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Amino acids and the kidney; friends or foes?
No full textPurpose of review Acute kidney injury (AKI) is common in hospitalized patients and is independently associated with morbidity and mortality. Moreover, AKI increases the risk of chronic kidney disease, which is a major healthcare problem. Currently, no single therapy has been proven to be effective in preventing AKI. The role of amino acids in the context of kidney function and AKI prevention has been controversial and most of the evidence is available from nutritional studies. However, knowledge of amino acids in recruiting renal functional reserve and their potential role to protect renal function under stress has recently expanded. Recent findings The nephroprotective effects of amino acids were first postulated in 1973. Recently, this strategy gained renewed interest and has been more extensively studied, reintroducing their use in clinical situations characterized by a high incidence of AKI. Intravenous amino acids administration for kidney protection is now supported by a large multinational randomized double-blind controlled trial in cardiac surgery and by experimental and observational data. All such data support the rationale for a biologically and clinically important nephroprotective effect. Summary The infusion of amino acids was recently found to reduce the incidence of AKI in cardiac surgery patients and surgical patients. This strategy for the protection of renal function is supported by a multicenter, international, double-blind randomized trial, with a huge potential for additional application in several clinical fields. Several mechanisms of action support the robustness of these findings and are summarized in this manuscript
Pregnancy during a pandemic: a deep phenotyping approach exploring the role of inflammation on postpartum cognitive decline and depression.
Get PDFPeripartum depression (PPD) results in physical, emotional, and behavioral changes during pregnancy and postpartum that occur in roughly 20% of women, yet COVID-19 may have increased the prevalence of PPD. Furthermore, during this period, women may be vulnerable to the development of cognitive deficits. The biological causes of PPD and cognitive decline are still unclear. These issues may arise due to brain structural and functional alterations; however, results are inconclusive. Moreover, dysregulation of immunological changes during and after pregnancy may impact mood and cognition.
Therefore, we investigated the neurobiological patterns of PPD. We first examined the neuroimaging and genetic associations of a history of PPD in a sample of mood disorder patients. Secondly, we explored the neuroimaging and inflammatory correlates of a current PPD episode and cognitive impairment. In both samples, we used structural and functional neuroimaging to investigate associations of PPD and cognitive impairment and partial least squares (PLS) regression models to predict PPD and cognitive impairment using polygenetic risk scores (PRSs) and inflammatory markers respectively.
In our retrospective sample, we found larger basal ganglia volumes in MDD women with a PPD history compared to those without a PPD history, as well as a differential effect of estradiol PRSs on the area based on PPD status. We also found DTI differences based on PPD onset and interactions between PPD and psychiatric PRSs on DTI measures. Women with a PPD history also had increased functional connectivity in visual areas. In the PLS regressions, multiple PRSs were associated with PPD status and slightly differed based on mood disorder diagnosis. In our prospective sample, we found numerous correlates of depressive, anxiety, and cognitive symptomatology including reduced grey matter volume and thickness with a differential effect of cytokines on grey matter structure according to depressive symptoms. We also found increased mean diffusivity in white matter tracts according to third-trimester anxiety and cognitive scores and reduced functional connectivity according to third-trimester depression and anxiety symptoms. Lastly, we identified significant predictive models of PPD symptoms and cognition using third-trimester and postpartum cytokine levels. Overall, we demonstrate current and long-term neuroimaging associations of PPD and that these neurobiological differences are associated with genetic predispositions and peripheral immune markers.La depressione peripartum (PPD) comporta cambiamenti fisici, emotivi e comportamentali durante la gravidanza e il post-partum che si verificano in circa il 20% delle donne, ma la pandemia COVID-19 potrebbe aver aumentato la prevalenza della PPD. Inoltre, durante questo periodo, le donne possono essere vulnerabili allo sviluppo di deficit cognitivi. Le cause biologiche della PPD e del declino cognitivo non sono ancora chiare. Questi problemi potrebbero derivare da alterazioni strutturali e funzionali del cervello, ma i risultati non sono conclusivi. Inoltre, la disregolazione dei cambiamenti immunologici durante e dopo la gravidanza può avere un impatto sull'umore e sulla cognizione.
