Medical Sciences — Open Access Journal

Background: Sepsis diagnosis can be incorrectly associated with the presence of hypotension during an infection, so the detection and management of non-hypotensive sepsis can be delayed. We aimed to evaluate how the presence or absence of hypotension, on admission at the emergency department, affects the initial management and outcomes of patients with community-onset severe sepsis. Methods: Demographic, clinical, laboratory, process of care, and outcome variables were recorded for all patients, at the emergency department of our university hospital, who presented with community-onset severe sepsis, between 1 March and 31 August in three consecutive years. Patient management consisted of standardized bundled care with five measures: Detection, blood cultures and empirical antibiotics, oxygen supplementation and fluid resuscitation (if needed), clinical monitoring, and noradrenalin administration (if needed). We compared all variables between patients who had hypotension (mean arterial pressure <65 mmHg), on admission to the emergency department, and those who did not. Results: We identified 153 episodes (84 (54.5%) men; mean age 73.6 ± 1.2; mean Sequential Organ Failure Assessment (SOFA) score 4.9 ± 2.7, and 41.2% hospital mortality). Hypotension was present on admission to the emergency department in 57 patients (37.2%). Hemodynamic treatment was applied earlier in patients who presented hypotension initially. Antibiotics were administered 48 min later in non-hypotensive sepsis (p = 0.08). A higher proportion of patients without initial hypotension required admission to the intensive care unit (ICU) (43.1% for patients initially hypotensive vs. 56.9% in those initially non-hypotensive, p < 0.05). Initial hypotension was not associated with mortality. A delay in door-to-antibiotic administration time was associated with mortality [OR 1.150, 95%CI: 1.043–1.268). Conclusions: Initial management of patients with community-onset severe sepsis differed according to their clinical presentation. Initial hypotension was associated with early hemodynamic management and less ICU requirement. A non-significant delay was observed in the administration of antibiotics to initially non-hypotensive patients. The time of door-to-antibiotic administration was related to mortality. Full article

With growing recognition of pediatric delirium in pediatric critical illness there has also been increased investigation into improving recognition and determining potential risk factors. Disturbed sleep has been assumed to be one of the key risk factors leading to delirium and is commonplace in the pediatric critical care setting as the nature of intensive care requires frequent and invasive monitoring and interventions. However, this relationship between sleep and delirium in pediatric critical illness has not been definitively established and may, instead, reflect significant overlap in risk factors and consequences of underlying neurologic dysfunction. We aim to review the existing tools for evaluation of sleep and delirium in the pediatric critical care setting and review findings from recent investigations with application of these measures in the pediatric intensive care unit. Full article

The intracellular levels of polyamines, cationic molecules involved in a myriad of cellular functions ranging from cellular growth, differentiation and apoptosis, is precisely regulated by antizymes and antizyme inhibitors via the modulation of the polyamine biosynthetic and transport systems. Antizymes, which are mainly activated upon high polyamine levels, inhibit ornithine decarboxylase (ODC), the key enzyme of the polyamine biosynthetic route, and exert a negative control of polyamine intake. Antizyme inhibitors (AZINs), which are proteins highly homologous to ODC, selectively interact with antizymes, preventing their action on ODC and the polyamine transport system. In this review, we will update the recent advances on the structural, cellular and physiological functions of AZINs, with particular emphasis on the action of these proteins in the regulation of polyamine metabolism. In addition, we will describe emerging evidence that suggests that AZINs may also have polyamine-independent effects on cells. Finally, we will discuss how the dysregulation of AZIN activity has been implicated in certain human pathologies such as cancer, fibrosis or neurodegenerative diseases. Full article

