Infant urinary metabolomic profile in a fatal acute methadone intoxication

A case report suspicious for a Sudden Infant Death Syndrome is here described. Pathological findings were consistent with an acute respiratory failure while toxicological analysis revealed an elevated blood methadone concentration. Death was then ascribed to an acute methadone intoxication. In addition to the routinary approach, the urinary sample collected at autopsy was investigated with a 1H NMR metabolomic approach and the identified metabolomic profile was challenged with the urinary metabolomic profiles previously obtained from 10 newborns who experienced perinatal asphyxia and 16 healthy control newborns. Intriguingly, the urinary profile of the methadone intoxicated infant was very similar to those belonging to the perinatal asphyxia newborns, especially to those belonging to the newborns characterised by the worst outcome. The results offer several hints on a shared metabolic derangement between different mechanisms of asphyxia/hypoxia. To the best of the authors’ knowledge, this is the first report of the use of a metabolomic approach in a pathological case, in which metabolomics offers useful additional information regarding the mechanism and the cause of death.

Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome

Mice with deletion of complex I subunit Ndufs4 develop mitochondrial encephalomyopathy resembling Leigh syndrome (LS). We report that LS mice also develop severe cardiac bradyarrhythmia and diastolic dysfunction. Human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) with Ndufs4 deletion recapitulate LS cardiomyopathy. Mechanistically, we demonstrate a direct link between complex I deficiency, decreased intracellular NAD+/ NADH and bradyarrhythmia, mediated by hyperacetylation of the cardiac sodium channel NaV1.5, particularly at K1479 site. Neuronal apoptosis in the cerebellar and midbrain regions in LS mice was associated with hyperacetylation of p53 and activation of microglia. Targeted metabolomics revealed increases in several amino acids and citric acid cycle intermediates, likely due to impairment of NAD+-dependent dehydrogenases, and a substantial decrease in reduced Glutathione (GSH). Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD+/ NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD+-dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes, concomitant with improvement of NaV1.5 current and SERCA2a function measured by Ca2+-transients. NR also attenuated neuronal apoptosis and microglial activation in the LS brain and human iPS-derived neurons with Ndufs4 deletion. Our study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human iPSC models of LS.

Serious acid-base disorder or life-threatening arrhythmia in patients with ABO-incompatible liver transplantation who received therapeutic plasma exchange : A report of two cases

Background: Excessive citrate load during therapeutic plasma exchange (TPE) can cause metabolic alkalosis with compensatory hypercarbia and electrolyte disturbances. If TPE is required immediately before ABO-incompatible (ABOi) liver transplant (LT) surgery, metabolic derangement and severe electrolyte disturbance could worsen during LT anesthesia.Case: We report two ABOi LT cases who received TPE on the day of surgery because isoagglutinin titers did not be dropped below 1:8. One case had a surprisingly high metabolic alkalosis with a pH of 7.73 immediately after tracheal intubation because of hyperventilation during mask bagging. The other experienced sudden ventricular tachycardia and blood pressure drop after surgical incision accompanied with severe hypokalemia of 1.8 mmol/L despite supplementation with potassium.Conclusions: Special attention should be paid to patients who just completed TPE the operative day morning as they are vulnerable to severe acid-base disturbances and life-threatening ventricular arrhythmias in ABOi LT.

The Efficacy of Photobiomodulation Therapy in Improving Tissue Resilience and Healing of Radiation Skin Damage

