Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.

Background: Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown. Methods: We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of U-13C-glucose. Cardiac glycogen was assessed biochemically and by transmission electron microscopy. Cardiac uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the CS-Mpc2-/- heart failure. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed low-fat or ketogenic diet. Results: Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, yet these hearts displayed increased enrichment from U-13C-glucose and increased glycolytic metabolite pool sizes. 13C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ~6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic 13C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin-II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet. Conclusions: Our results indicate that loss of MPC in the heart causes glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is reduced by consumption of a ketogenic diet.

T-cell expression of CXCL13 is associated with immunotherapy response in a sex-dependent manner in patients with lung cancer.

Emerging evidence in preclinical models demonstrates that antitumor immunity is not equivalent between males and females. However, more investigation in patients and across a wider range of cancer types is needed to fully understand sex as a variable in tumor immune responses. We investigated differences in T-cell responses between male and female patients with lung cancer by performing sex-based analysis of single cell transcriptomic datasets. We found that the transcript encoding CXC motif chemokine ligand 13 (CXCL13), which has recently been shown to correlate with T-cell tumor specificity, is expressed at greater levels in T cells isolated from female compared to male patients. Furthermore, increased expression of CXCL13 was associated with response to PD-1-targeting immunotherapy in female but not male patients. These findings suggest that there are sex-based differences in T-cell function required for response to anti-PD-1 therapy in lung cancer that may need to be considered during patient treatment decisions.

Momordicine-I Suppresses Head and Neck Cancer Growth by Reprogrammimg Immunosuppressive Effect of the Tumor-Infiltrating Macrophages and B Lymphocytes.

Head and neck cancer (HNC) is prevalent worldwide, and treatment options are limited. Momordicine-I (M-I), a natural component from bitter melon, shows antitumor activity against these cancers, but its mechanism of action, especially in the tumor microenvironment (TME), remains unclear. In this study, we establish that M-I reduces HNC tumor growth in two different immunocompetent mouse models using MOC2 and SCC VII cells. We demonstrate that the anticancer activity results from modulating several molecules in the monocyte/macrophage clusters in CD45+ populations in MOC2 tumors by single-cell RNA sequencing. Tumor-associated macrophages (TAM) often pose a barrier to antitumor effects, but following M-I treatment, we observe a significant reduction in the expression of Sfln4, a myeloid cell differentiation factor, and Cxcl3, a neutrophil chemoattractant, in the monocyte/macrophage populations. We further find that the macrophages must be in close contact with the tumor cells to inhibit Sfln4 and Cxcl3, suggesting that these TAMs are impacted by M-I treatment. Coculturing macrophages with tumor cells shows inhibition of Agr1 expression following M-I treatment, which is indicative of switching from M2 to M1 phenotype. Furthermore, the total B-cell population in M-I-treated tumors is significantly lower, whereas spleen cells also show similar results when cocultured with MOC2 cells. M-I treatment also inhibits PD1, PD-L1, and FoxP3 expression in tumors. Collectively, these results uncover the potential mechanism of M-I by modulating immune cells, and this new insight can help to develop M-I as a promising candidate to treat HNCs, either alone or as adjuvant therapy.

The chromatin landscape of healthy and injured cell types in the human kidney.

There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidney's active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.

The chromatin landscape of healthy and injured cell types in the human kidney.

There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. However, comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measured dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We established a comprehensive and spatially-anchored epigenomic atlas to define the kidney's active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we noted distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3 , KLF6 , and KLF10 regulated the transition between health and injury, while in thick ascending limb cells this transition was regulated by NR2F1 . Further, combined perturbation of ELF3 , KLF6 , and KLF10 distinguished two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.

Deletion of NuRD component Mta2 in nephron progenitor cells causes developmentally programmed FSGS.

Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.

Sarcoidosis in the older person: diagnostic challenges and treatment consideration.