Dendritic cells (DCs) are a type of cells derived from bone marrow that represent 1% or less of the total hematopoietic cells of any lymphoid organ or of the total cell count of the blood or epithelia. Dendritic cells comprise a heterogeneous population of cells localized in different tissues where they act as sentinels continuously capturing antigens to present them to T cells. Dendritic cells are uniquely capable of attracting and activating naïve CD4⁺ and CD8⁺ T cells to initiate and modulate primary immune responses. They have the ability to coordinate tolerance or immunity depending on their activation status, which is why they are also considered as the orchestrating cells of the immune response. The purpose of this review is to provide a general overview of the current knowledge on ontogeny and subsets of human dendritic cells as well as their function and different biological roles. Full article

Transglutaminase 2 (EC 2.3.2.13; TG2 or TGase 2) plays important roles in the pathogenesis of many diseases, including cancers, neurodegeneration, and inflammatory disorders. Under normal conditions, however, mice lacking TGase 2 exhibit no obvious abnormal phenotype. TGase 2 expression is induced by chemical, physical, and viral stresses through tissue-protective signaling pathways. After stress dissipates, expression is normalized by feedback mechanisms. Dysregulation of TGase 2 expression under pathologic conditions, however, can potentiate pathogenesis and aggravate disease severity. Consistent with this, TGase 2 knockout mice exhibit reversal of disease phenotypes in neurodegenerative and chronic inflammatory disease models. Accordingly, TGase 2 is considered to be a potential therapeutic target. Based on structure–activity relationship assays performed over the past few decades, TGase 2 inhibitors have been developed that target the enzyme’s active site, but clinically applicable inhibitors are not yet available. The recently described the small molecule GK921, which lacks a group that can react with the active site of TGase 2, and efficiently inhibits the enzyme’s activity. Mechanistic studies revealed that GK921 binds at an allosteric binding site in the N-terminus of TGase 2 (amino acids (a.a.) 81–116), triggering a conformational change that inactivates the enzyme. Because the binding site of GK921 overlaps with the p53-binding site of TGase 2, the drug induces apoptosis in renal cell carcinoma by stabilizing p53. In this review, we discuss the possibility of developing TGase 2 inhibitors that target the allosteric binding site of TGase 2. Full article

An imbalance of bacterial quantity and quality of gut microbiota has been linked to several pathologies. New strategies of microbiota manipulation have been developed such as fecal microbiota transplantation (FMT); the use of pre/probiotics; an appropriate diet; and phage therapy. The presence of bacteriophages has been largely underestimated and their presence is a relevant component for the microbiome equilibrium. As a promising treatment, phage therapy has been extensively used in Eastern Europe to reduce pathogenic bacteria and has arisen as a new method to modulate microbiota diversity. Phages have been selected and “trained” to infect a wide spectrum of bacteria or tailored to infect specific antibiotic resistant bacteria present in patients. The new development of genetically modified phages may be an efficient tool to treat the gut microbiota dysbiosis associated with different pathologies and increased production of bacterial metabolites and subsequently decrease systemic low-grade chronic inflammation associated with chronic diseases. Microbiota quality and mitochondria dynamics can be remodulated and manipulated by phages to restore the equilibrium and homeostasis of the system. Our aim is to highlight the great interest for phages not only to eliminate and control pathogenic bacterial infection but also in the near future to modulate the microbiota by adding new functions to selected bacteria species and rebalance the dynamic among phages and bacteria. The challenge for the medicine of tomorrow is to re-think and redesign strategies differently and far from our traditional thinking. Full article

Brain tumors are highly heterogeneous and have been classified by the World Health Organization in various histological and molecular subtypes. Gliomas have been classified as ranging from low-grade astrocytomas and oligodendrogliomas to high-grade astrocytomas or glioblastomas. These tumors are characterized by a peculiar pattern of genetic alterations. Pediatric high-grade gliomas are histologically indistinguishable from adult glioblastomas, but they are considered distinct from adult glioblastomas because they possess a different spectrum of driver mutations (genes encoding histones H3.3 and H3.1). Medulloblastomas, the most frequent pediatric brain tumors, are considered to be of embryonic derivation and are currently subdivided into distinct subgroups depending on histological features and genetic profiling. There is emerging evidence that brain tumors are maintained by a special neural or glial stem cell-like population that self-renews and gives rise to differentiated progeny. In many instances, the prognosis of the majority of brain tumors remains negative and there is hope that the new acquisition of information on the molecular and cellular bases of these tumors will be translated in the development of new, more active treatments. Full article

