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International Journal of Molecular... May 2024Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes... (Review)
Review
Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.
Topics: Humans; Renal Insufficiency, Chronic; Muscle, Skeletal; Animals; Sarcopenia
PubMed: 38791164
DOI: 10.3390/ijms25105117 -
The Lancet. Digital Health Jun 2024Children presenting to primary care with suspected type 1 diabetes should be referred immediately to secondary care to avoid life-threatening diabetic ketoacidosis....
BACKGROUND
Children presenting to primary care with suspected type 1 diabetes should be referred immediately to secondary care to avoid life-threatening diabetic ketoacidosis. However, early recognition of children with type 1 diabetes is challenging. Children might not present with classic symptoms, or symptoms might be attributed to more common conditions. A quarter of children present with diabetic ketoacidosis, a proportion unchanged over 25 years. Our aim was to investigate whether a machine-learning algorithm could lead to earlier detection of type 1 diabetes in primary care.
METHODS
We developed the predictive algorithm using Welsh primary care electronic health records (EHRs) linked to the Brecon Dataset, a register of children newly diagnosed with type 1 diabetes. Children were included from their first primary care record within the study period of Jan 1, 2000, to Dec 31, 2016, until either type 1 diabetes diagnosis, they turned 15 years of age, or study end. We developed an ensemble learner (SuperLearner) using 26 potential predictors. Validation of the algorithm was done in English EHRs from the Clinical Practice Research Datalink (primary care) and Hospital Episode Statistics, focusing on the ability of the algorithm to identify children who went on to develop type 1 diabetes and the time by which diagnosis could be anticipated.
FINDINGS
The development dataset comprised 34 754 400 primary care contacts, relating to 952 402 children, and the validation dataset comprised 43 089 103 primary care contacts, relating to 1 493 328 children. Of these, 1829 (0·19%) children younger than 15 years in the development dataset, and 1516 (0·10%) in the validation dataset had a reliable date of type 1 diabetes diagnosis. If set to give an alert in 10% of contacts, an estimated 71·6% (95% CI 68·8-74·4) of the children with type 1 diabetes would receive an alert by the algorithm in the 90 days before diagnosis, with diagnosis anticipated, on average, by an estimated 9·34 days (95% CI 7·77-10·9).
INTERPRETATION
If implemented into primary care settings, this predictive algorithm could substantially reduce the proportion of patients with new-onset type 1 diabetes presenting in diabetic ketoacidosis. Acceptability of alert thresholds should be explored in primary care.
FUNDING
Diabetes UK.
Topics: Humans; Diabetes Mellitus, Type 1; Electronic Health Records; Child; Primary Health Care; Machine Learning; Adolescent; Male; Female; Algorithms; United Kingdom; Child, Preschool; Infant; Diabetic Ketoacidosis
PubMed: 38789139
DOI: 10.1016/S2589-7500(24)00050-5 -
JA Clinical Reports May 2024The causes of perioperative hyperlactatemia vary, but they are generally associated with hypoperfusion. Here, we report the case of a pediatric patient who developed...
A case of pediatric Perthes' disease with unexplained hyperlactatemia at the time of initial surgery and anesthetic management with remimazolam for the subsequent surgery.
BACKGROUND
The causes of perioperative hyperlactatemia vary, but they are generally associated with hypoperfusion. Here, we report the case of a pediatric patient who developed unexplained hyperlactatemia during anesthesia with propofol and sevoflurane, which recurred during a second surgery under anesthesia with remimazolam.
CASE PRESENTATION
An 8-year-old boy with Perthes disease and no remarkable past or family history was scheduled for an osteotomy. Anesthesia was induced with propofol and rocuronium and then maintained with sevoflurane and remifentanil. The patient developed lactic acidosis without hemodynamic instability during anesthesia, with a normal lactate/pyruvate ratio after surgery, suggesting a lack of hypoperfusion. We used remimazolam instead of propofol during the second surgery 6 months later, considering the possibility of drug-induced lactic acidosis, including malignant hyperthermia and propofol infusion syndrome, where the unexplained hyperlactatemia recurred.