BACKGROUND: Sarcoidosis is a multi-system disorder with an increasing propensity to present in older patients. Diagnostic uncertainty is common and understandable given the higher prevalence of co-morbidities in older patients and broad differential for multi-system clinical presentations. Excluding malignancy and infection with a high degree of certainty is challenging and may require repeated confirmatory investigation where the diagnosis remains in doubt. SUMMARY OF MAIN FINDINGS: There are a paucity of studies examining late-onset sarcoidosis. Female predominance, pulmonary, ocular, skin and systemic symptoms are common, while more classical presentations such as Lofgren's syndrome are uncommon. Positivity rates of biopsies vary between studies; however, targeted biopsies of accessible sites with organ involvement are the most successful. Therapeutic management is directed at reducing inflammation, and thereby reducing symptom burden, improving quality of life and avoiding progression of organ damage. While most older patients will require corticosteroid therapy, they are also more prone to developing adverse effects. Most older patients will experience a clinical remission; however, the risk of developing chronic sarcoidosis and organ damage is higher compared with younger counterparts. Patients with evidence of pulmonary fibrosis and pulmonary hypertension are at particular risk. IMPACT ON CLINICAL PRACTICE: Health care providers who care for older adults should be aware of the increasing prevalence of late-onset sarcoidosis and consider the diagnosis in those who present with otherwise unexplained systemic symptoms, thoracic abnormalities on imaging and/or evidence of other organ involvement. Earlier diagnosis and therapeutic intervention to halt the development of pulmonary fibrosis and pulmonary hypertension and monitoring for treatment-related adverse effects will confer a mortality benefit.

Antimicrobial therapies for prevention of recurrent acute exacerbations of COPD (AECOPD): beyond the guidelines.

BACKGROUND: Unfortunately, many COPD patients continue to exacerbate despite good adherence to GOLD Class D recommended therapy. Acute exacerbations lead to an increase in symptoms, decline in lung function and increased mortality rate. The purpose of this review is to do a literature search for any prophylactic anti-microbial treatment trials in GOLD class D patients who 'failed' recommended therapy and discuss the role of COPD phenotypes, lung and gut microbiota and co-morbidities in developing a tailored approach to anti-microbial therapies for high frequency exacerbators. MAIN TEXT: There is a paucity of large, well-conducted studies in the published literature to date. Factors such as single-centre, study design, lack of well-defined controls, insufficient patient numbers enrolled and short follow-up periods were significant limiting factors in numerous studies. One placebo-controlled study involving more than 1000 patients, who had 2 or more moderate exacerbations in the previous year, demonstrated a non-significant reduction in exacerbations of 19% with 5 day course of moxifloxacillin repeated at 8 week intervals. In Pseudomonas aeruginosa (Pa) colonised COPD patients, inhaled antimicrobial therapy using tobramycin, colistin and gentamicin resulted in significant reductions in exacerbation frequency. Viruses were found to frequently cause acute exacerbations in COPD (AECOPD), either as the primary infecting agent or as a co-factor. However, other, than the influenza vaccination, there were no trials of anti-viral therapies that resulted in a positive effect on reducing AECOPD. Identifying clinical phenotypes and co-existing conditions that impact on exacerbation frequency and severity is essential to provide individualised treatment with targeted therapies. The role of the lung and gut microbiome is increasingly recognised and identification of pathogenic bacteria will likely play an important role in personalised antimicrobial therapies. CONCLUSION: Antimicrobial therapeutic options in patients who continue to exacerbate despite adherence to guidelines-directed therapy are limited. Phenotyping patients, identification of co-existing conditions and assessment of the microbiome is key to individualising antimicrobial therapy. Given the impact of viruses on AECOPD, anti-viral therapeutic agents and targeted anti-viral vaccinations should be the focus of future research studies.

Suboptimal management of hypernatraemia in acute medical admissions.

BACKGROUND: Hypernatraemia arises commonly in acute general medical admissions. Affected patients have a guarded prognosis with high rates of morbidity and mortality. Age-related physiology and physical/cognitive barriers to accessing water predispose older patients to developing hypernatraemia. This study sought to perform a descriptive retrospective review of hypernatraemic patients admitted under acute general medicine teams. METHODS: A retrospective cross-sectional study of a sample of acute medical in-patients with serum[sodium]>145 mmol/L was conducted. Patients were exclusively older(>69 years) and admitted from Nursing homes (NH)(41%) and non-NH pathways(59%). A comparison of management of NH /non-NH patients including clinical presentation, comorbidities, laboratory values, [sodium] monitoring, intravenous fluid regimes and patient outcomes was performed. RESULTS: In total, 102 consecutive patients (males, n=69(67.6%)) were included. Dementia and reduced mobility were more common in NH residents and admission serum [Sodium] higher (148 vs 142 mmol/L/p=0.003). Monitoring was inadequate: no routine bloods within the first 12h in >80% of patients in both groups. No patient had calculated free water deficit documented. More NH patients received correct fluid management (60% vs 33%/p%0.015). Incorrect fluid regimes occurred in both groups (38% vs 58%/p=0.070). Length of stay in discharged patients was lower in NH, (8(4-20) vs 20.5(9.8-49.3 days)/p=0.003). Time to death for NH residents was shorter (9(5.5-11.5) vs 16 (10.25-23.5) days/p=0.011). CONCLUSION: This study highlights suboptimal management of hypernatraemia. Implementation of hypernatraemia guidelines for general medical older inpatients are clearly required with mechanisms to confirm adherence. Health care workers require further education on diagnostic challenges of dehydration in older people and the importance of maintaining adequate hydration.