During glioblastoma treatment, the pharmaceutical monoclonal antibody to vascular endothelial growth factor A, bevacizumab, has improved the quality of life and delayed progression for several months, but has not (or only marginally) prolonged overall survival. In 2017, several dramatic research papers appeared that are crucial to our understanding of glioblastoma vis-a-vis the mode of action of bevacizumab. As a consequence of these papers, a new, potentially more effective treatment protocol can be built around bevacizumab. This is the ADZT regimen, where four old drugs are added to bevacizumab. These four drugs are apremilast, marketed to treat psoriasis, dapsone, marketed to treat Hansen’s disease, zonisamide, marketed to treat seizures, and telmisartan, marketed to treat hypertension. The ancillary attributes of each of these drugs have been shown to augment bevacizumab. This paper details the research data supporting this contention. Phase three testing of AZDT addition to bevacizumab is required to establish safety and effectiveness before general use. Full article

Patients with chronic obstructive pulmonary disease (COPD) have a higher risk of acute cardiovascular events, and around 30% die from cardiovascular diseases. Recent data suggest an increased risk of myocardial infarction in the following days of a severe exacerbation of COPD. Disruption in the balance during the exacerbation with tachycardia, increased inflammation and systemic oxidative stress as well as some other factors may confer an increased risk of subsequent cardiovascular events. A number of investigations may be useful to an early diagnosis, including electrocardiography, imaging techniques and blood test for biomarkers. Some drugs that have changed prognosis in the cardiovascular setting such as cardioselective beta-blockers may be underused in patients with COPD despite its demonstrated benefits. This review focuses on several aspects of exacerbation of COPD and cardiovascular events including epidemiology, possible mechanism, diagnosis and treatment. Full article

Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn’s disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 μg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 μg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed. Full article

Since the advent of new direct acting antivirals (DAA), substantial changes in hepatitis C (HCV) treatment guidelines have occurred. However, little is known about how these recommendations have been adopted into clinical practice. We conducted a retrospective review of human immunodeficiency virus (HIV)/HCV coinfected patients treated with DAAs at the Ryan White Clinic of the Jackson Health System in Miami, FL, USA. Our aim was to determine changes in HCV evaluation and treatment patterns in the use of DAAs over a four-year period from January 2014 to December 2017. Data were divided into two periods: period 1 (2014–2015) and period 2 (2016–2017). In comparison with the rest of the cohort, patients in period 2 had a lower frequency of advanced liver disease (24.4% vs. 48.6%, p = 0.026) and underwent more elastography (34.1% vs. 2.7%, p < 0.001) and less ultrasound (78.0% vs. 97.3%, p = 0.011). They were more often treated with ledipasvir/sofosbuvir (85.4% vs. 56.8%, p = 0.005) and less often with simeprevir/sofosbuvir (0% vs. 32.4%, p < 0.001). Gastrointestinal side effects were reported less frequently (2.4% vs. 18.9%, p = 0.017) in this period. In accordance with the updated guidelines, our study demonstrated a growing preference for non-invasive methods to assess fibrosis in recent years. Regarding treatment, there was a clear preference for second generation DAAs in 2016–2017, along with initiation of treatment in the early stages of liver disease. Full article