The increased precision, efficacy, and safety of radiation brachytherapy has tremendously improved its popularity in cancer care. However, an unfortunate side effect of this therapy involves localized skin damage and breakdown that are managed palliatively currently. This study was motivated by prior reports on the efficacy of photobiomodulation (PBM) therapy in improving tissue resilience and wound healing. We evaluated the efficacy of PBM therapy on 36 athymic mice with 125I seed (0.42 mCi) implantation over 60 days. PBM treatments were performed with either red (660 nm) or near-infrared (880 nm, NIR) LEDs irradiance of 40 mW/cm2, continuous wave, fluence of 20 J/cm2 once per week. Animals were evaluated every 7 days with digital imaging, laser Doppler flowmetry, thermal imaging, µPET-CT imaging using 18F-FDG, and histology. We observed that both PBM treatments—red and NIR—demonstrated significantly less incidence and severity and improved healing with skin radionecrosis. Radiation exposed tissues had improved functional parameters such as vascular perfusion, reduced inflammation, and metabolic derangement following PBM therapy. Histological analysis confirmed these observations with minimal damage and resolution in tissues exposed to radiation. To our knowledge, this is the first report on the successful use of PBM therapy for brachytherapy. The results from this study support future mechanistic lab studies and controlled human clinical studies to utilize this innovative therapy in managing side effects from radiation cancer treatments.

Gender-Specific Behaviour in Obesity Stages I-II: Imbalance of Aminothiol Status and Adipomyokine Profile in Subjects with Different Insulin Resistance Severity

The hyperproduction of oxidative stress and inflammatory biomarkers, which is paralleled by decreased levels of antioxidant and anti-inflammatory mediators, is part of cellular mechanisms that contribute to the disruption of metabolic homeostasis in obesity. Whether gender-specific alterations and gender-restricted associations in these biomarkers underlie the increased cardiometabolic risk in men compared to women is unclear. We enrolled 31 women and 29 men, aged ≥50 and ≤70 years and with body mass index ≥ 30 and <40 kg/m2. We assessed the concentrations of aminothiols (cysteine, homocysteine, and glutathione), expression of oxidant/antioxidant balance, adipomyokines (leptin, adiponectin, myostatin, and interleukin-6), markers of chronic inflammation, and vitamin D, an index of nutritional state, in plasma and serum samples by using HPLC, ELISA, and chemiluminescent immunoassay methods. We measured insulin resistance (IR) by the homeostasis model assessment (HOMA) index. Despite comparable levels of visceral adiposity, IR, and a similar dietary regimen, men showed, with respect to women, higher oxidant concentrations and lower antioxidant levels, which paralleled IR severity. Myostatin levels correlated with prooxidant aminothiols among men only. Gender-specific alterations in aminothiol status and adipomyokine profile and the gender-restricted association between these biomarkers and metabolic derangement are consistent with an increased cardiometabolic risk in men compared to age-matched women with stage I-II obesity. Strict control of redox and inflammatory status, even addressing gender-specific nutritional targets, may be useful to prevent obesity-related metabolic alterations and comorbidities.

Management of Mutrashmari (Urolithiasis)- A Case Report

Ashmari comes under Mutravaha srotovikara and Ashtamahagada as described in Susruta Samhita.The prevalence of urinary stone is approximately 3 to 5% in general population and is increasing across the world mainly due to metabolic derangement, global climatic changes. Acharya Susruta said, before attempting surgical procedures one should try with oral medications like ghrita, paneeyakshara, taila etc. which possesses properties like chedana, lekhana, bhedana and mutrala for facilitating the disintegration of urinary stones. A 39 years old male patient came to OPD at Taranath Govt. Ayurveda Medical College, Ballari on 20 May 2021 presented with complaints of pain in right flank region, pain in right loin radiating to groin, burning micturition, orange coloured urine for 2 days, diagnosed as Urolithiasis and advised for surgery. He visited our hospital to avoid the surgery and for the treatment of the same. Kokilaksha Paneeya Kshara and Punarnavadi Kashaya given to patient for 28 days and got relief from symptoms. Key words: Ashmari, Ashtamahagada, Paneeya kshara, Punarnavadi Kashaya.

