Thrombospondin-1 promotes fibro-adipogenic stromal expansion and contractile dysfunction of the diaphragm in obesity.

Pulmonary disorders impact 40% to 80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragmatic weakness. Increased intra-diaphragmatic adiposity and extracellular matrix (ECM) content correlate with reductions in contractile force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein linked with muscular damage in genetic myopathies. THBS1 induces proliferation of fibro-adipogenic progenitors (FAPs) - mesenchymal cells that differentiate into adipocytes and fibroblasts. We hypothesized that THBS1 drives FAP-mediated diaphragm remodeling and contractile dysfunction in DIO. We tested this by comparing the effects of dietary challenge on diaphragms of wild-type (WT) and Thbs1 knockout (Thbs1-/-) mice. Bulk and single-cell transcriptomics demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs displayed upregulation of ECM and TGF β-related expression signatures and augmentation of a Thy1-expressing sub-population previously linked to type 2 diabetes. Despite similar weight gain, Thbs1-/- mice were protected from these transcriptomic changes and from obesity-induced increases in diaphragm adiposity and ECM deposition. Unlike WT controls, Thbs1-/- diaphragms maintained normal contractile force and motion after DIO challenge. These findings establish THBS1 as a necessary mediator of diaphragm stromal remodeling and contractile dysfunction in overnutrition and a potential therapeutic target in obesity-associated respiratory dysfunction.

Excessive daytime sleepiness in myotonic dystrophy: a narrative review.

Excessive daytime sleepiness (EDS) is a common and debilitating symptom in both forms of myotonic dystrophy (DM), significantly impacting patients' quality of life. The review focuses on the purpose of examining the current understanding of EDS in these conditions, the difficulty in correctly accessing it, the recent findings related to its etiology and prevalence, and a summary of potential therapeutic implications. We conducted a comprehensive search through PubMed, selecting studies that provided significant insights into the mechanisms, prevalence, and management of EDS in DM1 and DM2. EDS is highly prevalent in both DM1 and DM2. Polysomnographic studies have revealed prominent dysregulation of REM sleep in DM1, suggesting a possible narcoleptic-like phenotype and alterations in NREM sleep that contributes to daytime sleepiness. Other factors have been proposed to explain EDS in DM1, including dysregulation of the sleep-wake circadian rhythm through nocturnal actigraphy analysis. The central origin of EDS is increasingly delineated supported by serotonin and orexin pathways dysfunction, and recent neuroradiological findings showing that in DM1 hippocampus volume was positively correlated with self-reported fatigue and somnolence. Sleep-disordered breathing and respiratory dysfunctions are prevalent in DM, their direct correlation with EDS remains complex and inconclusive, but respiratory evaluation should be recommended if obstructive sleep apneas or respiratory muscle dysfunctions are suspected. Drug interventions, such as modafinil and mexiletine, have shown promise in managing excessive daytime sleepiness and reducing myotonia without significant cardiac conduction effects. Enhancing EDS management in myotonic dystrophy is key to improving overall patient well-being.

Effect of deep squat intervention in patients with chronic respiratory diseases

Abstract Background: This study aimed to evaluate the impact of a structured, tailor-made 12-week deep squat intervention on lower extremity muscle strength, cardiorespiratory functional capacity, and health-related quality of life in patients with chronic respiratory dysfunction. Materials and Methods: Thirty patients aged 18–65 years were randomly assigned to a deep squat intervention group (n = 15) or a walking program group (n = 15). Assessments conducted before and after the 12-week intervention included lower extremity muscle strength, pulmonary function, cardiorespiratory endurance, and health-related quality of life (HRQoL). These were measured using trunk-leg dynamometry, the chair-stand test, the deep squat test, lung volume measurements, maximum inspiratory and expiratory pressures, the 6-min walk test, and the 12-item Short Form Survey questionnaire. Results: The results revealed that the deep squat intervention group showed greater muscle strength and cardiorespiratory endurance improvements than the walking group. Significant improvements were observed in lower extremity muscle strength (42.9%), chair-stand repetitions (26%), deep squat repetitions (30.2%), maximum inspiratory pressure (67%), maximum expiratory pressure (29%), peak expiratory flow rate (32%), 6-min walk test distance (16%), forced expiratory volume in 1 s (53%), forced vital capacity (36%), and HRQoL (physical component 42% and mental component 25%) with a large effect size ranging from 1.6 to 10.7 (P &lt; 0.001). Conclusion: This study concludes that the deep squat intervention proved to be a safe and effective exercise program for mitigating physical deconditioning in individuals with mild to moderate chronic respiratory dysfunction compared with a walking program. These findings support the inclusion of deep squat training in routine pulmonary rehabilitation programs.