Arrhythmogenic right ventricular dysplasia (ARVD) is an abnormality in the right side of the heart that may lead to sudden death. The study aims to compare cardiac MRI (magnetic resonance imaging findings) with echocardiography in patients with ARVD. For the cross-sectional study, patients with ARVD that were diagnosed using Task Force criteria were included, and their cardiac MRI findings were evaluated. Additionally, the right ventricle was divided into three levels—basal, middle, and apical—and each of them was also subdivided into three secondary segments. Gadolinium enhancement was evaluated in each segment. Overall, 39 patients were studied. Thirty-one patients (81%) were men. The average age of female and male patients was 37.8 ± 4.6 and 32.48 ± 5.8, respectively. The average ejection fraction found was 43 ± 9.4 and 42.8 ± 8.5% by MRI and echocardiography, respectively. Additionally, 46 and 35.8% of the patients had hypokinesia in the right ventricle, found based on MRI and echocardiography, respectively. The right ventricular aneurysm was found in 20.5 and 5.1% of patients based on MRI and echocardiography, respectively. The cardiac MRI managed to diagnose some cases which echocardiography was not able to detect. Thus, MRI plays an important role in presenting diagnostic data for the management of patients with ARVD and also making the diagnosis in suspicious patients definitive. Full article

Chronic liver diseases are a major cause of morbidity and mortality worldwide. Recently, gut dysbiosis was identified as an important factor in the pathogenesis of liver diseases. The relationship between gut microbiota and the liver is still not well understood; however, dysfunction of the gut mucosal barrier (“leaky gut”) and increased bacterial translocation into the liver via the gut–liver axis probably play crucial roles in liver disease development and progression. The liver is an important immunological organ, and, after exposure to gut-derived bacteria via portal circulation, it responds with activation of the innate and adaptive immune system, leading to hepatic injury. A better understanding of the pathophysiological links among gut dysbiosis, the integrity of the gut barrier, and the hepatic immune response to gut-derived factors is essential for the development of new therapies to treat chronic liver diseases. Full article

The annual incidence of mild traumatic brain injury (MTBI) is 3.8 million in the USA with 10–15% experiencing persistent morbidity beyond one year. Chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by accumulation of hyperphosphorylated tau, can occur with repetitive MTBI. Risk factors for CTE are challenging to identify because injury mechanisms of MTBI are heterogeneous, clinical manifestations and management vary, and CTE is a postmortem diagnosis, making prospective studies difficult. There is growing interest in the genetic influence on head trauma and development of CTE. Apolipoprotein epsilon 4 (APOE-ε4) associates with many neurologic diseases, and consensus on the ε4 allele as a risk factor is lacking. This review investigates the influence of APOE-ε4 on MTBI and CTE. A comprehensive PubMed literature search (1966 to 12 June 2018) identified 24 unique reports on the topic (19 MTBI studies: 8 athletic, 5 military, 6 population-based; 5 CTE studies: 4 athletic and military, 1 leucotomy group). APOE-ε4 genotype is found to associate with outcomes in 4/8 athletic reports, 3/5 military reports, and 5/6 population-based reports following MTBI. Evidence on the association between APOE-ε4 and CTE from case series is equivocal. Refining modalities to aid CTE diagnosis in larger samples is needed in MTBI. Full article

Sleep is essential to human development. Poor sleep can have significant effects on cognition, learning and memory, physical and behavioral health, and social-emotional well-being. This paper highlights the prevalence of common pediatric sleep problems and posits that a multidisciplinary approach to the assessment and intervention of sleep problems is ideal. Primary care providers are often the first professionals to discuss sleep issues with youth and families. However, dentists, otolaryngologists, childcare providers, school personnel, and behavioral health providers have a vital role in screening and prevention, providing intervention, and monitoring the progress of daily functioning. The strengths of this approach include better provider-to-provider and provider-to-family communication, streamlined assessment and intervention, earlier identification of sleep issues with more efficient referral, and longer-term monitoring of progress and impact on daily functioning. Barriers to this approach include difficulty initiating and maintaining collaboration among providers, limited provider time to obtain the necessary patient permission to collaborate among all multidisciplinary providers, lack of financial support for consultation and collaboration outside of seeing patients face-to-face, geographic location, and limited resources within communities. Research investigating the utility of this model and the overall impact on pediatric patient sleep issues is warranted and strongly encouraged. Full article