The Role of HbA1c as a Positive Perioperative Predictor of Surgical Site and Other Postoperative Infections: An Explorative Analysis in Patients Undergoing Minor to Major Surgery

Background Patients with diabetes mellitus type 2 (DM2) inhere impaired peripheral insulin action leading to higher perioperative morbidity and mortality rates, with hospital-acquired infections being one important complication. This post hoc, observational study aimed to analyze the impact of surgical and metabolic stress as defined by the surrogate marker hemoglobin A1c (HbA1c), in relation to self-reported DM2, on perioperative infection rates in a subcohort of the Surgical Site Infection (SSI) Trial population. Methods All patients of the SSI study were screened for HbA1c levels measured perioperatively for elective or emergency surgery and classified according to the American Diabetes Association HbA1c cutoff values. SSI and nosocomial infections, self-reported state of DM2 and type of surgery (minor, major) were assessed. Results HbA1c levels were measured in 139 of 5175 patients (2.7%) of the complete SSI study group. Seventy patients (50.4%) self-reported DM2, while 69 (49.6%) self-reported to be non-diabetic. HbA1c levels indicating pre-diabetes were found in 48 patients (34.5%) and diabetic state in 64 patients (46%). Forty-five patients of the group self-reporting no diabetes (65.2%) were previously unaware of their metabolic derangement (35 pre-diabetic and 10 diabetic). Eighteen infections were detected. Most infections (17 of 18 events) were found in patients with HbA1c levels indicating pre-/diabetic state. The odds for an infection was 3.9-fold (95% CI 1.4 to 11.3) higher for patients undergoing major compared to minor interventions. The highest percentage of infections (38.5%) was found in the group of patients with an undiagnosed pre-/diabetic state undergoing major surgery. Conclusions These results encourage investment in further studies evaluating a more generous and specific use of HbA1c screening in patients without self-reported diabetes undergoing major surgery. Trial registration Clinicaltrials.gov identifier: NCT 01790529

Circulating Metabolomics Suggest Neutropenic Fever As a Metabolic Derangement Related to Intestinal Tissue Damage and Gut Dysbiosis

Introduction: Despite antibiotic prophylaxis, most patients with acute myeloid leukemia (AML) develop neutropenic fever (NF) during intensive chemotherapy, suggesting a non-infectious etiology in many cases. In addition, escalated antibiotics used to treat NF increase the risk of Clostridioides difficile infection, promote pathogen colonization, prolong hospitalization, and increase healthcare costs. More effective prevention of NF, preferably using non-antibiotic approaches, is needed. We hypothesized that a longitudinal analysis of the circulating metabolome may reveal novel aspects of NF pathogenesis and identify potential targets for new preventative interventions. Methods: We analyzed 128 longitudinal serum samples from 17 intensively treated adult patients with AML between hospital admission and day 28 of chemotherapy. Samples were collected between 6-8 AM every Mon and Thu. Samples were subjected to ultrahigh performance liquid chromatography-tandem mass spectrometry. Results: All patients developed NF. A total of 1,031 metabolites were identified. Principal components analysis of the circulating metabolome could not resolve individual patients (Fig. 1a). In contrast, pre- vs. post-NF samples were partially clustered (Fig. 1b), suggesting a metabolomic shift associated with NF. After correcting for false discovery, 26 and 27 metabolites were higher in pre- and post-NF samples, respectively (q&lt;0.05, |log fold-change| &gt;1; Fig. 1c). The most significant metabolite that was different between post- and pre-NF samples was citrulline, with a mean concentration ratio of 0.65 between the two groups (q&lt;10-5, Fig. 1c). Citrulline is a known biomarker for total enterocyte mass and its lower levels in post-NF samples indicate intestinal tissue damage as a potential etiology for NF. Another notable metabolite was 3-indoxyl sulfate (3-IS), a tryptophan metabolite and biomarker of gut microbiota diversity and clostridia abundance. 3-IS levels also decreased in post-NF (post vs. pre ratio: 0.45, q=0.02; Fig. 1c), suggesting a protective role for commensal microbiota against NF. Indoles act via the aryl hydrocarbon receptor to repair the intestinal epithelial barrier. Sparse partial least squares discriminant analysis (sPLS-DA) further improved group separation (Fig. 1d). Significantly altered metabolites in the first analysis along with the top 50 metabolites in sPLS-DA were fed into a random forest which generated the final list of 47 metabolites with largest contributions to group separation, including 3-IS and several citrulline metabolites (top 10 metabolites in Table 1). The most frequent metabolites on this list were those in amino acid (n = 17) and lipid (n = 14, including a secondary bile acid) pathways. Conclusions: This first-time analysis of the circulating metabolome in AML patients with NF suggests NF as a metabolic derangement rather than an infectious event in many patients. Augmenting the intestinal epithelium and maintaining a commensal clostridia-rich gut microbiome may help prevent NF. In addition, our list of altered metabolites introduces an unexplored niche for the development of novel, non-antibiotic-based approaches to prevent NF. Figure 1 Figure 1. Disclosures Holtan: Incyte: Consultancy, Research Funding; Generon: Consultancy. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding.