CONCLUSIONS
Distinguishing the causes of hyperlactatemia, particularly in the absence of other symptoms, is challenging. The lactate/pyruvate ratio during episodes of hyperlactatemia can provide insights into the underlying pathology.
PubMed: 38787500
DOI: 10.1186/s40981-024-00715-2 -
Metabolites Apr 2024The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in... (Review)
Review
The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in transcriptional and signaling networks, which result in changes in global genetic expression. The signaling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK stimulate cell metabolism, either directly or indirectly, by modulating the transcriptional factors p53, HIF1, and c-Myc. The overexpression of HIF1 and c-Myc, master regulators of cellular metabolism, is a key contributor to the synthesis of bioenergetic molecules that mediate glioma cell transformation, proliferation, survival, migration, and invasion by modifying the transcription levels of key gene groups involved in metabolism. Meanwhile, the tumor-suppressing protein p53, which negatively regulates HIF1 and c-Myc, is often lost in glioblastoma. Alterations in this triad of transcriptional factors induce a metabolic shift in glioma cells that allows them to adapt and survive changes such as mutations, hypoxia, acidosis, the presence of reactive oxygen species, and nutrient deprivation, by modulating the activity and expression of signaling molecules, enzymes, metabolites, transporters, and regulators involved in glycolysis and glutamine metabolism, the pentose phosphate cycle, the tricarboxylic acid cycle, and oxidative phosphorylation, as well as the synthesis and degradation of fatty acids and nucleic acids. This review summarizes our current knowledge on the role of HIF1, c-Myc, and p53 in the genic regulatory network for metabolism in glioma cells, as well as potential therapeutic inhibitors of these factors.
PubMed: 38786726
DOI: 10.3390/metabo14050249 -
The Journal of International Medical... May 2024Pyruvate dehydrogenase complex (PDHC) deficiency is a common genetic disorder leading to lactic acidosis, which can also result from several nongenetic conditions, such...
Pyruvate dehydrogenase complex (PDHC) deficiency is a common genetic disorder leading to lactic acidosis, which can also result from several nongenetic conditions, such as septic shock. The present study reports a case of PDHC deficiency masked by septic shock-induced lactic acidosis. This case involved a 16-year-old adolescent with poor exercise tolerance compared with his peers, and no underlying diseases. The disease onset was characterized by cough, fever, and dyspnea, with hypotension and elevated lactate levels, which indicated septic shock. However, severe hypoglycemia and lactic acidosis persisted despite resolution of a pulmonary infection and correction of septic shock, requiring continuous intravenous infusion of 50% glucose. Although the patient did not experience acute kidney injury and had normal urine output, continuous renal replacement therapy was used to regulate the internal environment owing to the severity of the acidosis. The diagnosis of PDHC deficiency was considered on the basis of the persistent hypoglycemia and hyperlactatemia, before genetic mutation testing was completed. The clinical thinking process required a rich accumulation of pathophysiological knowledge. This article reports a case of PDHC deficiency masked by septic shock-induced lactic acidosis to raise awareness of the disease and avoid misdiagnosis and missed diagnosis.
Topics: Humans; Shock, Septic; Male; Acidosis, Lactic; Adolescent; Pyruvate Dehydrogenase Complex Deficiency Disease; Hypoglycemia; Diagnosis, Differential
PubMed: 38785224
DOI: 10.1177/03000605241252112 -
Journal of Orthopaedic Case Reports May 2024Multiple spinal epidual abscesses with multifocal systemic abscess and multiple joint septic arthritis present with a large infective burden resulting in sepsis,...
INTRODUCTION
Multiple spinal epidual abscesses with multifocal systemic abscess and multiple joint septic arthritis present with a large infective burden resulting in sepsis, systemic inflammatory dysregulation, and multi-organ failure. This requires pre-operative resuscitation and surgery of greater complexity, longer operative duration, and blood loss, creating challenges to surgical management.