Sleep disorders are common in several psychiatric disorders, including schizophrenia. In the pediatric population, the relationship between sleep and psychosis is not completely understood due to limited research studies investigating the link. Insomnia is noted to be a predictor of psychosis, especially in ultrahigh risk adolescents. Sleep difficulties are also associated with a two to three-fold increase in paranoid thinking. Biological factors, such as decrease in thalamic volume, have been observed in children with schizophrenia and ultrahigh risk adolescents with associated sleep impairment. Objective studies have indicated possible actigraphy base measures to be the predictor of psychosis after a one year follow-up. The studies using polysomnography have rare and inconsistent results. In this brief review, we provide an overview of existing literature. We also posit that future research will be beneficial in understanding the initiation, course and progression of sleep disturbance in the high risk pediatric population with the goal of implementing interventions to alter the development of psychosis. Full article

In idiopathic pulmonary fibrosis (IPF) breathing pattern changes with disease progress. This study aims to determine if unsupervised hierarchal cluster analysis (HCA) can be used to define airflow profile differences in people with and without IPF. This was tested using 31 patients with IPF and 17 matched healthy controls, all of whom had their lung function assessed using spirometry and carbon monoxide CO transfer. A resting tidal breathing (RTB) trace of two minutes duration was collected at the same time. A Euclidian distance technique was used to perform HCA on the airflow data. Four distinct clusters were found, with the majority (18 of 21, 86%) of the severest IPF participants (Stage 2 and 3) being in two clusters. The participants in these clusters exhibited a distinct minute ventilation (p < 0.05), compared to the other two clusters. The respiratory drive was greatest in Cluster 1, which contained many of the IPF participants. Unstructured HCA was successful in recognising different airflow profiles, clustering according to differences in flow rather than time. HCA showed that there is an overlap in tidal airflow profiles between healthy RTB and those with IPF. The further application of HCA in recognising other respiratory disease is discussed. Full article

In an era of precision medicine, it seems regressive that we do not use stratified approaches to direct treatment of oral corticosteroids during an exacerbation of chronic obstructive pulmonary disease (COPD). This is despite evidence suggesting that 40% of COPD patients have eosinophilic inflammation and this is an indicator of corticosteroid response. Treatments with oral corticosteroids are not always effective and not without harm, with significant and increased risk of hyperglycemia, sepsis, and fractures. Eosinophils are innate immune cells with an incompletely understood role in the pathology of airway disease. They are detected at increased levels in some patients and can be measured using non-invasive methods during states of exacerbation and stable periods. Despite the eosinophil having an unknown mechanism in COPD, it has been shown to be a marker of length of stay in severe hospitalized exacerbations, a predictor of risk of future exacerbation and exacerbation type. Although limited, promising data has come from one prospective clinical trial investigating the eosinophil as a biomarker to direct systemic corticosteroid treatment. This identified that there were statistically significant and clinically worsened symptoms in patients with low eosinophil levels who were prescribed prednisolone, demonstrating the potential utility of the eosinophil. In an era of precision medicine our patients’ needs are best served by accurate diagnosis, correct identification of maximal treatment response and the abolition of harm. The peripheral blood eosinophil count could be used towards reaching these aims. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic interstitial lung disease of unknown origin with a characteristic imaging and histologic pattern called usual interstitial pneumonia (UIP). The diagnosis of IPF is a complex procedure that requires the support of various specialists, who must integrate clinical, radiological, and histological data. The multidisciplinary team (MDT) has become the new gold standard to diagnose and manage the disease, increasing the accuracy and agreement of the diagnosis between different centers. It is mandatory to exclude nonspecific interstitial pneumonia or other diseases that can cause the UIP pattern, particularly drugs or exposure diseases, including chronic hypersensitivity pneumonitis or systemic autoimmune disease. The role of the MDT is also to decide who could need a biopsy or to review patient diagnoses at regular intervals in those with additional information or unexpected evolution. This review provides updated information to achieve a proper IPF diagnosis. Full article