Targeting the AMPK/Nrf2 Pathway: A Novel Therapeutic Approach for Acute Lung Injury.

ALI(acute lung injury) is a severe respiratory dysfunction caused by various intrapulmonary and extrapulmonary factors. It is primarily characterized by oxidative stress and affects the integrity of the pulmonary barrier. In severe cases, ALI can progress to ARDS(acute respiratory distress syndrome), a condition that poses a serious threat to the lives of affected patients. To date, the etiological mechanisms underlying ALI remain elusive, and available therapeutic options are quite limited. AMPK(AMP-activated protein kinase), an essential serine/threonine protein kinase, performs a pivotal function in the regulation of cellular energy levels and cellular regulatory mechanisms, including the detection of redox signals and mitigating oxidative stress. Meanwhile, Nrf2(nuclear factor erythroid 2-related factor 2), a critical transcription factor, alleviates inflammation and oxidative responses by interacting with multiple signaling pathways and contributing to the modulation of oxidative enzymes associated with inflammation and programmed cell death. Indeed, AMPK induces the dissociation of Nrf2 from Keap1(kelch-like ECH-associated protein-1) and facilitates its translocation into the nucleus to trigger the transcription of downstream antioxidant genes, ultimately suppressing the expression of inflammatory cells in the lungs. Given their roles, AMPK and Nrf2 hold promise as novel treatment targets for ALI. This study aimed to summarise the current status of research on the AMPK/Nrf2 signaling pathway in ALI, encompassing recently reported natural compounds and drugs that can activate the AMPK/Nrf2 signaling pathway to alleviate lung injury, and provide a theoretical reference for early intervention in lung injury and future research on lung protection.

Multiorgan dysfunction in birth asphyxia

To obtain multi-organ dysfunction frequency, associated factors in neonates with birth asphyxia, and explore its relationship with short-term outcomes. A prospective study included 120 asphyxiated neonates admitted to Hue Central Hospital, Vietnam. Central nervous system (CNS), renal, pulmonary, cardiovascular, liver, and gastrointestinal evaluations were conducted systematically. Of the asphyxiated neonates, 33.3% had severe asphyxia, while 66.7% had moderate asphyxia. Multiorgan dysfunction was observed in 55.8%, with involvement of two or more systems. CNS, pulmonary, liver, renal, cardiovascular, and gastrointestinal dysfunction occurred in 50.0%, 51.7%, 45.0%, 31.7%, 17.5%, and 13.3% of asphyxiated neonates, respectively. The overall mortality rate was 21.6%. Organ dysfunction was significantly associated with increased mortality, particularly respiratory, renal, and CNS dysfunction (odds ratios: 7.43, 6.56, and 5.92, respectively; p&lt;0.001). Mortality risk increased with the number of affected organs/systems, with odds ratios of 41.33 and 5.52 for involvement of five and four organs, respectively (p&lt;0.01). Severe asphyxia, Apgar score≤5 at 5 minutes, and elevated serum lactate levels (≥5 mmol/L) were significantly associated with multiorgan dysfunction (p&lt;0.05). Birth asphyxia in neonates often leads to multiorgan damage, increasing the risk of mortality. Preventive methods, prompt resuscitation, and systematic organ dysfunction screening are crucial to manage affected organs and improve outcomes.