Pertanto, abbiamo studiato i correlati neurobiologici della PPD. Abbiamo innanzitutto esaminato le associazioni genetiche e di neuroimaging di una storia di PPD in un campione di pazienti con disturbi dell'umore. In secondo luogo, abbiamo esplorato i correlati neurali e infiammatori di un episodio attuale di PPD e del deterioramento cognitivo. In entrambi i campioni, abbiamo utilizzato neuroimaging strutturale e funzionale per indagare le associazioni tra PPD e deterioramento cognitivo e modelli di regressione partial least squares (PLS) per prevedere PPD e deterioramento cognitivo utilizzando rispettivamente punteggi di rischio poligenici (polygenic risk score, PRS) e marcatori infiammatori.
Nel nostro campione retrospettivo, abbiamo riscontrato volumi più grandi dei gangli basali nelle donne con disturbo depressivo maggiore con una storia di PPD rispetto a quelle senza storia di PPD, nonché un effetto differenziale del PRS dell'estradiolo sull'area in base allo stato di PPD. Abbiamo anche riscontrato differenze nell’integrita’ della sostanza bianca della in base all'insorgenza del PPD e interazioni tra PPD e PRS psichiatrici su queste misure. Le donne con una storia di PPD presentavano anche una maggiore connettività funzionale nelle aree visive. Nelle regressioni PLS, diversi PRS erano associati allo stato di PPD e differivano leggermente in base alla diagnosi di disturbo dell'umore. Nel nostro campione prospettico, abbiamo trovato numerosi correlati della sintomatologia depressiva, ansiosa e cognitiva, tra cui una riduzione del volume e dello spessore della materia grigia con un effetto differenziale delle citochine sulla struttura della materia grigia in base ai sintomi depressivi. Abbiamo anche riscontrato un aumento della diffusività media nei tratti di materia bianca in base ai punteggi di ansia e sintomi cognitivi del terzo trimestre e una riduzione della connettività funzionale in base ai sintomi di depressione e ansia del terzo trimestre. Infine, abbiamo identificato modelli predittivi significativi dei sintomi della PPD e della cognizione utilizzando i livelli di citochine del terzo trimestre e del post-partum. Nel complesso, abbiamo dimostrato l’esistenza di correlati neurali associati alla PPD sia attuale che nel lungo termine e che queste differenze neurobiologiche sono associate a predisposizioni genetiche e a marcatori immunitari periferici
Safety and Efficacy Intravenous Istaroxime up to 60 hours for Patients with Pre-Cardiogenic Shock
No full textBackground and aims: A drug that improves blood pressure (BP) and cardiac output (CO) while reducing pulmonary wedge pressure safely is needed for patients with cardiogenic shock (CS) due to acute heart failure (AHF). Methods: In a randomized, double-blind, placebo-controlled trial, istaroxime 0.5 to 1.5 μg/kg/min for 24 - 60 hours was administered to 48 patients, and placebo to 42 patients, with pre-CS due to AHF under hemodynamic monitoring. Echocardiographic, and Holter monitoring were done in both parts. Results: Patients randomized to istaroxime had a greater increase in SBP during the first 6 hours (primary endpoint), ls-mean (SE) 62.0 (6.59) mmHg*hour vs 36.4 (7.11) in the placebo arm (LS mean difference of 25.6 mmHg*hour, 95% CI 7.2-44.0 mmHg*h, p= 0.007). In patients administered istaroxime for at least 48 hours SBP increase persisted for 60 hours. Istaroxime led to a greater increase in CO (0.66 L/min, p=0.017) and decrease in wedge pressure (3.8 mmHg, p=0.0017). Relative to average baselines of 3.6 L/min for CO and 22.5 mmHg, this translates into improvements of 18.3% and 16.9%. respectively. Echocardiographic assessments showed improvements in E/A, TAPSE, and LA volume at 24 hours. There were improvements in eGFR at 24-72 hours and NYHA class to 72 hours. NT-proBNP increased more in istaroxime-treated patients. Heart rate decreased more in the first 24 hours in istaroxime-treated patients. No significant malignant arrythmias were detected in patients treated with istaroxime on Holter monitoring. Conclusions: In this small study, istaroxime doses of up to 1.0 μg/kg/min for up to 60 hours were associated with improvements in SBP, CO and reduction in wedge pressure and heart rate without increase in arrythmias