Preventative strategies and interventions to improve outcomes during heatwaves.

Extreme weather events including recently experienced prolonged heatwaves are predicted to increase in frequency and intensity as a result of climate change. Vulnerable groups, and particularly older persons, are at increased risk of heat-related illness and mortality. Multimodal interventions that incorporate community, primary and secondary care programmes are required. Social programmes such as early warning systems, regional heat plans and community-led initiatives that specifically target the isolated, dependent older person are protective. Establishing clear and effective communication on health promotion and preventative measures is the key. Energy-efficient building design and eco-city planning are vital to reduce the impact of heatwaves at both a population and individual level. Anticipatory strategies should be adopted to ensure ample access to fluids, target barriers to increase oral intake and allow early identification of intercurrent illness, along with regular medication reviews. Prompt management of risk factors for the development of heat-related illness and treatment of complications such as heat stroke and cardiovascular events are keys to reducing the negative health impact of extreme heat in at-risk populations. Morbidity and mortality in heatwaves should be preventable. Evidence-based interventions are available to mitigate and prevent the negative health impact of extreme heat and should be implemented in all residential settings.

Clindamycin induced toxic epidermal necrolysis versus Staphylococcal scalded skin syndrome: a case report.

Toxic epidermal necrolysis and Staphylococcal scalded skin syndrome (SSSS) are potentially life-threatening dermatological emergencies that present in a similar clinical fashion. Toxic epidermal necrolysis is typically triggered by anticonvulsant and other neurological medications and reports clindamycin inducing the disease is exceedingly rare. SSSS seldomly occurs in adult patients. We present the case of a 60-year-old male presenting with dermatological rash covering >80% his body surface. Diagnosis and therapy involved multidisciplinary contribution from medical physicians, dermatologists, microbiologists and histopathologists to provide a favourable outcome.

Dehydration and renal failure in older persons during heatwaves-predictable, hard to identify but preventable?

Extremes of temperature are likely to increase in frequency associated with climate change. Older patients are particularly vulnerable to the effects of heat with excess mortality well documented in this population. Age-associated neurohormonal changes particularly affecting the renin angiotensin aldosterone system (RAAS), alterations in thermoregulatory mechanisms, changes in renal function and body composition render older persons vulnerable to dehydration, renal failure, heat stroke and increased mortality. Barriers to diagnosis and recognition of dehydration and renal failure include the absence of reliable clinical signs and cost-effective diagnostic tools. Regularly used medications also impact on physiological responses to excess heat as well as interfering with the recognition and management of dehydration during heat waves. In view of the above, anticipatory measures should be instituted ideally prior to the onset of heat waves to minimise morbidity and mortality for older people during periods of excess heat.

Indications and outcomes of home visits by geriatricians.

PURPOSE: The value of the home (domiciliary) visit (HV) by geriatricians at the request of general practitioners has been questioned. We analysed HVs conducted by geriatricians in a west of Ireland hospital over a 14-year period. METHODS: From 2002 to 2016, a systematic record was maintained of all HVs conducted by a geriatrician. RESULTS: Consent to publication was obtained for 114 (81%) of 141 visits performed. A HV was requested in 47 (41%) cases because the person would not attend a clinic, most having a long history of refusing care, and in 40 (35%) cases because the person was severely immobile or too unwell to leave home. In 27 (24%) cases, assessment was best conducted in the home for other reasons including squalor. Of the referrals, only 40 (35%) sought specific medical advice and 15 (13%) sought advice regarding end-of-life planning. In many cases, general advice regarding management of self-neglect, unexplained decline, poor home circumstances and undue risk taking was sought. The commonest decision [45 (39%) participants] was that no major intervention would be appropriate or achievable in the person's circumstances and having regard to his or her own preferences. Twenty-three (20%) participants were persuaded to accept a major intervention they had previously declined. In 14 (12%) cases, a palliative care approach in the home was agreed. An application to court to determine what care the person should receive occurred in five (5%) cases. Many medications were stopped. CONCLUSIONS: Home visits by geriatricians remain a valuable option for selected older people.

Comparing P300 modulations: target-to-target interval versus infrequent nontarget-to-nontarget interval in a three-stimulus task.