Oxygen saturation and work of breathing indices in preterm infants with bronchopulmonary dysplasia compared to healthy preterm infants at discharge.

Thoracoabdominal asynchrony (TAA) is commonly seen in preterm infants. Respiratory inductive plethysmography (RIP) is a noninvasive way to objectively assess work of breathing (WOB) indices. The impact of bronchopulmonary dysplasia (BPD) on TAA at discharge has not been established. The aim of this study is to compare WOB indices in premature infants with a diagnosis of BPD to premature infants without a diagnosis of BPD at discharge. A prospective, observational study of premature infants (<32 weeks gestation) at discharge during quiet breathing in the supine position. RIP noninvasively measured WOB indices. A high-resolution pulse oximeter collected oxygen saturation and heart rate data. This study included thirty-one infants with BPD and thirty-four infants without BPD. Infants diagnosed with BPD had increased phase angle [BPD Φ=73.90 (8.2) vs NoBPD Φ=52.6 (8.2), p = 0.039]. Infants diagnosed with BPD had decreased saturations [BPD SpO2 = 96% (0.4) vs NoBPD Sp02 98% (0.3), p=<0.001], increased time with saturations less than 85% [BPD % =2.74 (0.7) vs NoBPD % =0.91 (0.4), p = .018], and increased time with saturations less than 80% [BPD % =1.57 (0.5) vs NoBPD % =0.52 (0.3), p = 0.045]. There was no difference in heart rate or breaths per minute for infants with BPD versus controls. Premature infants with BPD demonstrated increased TAA and had lower saturations compared to infants without BPD at discharge despite being chronologically older and being discharged at an older corrected gestational age. The impact of BPD on breathing patterns persists at discharge and suggests these patients may have residual lung and/or respiratory muscle dysfunction.

Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis.

Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23-75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients.

High-intensity interval training using electrical stimulation ameliorates muscle fatigue in chronic kidney disease-related cachexia by restoring mitochondrial respiratory dysfunction.

Exercise, especially high-intensity interval training (HIIT), can increase mitochondrial respiratory capacity and enhance muscular endurance, but its systemic burden makes it difficult to safely and continuously prescribe for patients with chronic kidney disease (CKD)-related cachexia who are in poor general condition. In this study, we examined whether HIIT using electrical stimulation (ES), which does not require whole-body exercise, improves muscle endurance in the skeletal muscle of 5/6 nephrectomized rats, a widely used animal model for CKD-related cachexia. Male Wistar rats (10weeks old) were randomly assigned to a group of sham-operated (Sham) rats and a group of 5/6 nephrectomy (Nx) rats. HIIT was performed on plantar flexor muscles in vivo with supramaximal ES every other day for 4weeks to assess muscle endurance, myosin heavy-chain isoforms, and mitochondrial respiratory function in Nx rats. A single session was also performed to identify upstream signaling pathways altered by HIIT using ES. In the non-trained plantar flexor muscles from Nx rats, the muscle endurance was significantly lower than that in plantar flexor muscles from Sham rats. The proportion of myosin heavy chain IIa/x, mitochondrial content, mitochondrial respiratory capacity, and formation of mitochondrial respiratory supercomplexes in the plantaris muscle were also significantly decreased in the non-trained plantar flexor muscles from Nx rats than compared to those in plantar flexor muscles from Sham rats. Treatment with HIIT using ES for Nx rats significantly improved these molecular and functional changes to the same degrees as those in Sham rats. Furthermore, a single session of HIIT with ES significantly increased the phosphorylation levels of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), pathways that are essential for mitochondrial activation signaling by exercise, in the plantar muscles of both Nx and Sham rats. The findings suggest that HIIT using ES ameliorates muscle fatigue in Nx rats via restoration of mitochondrial respiratory dysfunction with activation of AMPK and p38 MAPK signaling. Our ES-based HIIT protocol can be performed without placing a burden on the whole body and be a promising intervention that is implemented even in conditions of reduced general performance status such as CKD-related cachexia.