Osteopontin levels in the serum reflect anatomical disease progression in patients with amyotrophic lateral sclerosis
No full textBackground: Amyotrophic lateral sclerosis (ALS) lacks biomarkers for diagnosis, prognostic stratification, and evaluation of response to potential treatments. Previous research supported the role of serum osteopontin (OPN) levels as a potential biomarker in ALS. However, the associations of OPN serum levels with clinical features and their trend over the disease course have not been explored yet. Methods: We measured OPN serum levels in a retrospective cohort of 110 well-characterized patients with ALS, using a commercial ELISA kit, and analyzed their association with demographic and clinical features, as well as with other serum biomarkers. For a subset of patients, longitudinal measurements were available. Results: OPN serum levels differed significantly between patients with ALS and a cohort of 45 age and sex-matched healthy controls. However, when considering potential differential diagnoses, elevated OPN serum levels were not specific for ALS. Patients with an advanced disease stage (King’s stage 3 or 4) exhibited significantly higher OPN serum levels compared to patients at earlier disease stages, whereas we did not observe any correlation with ALSFRS-R and progression rate. We observed an inverse correlation between OPN serum levels and BMI at diagnosis. Higher OPN serum levels predicted a shorter survival time and a shorter time to King’s stage 4. No significant association between serum OPN and serum neurofilament light or glial fibrillary acid protein levels was observed. OPN serum levels were substantially stable over a 9-month observation time. Conclusion: Our findings indicate that serum OPN is an informative biomarker in ALS, providing valuable prognostic insights, potentially reflecting the extent of disease, and demonstrating potential applications in clinical trials
When Severe Hypothyroidism Mimics Neuromuscular Diseases: A Case Supporting Outpatient Management in Contemporary Endocrinology
Get PDFBackground: Severe hypothyroidism may present with symptoms that resemble primary neuromuscular or acute neurological disorders, leading to diagnostic delays and potentially unnecessary hospitalizations. Case: A 38-year-old man presented with postural instability, diplopia, myalgia, and elevated CK, suggestive of a neuromuscular disorder. Labs revealed TSH > 170 μU/mL and suppressed fT4. Despite severe biochemistry, clinical stability allowed for outpatient management with levothyroxine and endocrinology follow-up. Discussion: The case mimicked inflammatory myopathy and brainstem stroke, but absence of red flags enabled safe outpatient treatment. Literature confirms that hypothyroidism can present with neurologic signs and that structured outpatient pathways are effective. Conclusion: This case highlights the importance of recognizing endocrine causes in neuromuscular presentations and supports outpatient management models for stable hypothyroid patients. Keywords: hypothyroidism; neuromuscular disorders; acute neurological disorders; unnecessary hospitalization; outpatient management
Unlocking hope: The future of ustekinumab biosimilars in Crohn's disease treatment
No full textBiologic therapies have revolutionized Crohn's disease (CD) management, but their high costs pose a significant barrier to access. Biosimilars can provide increased access to treatment because of significant cost-savings. Ustekinumab is a biological drug against interleukin 12–23 that is employed in treating moderate-to-severe CD. As the patent of the reference product (RP) is expiring, ustekinumab biosimilars have been developed and are currently becoming available for patients. Available data demonstrate that ustekinumab biosimilars exhibit comparable efficacy, pharmacokinetics, safety and immunogenicity as the RP. Ustekinumab biosimilars have been approved for CD based on extrapolation and there is no real-world data available yet for this indication. While biosimilars of ustekinumab promise cost savings in treating moderate-to-severe CD, it is not yet known whether their availability will change the treatment algorithm in CD. This review focuses on the available data on ustekinumab biosimilars, focusing on their pros and cons for their forthcoming role in treating moderate to severe CD