This study examined temporal determinants of the P300 component of the ERP in a three-stimulus visual oddball task. Frequent standards, with equiprobable targets and infrequent nontargets, were utilized. We tested whether the infrequent nontarget-to-nontarget interval (infrequent NNI) influences P300 amplitudes and latencies analogously to the target-to-target interval (TTI). EEG was recorded from 27 participants, and response time and P300 effects of TTIs and infrequent NNIs were assessed. Increases in TTI augmented target P300 amplitudes and decreased latencies and response times. However, this modulation of P300 amplitude was weak for manipulations of infrequent NNI. P300 latencies increased initially before decreasing across infrequent NNI levels. Together, these findings support the notion that the P300 has an underlying temporal mechanism that is modulated by motivationally significant events. Theoretical implications are discussed.

Emergency oxygen delivery 2: patients with asthma and COPD.

This is the second of a two-part unit on the use of emergency oxygen in adults. Part 1 outlined the main recommendations of the recently published British Thoracic Society guidance. It also examined managing breathlessness in non-hypoxaemic patients. This part discusses some potential changes to clinical practice and provides practical examples on administering oxygen to patients with acute asthma and COPD. It also outlines issues around administering oxygen that lack evidence and need good-quality studies.

Emergency oxygen delivery in adults 1: updating nursing practice.

The first in this two-part unit discusses new British Thoracic Society guidance on using emergency oxygen in adults. This is the first national guidance on this area and the implications for possible changes to practice are highlighted here. This part outlines the philosophy behind the guideline, the differences between hypoxaemic and hypercapnic patients and essential assessments for critically ill patients who need emergency oxygen. It also discusses using this therapy for patients with lung cancer in acute situations.

Palliative care volunteerism among college students in Canada.

The goal of Study 1 was to investigate whether young Canadian adults were interested in becoming involved in palliative care volunteer work. After reading a brief description of what volunteering in a palliative care environment typically involves, participants (undergraduate students) were asked to indicate whether they would be interested in this kind of volunteer experience and to provide a written explanation of their answer. Of the 105 participating students, only 39 (37.1 percent) expressed an interest in volunteering, while 66 (62.9 percent) were not interested. Not surprisingly, the results revealed that significantly more females than males were interested in palliative care volunteer work (45.9 percent and 25.0 percent, respectively). The most common reason students gave for wanting to become a palliative care volunteer was to help others; the reason given most often for not wanting to volunteer was that it would be too emotionally demanding. It is important to note that prior to taking part in this study the majority of the participating students (75.9 percent) did not know what palliative care was. The goal of Study 2 was to investigate undergraduate students' interest in volunteering in a nursing home, in a classroom, and at a food bank. Of the 111 participating students, 74 (66.7 percent) expressed an interest in volunteering at a food bank and in a nursing home, and 89 (80.2 percent) were interested in becoming a classroom volunteer. Together, the results of Studies 1 and 2 support the view that young people in Canada (especially males) are not interested in becoming involved in the care of dying persons. However, the results also indicate that they are very interested in volunteering with other populations (e.g., the elderly, school children) and in other settings (e.g., food bank).

Structure-activity study of LVV-hemorphin-7: angiotensin AT4 receptor ligand and inhibitor of insulin-regulated aminopeptidase.

The decapeptide LVV-hemorphin-7 binds with high affinity to the angiotensin IV (Ang IV) receptor (AT(4) receptor), eliciting a number of physiological effects, including cellular proliferation and memory enhancement. We have recently shown that the AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and that both LVV-hemorphin-7 and Ang IV inhibit the catalytic activity of IRAP. In the current study, a series of alanine-substituted and N- or C-terminally modified analogs of LVV-hemorphin-7 were evaluated for their abilities to compete for (125)I-Ang IV binding in sheep adrenal and cerebellar membranes. Selected analogs were also analyzed for binding to recombinant human IRAP and inhibition of IRAP aminopeptidase activity. C-Terminal deletions of LVV-hemorphin-7 resulted in modest changes in affinity for IRAP, whereas deletion of the first three N-terminal residues abolished binding. Monosubstitutions of Tyr(4) and Trp(6) with alanine resulted in a 10-fold reduction in affinity. Competition binding studies using recombinant human IRAP demonstrated the same rank order of affinity as obtained for the ovine tissues. All LVV-hemorphin-7 analogs tested, except for Leu-Val-Val-Tyr, inhibit the cleavage of the synthetic substrate, leucine beta-naphthylamide, by IRAP, with K(i) values between 56 and 620 nM. We find that the Val(3) residue is crucial for LVV-hemorphin-7 binding to IRAP, whereas the C-terminal domain seems to play a minor role. The current study highlights the minimal residues necessary for binding and inhibition of IRAP and provides a basis to design peptidomimetic analogs for experimental and potentially clinical use.