Bacillus thuringiensis Spores and Cry3A Toxins Act Synergistically to Expedite Colorado Potato Beetle Mortality

The insect integument (exoskeleton) is an effective physiochemical barrier that limits disease-causing agents to a few portals of entry, including the gastrointestinal and reproductive tracts. The bacterial biopesticide Bacillus thuringiensis (Bt) enters the insect host via the mouth and must thwart gut-based defences to make its way into the body cavity (haemocoel) and establish infection. We sought to uncover the main antibacterial defences of the midgut and the pathophysiological features of Bt in a notable insect pest, the Colorado potato beetle Leptinotarsa decemlineata (CPB). Exposing the beetles to both Bt spores and their Cry3A toxins (crystalline δ-endotoxins) via oral inoculation led to higher mortality levels when compared to either spores or Cry3A toxins alone. Within 12 h post-exposure, Cry3A toxins caused a 1.5-fold increase in the levels of reactive oxygen species (ROS) and malondialdehyde (lipid peroxidation) within the midgut – key indicators of tissue damage. When Cry3A toxins are combined with spores, gross redox imbalance and ‘oxidation stress’ is apparent in beetle larvae. The insect detoxification system is activated when Bt spores and Cry3A toxins are administered alone or in combination to mitigate toxicosis, in addition to elevated mRNA levels of candidate defence genes (pattern-recognition receptor, stress-regulation, serine proteases, and prosaposin-like protein). The presence of bacterial spores and/or Cry3A toxins coincides with subtle changes in microbial community composition of the midgut, such as decreased Pseudomonas abundance at 48 h post inoculation. Both Bt spores and Cry3A toxins have negative impacts on larval health, and when combined, likely cause metabolic derangement, due to multiple tissue targets being compromised.

Don’t Forget That Chorea!

Background: Hemichorea-hemiballismus is a spectrum of involuntary, continuous non-patterned movement involving one side of the body. Possible causes of hemichorea-hemiballismus include haemorrhagic or ischemic stroke, neoplasm, systemic lupus erythematosus, NHH (non-ketotic hyperglycaemic hemichorea), Wilson’s disease, and thyrotoxicosis. Amongst the metabolic causes, chorea associated with NHH is noteworthy and is mainly reported in elderly Asian women. The pathophysiology of this syndrome remains controversial. It is likely that a combination of hyperglycaemia induced basal ganglia metabolic derangement and failure of cerebral blood flow autoregulation contribute to the syndrome.Case presentation: A 45-year-old Malay gentleman presented to our Emergency Department with right upper and lower limb weakness associated with hemichorea for 3-4 days. His initial blood glucose level was 22 mg/dl with normal serum ketone and bicarbonate levels. CT brain showed a hyperdensity in the left caudate nucleus and globus pallidus region. Subsequent brain MRI revealed an asymmetric T1 hyperintensity of the left putamen. This specific finding was compatible with hyperglycaemia-induced hemichorea-hemiballismus syndrome. The hemiballismus/hemichorea improved rapidly within the next day. Conclusions: This unusual clinical presentation is often accompanied by severe hyperglycaemia. Appropriate blood glycaemic control is important because it is reversible with correction of hyperglycaemia. Thus, prompt recognition and treatment is essential to avoid adverse outcomes.