CASE REPORT
A 69-year-old Chinese female presented with multilevel discrete spinal epidural abscesses along the cervical, thoracic, and lumbar spine, alongside concomitant multifocal systemic abscesses and multiple small joint septic arthritis. She received pre-operative resuscitation to restore organ function, reverse acidosis, and coagulopathy, prior tobefore surgical decompression of selected abscesses and joints under a multidisciplinary team. Remaining sites of infection without significant compression were undrained. The patient recovered well with no residual neurological deficits.
CONCLUSION
Multifocal infections in critically ill patients require a multidisciplinary team for preoperative resuscitation, joint surgical planning, and prioritiszing surgical interventions to prevent excessive surgical stress to the patient.
PubMed: 38784864
DOI: 10.13107/jocr.2024.v14.i05.4414 -
Conservation Physiology 2024The mechanisms that determine the temperature tolerances of fish are poorly understood, creating barriers to disentangle how additional environmental challenges-such as...
The mechanisms that determine the temperature tolerances of fish are poorly understood, creating barriers to disentangle how additional environmental challenges-such as CO-induced aquatic acidification and fluctuating oxygen availability-may exacerbate vulnerability to a warming climate and extreme heat events. Here, we explored whether two acute exposures (~0.5 hours or ~72 hours) to increased CO impact acute temperature tolerance limits in a freshwater fish, rainbow trout (). We separated the potential effects of acute high CO exposure on critical thermal maximum (CT), caused via either respiratory acidosis (reduced internal pH) or O supply capacity (aerobic scope), by exposing rainbow trout to ~1 kPa CO (~1% or 10 000 μatm) in combination with normoxia or hyperoxia (~21 or 42 kPa O, respectively). In normoxia, acute exposure to high CO caused a large acidosis in trout (blood pH decreased by 0.43 units), while a combination of hyperoxia and ~1 kPa CO increased the aerobic scope of trout by 28%. Despite large changes in blood pH and aerobic scope between treatments, we observed no impacts on the CT of trout. Our results suggest that the mechanisms that determine the maximum temperature tolerance of trout are independent of blood acid-base balance or the capacity to deliver O to tissues.
PubMed: 38779432
DOI: 10.1093/conphys/coae026 -
Cureus Apr 2024The clinical Warburg effect is a rare occurrence in cancer biology where tumor cells primarily utilize glycolysis for energy production, leading to significant...
The clinical Warburg effect is a rare occurrence in cancer biology where tumor cells primarily utilize glycolysis for energy production, leading to significant hypoglycemia and lactate formation. This presentation is associated with a poor prognosis for the patient. In this context, we describe the case of a 53-year-old woman with stage IV mantle cell lymphoma who developed the clinical Warburg effect with solely arrhythmia and without neurological symptoms. She received prompt treatment for glucose stabilization and underwent inpatient chemotherapy. This case underscores the importance of early intervention to reduce tumor burden and highlights the effectiveness of hemodialysis in stabilizing metabolic acidosis. Further investigation into this approach is warranted.
PubMed: 38779236
DOI: 10.7759/cureus.58768 -
Clinical and Experimental Emergency... May 2024In a case of contrast media-induced anaphylactic shock managed with epinephrine, a 57-year-old male developed lactic acidosis without cardiogenic shock or global...
In a case of contrast media-induced anaphylactic shock managed with epinephrine, a 57-year-old male developed lactic acidosis without cardiogenic shock or global hypoperfusion, highlighting epinephrine's potential to trigger lactic acidosis. Despite previous management of similar reactions with antihistamines and corticosteroids, this case required intensive care unit admission and emergency intervention, with lactate levels peaking alarmingly. The rapid resolution of acidosis following epinephrine discontinuation underscores the need for careful monitoring and the consideration of alternative vasopressor strategies in severe anaphylaxis, illustrating the complex relationship between epinephrine's metabolic effects and anaphylaxis-induced tissue hypoperfusion.
PubMed: 38778486
DOI: 10.15441/ceem.24.239 -
Intensive Care Medicine Experimental May 2024
PubMed: 38775998
DOI: 10.1186/s40635-024-00633-8