Implementation of guideline-recommended medical therapy for patients with heart failure in Europe
No full textPhysicians' adherence to guideline-recommended heart failure (HF) treatment remains suboptimal, especially regarding the target doses. In particular, there is evidence that non-cardiologists are less compliant with HF guideline recommendations. This is likely to have a detrimental impact on patients' survival, readmissions and quality of life. Thus, the present document aims to address the reasons underlying low implementation and under-dosing of guideline-directed medical therapy in HF and to update a guidance for the initiation and rapid titration of HF drugs. In particular, aim of this document is to provide practical indications for drug implementation, to be applied not only by cardiologists but also by GPs and internal medicine doctors
Microbiome modulation uncouples efficacy and toxicity induced by immune checkpoint blockade in mouse multiple myeloma
No full text: Smoldering multiple myeloma (SMM), which is in principle curable, may develop into life-threatening MM. Intestinal microbiota and gut-born T helper-17 (Th17) lymphocytes may contribute to this development, but the mechanisms are unclear. Here we demonstrate that administering the human commensal Prevotella melaninogenica to transgenic Vk*MYC mice that exhibit SMM-like phenotypes delays the evolution to full-blown MM. Mechanistically, P. melaninogenica increases the production of short-chain fatty acids (SCFA), thereby preventing the skewing of dendritic cells towards a pro-Th17 phenotype and subsequently accumulation of Th17 cells in the bone marrow of treated mice. P. melaninogenica or butyrate synergizes with anti-PD-L1 or anti-TIGIT to suppress myeloma progression by restraining Th17 cell expansion while inducing effector CD8+ T cells. P. melaninogenica also attenuates IL-17-mediated skin lesions that mimic anti-PD-L1-induced adverse events. Our results thus suggest that gut microbiota modulation or SCFAs administration may represent treatment options for patients affected by plasma cell dyscrasias
Two-step-7-Pink Rule: A Practical Tool for the Dermoscopic Evaluation of Fully Amelanotic Skin Lesions
No full textIntroduction: The diagnosis of fully amelanotic skin tumors is difficult on clinical and dermoscopic examination. Objectives: We sought to identify an accurate and user-friendly dermoscopic algorithm to differentiate between benign and malignant pink lesions. Methods: The database of 1 referral center was retrospectively reviewed for images of noninflammatory fully amelanotic skin lesions. Two dermatologists jointly assessed a validation set of images for dermoscopic criteria and constructed a diagnostic algorithm, the 2-step-7-pink rule (2S-7PR). Two external clinicians, with different skills in dermoscopy and blinded to the final diagnosis, separately evaluated images from the validation test sets using the prevalent criterion method and the new 2S-7PR algorithm. Results: A total of 763 lesions from 652 patients were included in the validation set database, of which 68.3% were malignant and 31.7% were benign. Three suspicious dermoscopic criteria were included in the first step of the 2S-7PR: polymorphous or sharply focused vessels, scales or crusts, and erosions or ulcerations; and 4 non-suspicious criteria were included in the second: white collarette, white scar-like area, vascular lacunae, and necklace pinpoint vessels. High levels of specificity and sensitivity were calculated in the validation and test phases for both the expert and non-expert evaluators, the former achieving higher levels of both sensitivity and specificity by employing the 2S-7PR compared to the prevalent method, and the latter only improved specificity. Conclusions: The present study showed that an algorithm focused on a few reproducible and easily recognizable criteria could improve diagnostic accuracy in the management of amelanotic lesions