Monoaminergic and histaminergic strategies and treatments in brain diseases

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.peer-reviewe

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Key Role of Inflammation in Myeloproliferative Neoplasms: Instigator of Disease Initiation, Progression. and Symptoms

Purpose of reviewChronic inflammation is a characteristic feature of myeloproliferative neoplasm (MPN) and impacts many aspects of the disease including initiation, progression, and symptomatology.Recent findingsThe chronic inflammatory state of MPN results from disruption of immune signaling pathways leading to overproduction of inflammatory cytokines by both the neoplastic clones and bystander immune cells. This chronic inflammation may allow for the neoplastic clone to gain a selective advantage. The symptomatic burden felt by MPN patients may be a result of the chronic inflammation associated with MPN, as several cytokines have been linked with different symptoms. Pharmacologic as well as nonpharmacologic treatments of the inflammatory component of this disease may lead to decreased symptomatic burden, prevention of disease progression, and improvement in overall disease trajectory. Inflammation plays a key role in the pathogenesis of MPN and represents an important therapeutic target

Fecal Microbial Community Composition in Myeloproliferative Neoplasm Patients Is Associated with an Inflammatory State.

The capacity of the human microbiome to modulate inflammation in the context of cancer is becoming increasingly clear. Myeloproliferative neoplasms (MPNs) are chronic hematologic malignancies in which inflammation plays a key role in disease initiation, progression, and symptomatology. To better understand the composition of the gut microbiome in patients with MPN, triplicate fecal samples were collected from 25 MPN patients and 25 non-MPN controls. Although most of the variance between the microbial community compositions could be attributed to the individual (permutational analysis of variance [PERMANOVA], R2 = 0.92, P = 0.001), 1.7% of the variance could be attributed to disease status (MPN versus non-MPN). When a more detailed analysis was performed, significantly fewer reads mapping to a species of Phascolarctobacterium, a microbe previously associated with reduced inflammation, were found in MPNs. Further, our data revealed an association between Parabacteroides and tumor necrosis factor alpha (TNF-α), an inflammatory cytokine elevated in MPNs. Taken together, our results indicate a significant difference in the microbiome of MPN patients compared to non-MPN controls, and we identify specific species which may have a role in the chronic inflammation central to this disease. IMPORTANCE MPNs are chronic blood cancers in which inflammation plays a key role in disease initiation, progression, and symptomatology. The gut microbiome modulates normal blood development and inflammation and may also impact the development and manifestation of blood cancers. Therefore, the microbiome may be an important modulator of inflammation in MPN and could potentially be leveraged therapeutically in this disease. However, the relationship between the gut microbiome and MPNs has not been defined. Therefore, we performed an evaluation of the MPN microbiome, comparing the microbiomes of MPN patients with healthy donors and between MPN patients with various states of disease

Characterizing the microbiome of patients with myeloproliferative neoplasms during a Mediterranean diet intervention

Myeloproliferative neoplasms (MPNs) are a class of rare hematological malignancies that result in the overproduction of myeloid lineage cells. These malignancies result in increased cytokine production and inflammation, which correlate with worsened symptom burden and prognosis. Other than bone marrow transplantation, there is no cure for myeloproliferative neoplasms. As such, treatments focus on reducing thrombotic risk, inflammation, and symptom burden. Because current pharmacological treatments carry significant side effects, there is a need to explore low-risk therapies that may modulate inflammation and alleviate symptom burden. One potential way to achieve this is adherence to a Mediterranean (MED) diet, which is rich in anti-inflammatory foods, reduces inflammatory biomarkers, and beneficially alters the gut microbiome. We performed a 15-week clinical trial of 28 individuals with MPN who were randomized to dietary counseling based on either a Mediterranean diet or standard U.S. Guidelines for Americans. Our primary objective was to determine whether MPN patients could adopt a Mediterranean eating pattern when supported with dietician counseling. As exploratory endpoints, we investigated the impact of diet and inflammation on the gut microbiome. Using shotgun metagenomic sequencing, we found that microbiome diversity and composition were stable throughout the study duration in both cohorts. Furthermore, we discovered significant differences in the microbiomes between MPN subtypes, such as increased beta-dispersion in subjects with myelofibrosis. Lastly, we found several significant correlations between the abundance of multiple bacterial taxa and cytokine levels. Together, this study provides insight into the interaction between diet, inflammation, and the gut microbiome. IMPORTANCE The gut microbiome serves as an interface between the host and the diet. Diet and the gut microbiome both play important roles in managing inflammation, which is a key aspect of myeloproliferative neoplasm (MPN). Studies have shown that a Mediterranean (MED) diet can reduce inflammation. Therefore, we longitudinally characterized the gut microbiomes of MPN patients in response to Mediterranean or standard 2020 US Guidelines for Americans dietary counseling to determine whether there were microbiome-associated changes in inflammation. We did not find significant changes in the gut microbiome associated with diet, but we did find several associations with inflammation. This research paves the way for future studies by identifying potential mechanistic targets implicated in inflammation within the MPN gut microbiome

N-acetylcysteine inhibits thrombosis in a murine model of myeloproliferative neoplasm

Thrombosis is a major cause of mortality in patients with myeloproliferative neoplasms (MPNs), though there is currently little to offer patients with MPN beyond aspirin and cytoreductive therapies such as hydroxyurea for primary prevention. Thrombogenesis in MPN involves multiple cellular mechanisms, including platelet activation and neutrophil-extracellular trap formation; therefore, an antithrombotic agent that targets one or more of these processes would be of therapeutic benefit in MPN. Here, we treated the JAK2V617F knockin mouse model of polycythemia vera with N-acetylcysteine (NAC), a sulfhydryl-containing compound with broad effects on glutathione replenishment, free radical scavenging, and reducing disulfide bonds, to investigate its antithrombotic effects in the context of MPN. Strikingly, NAC treatment extended the lifespan of JAK2V617F mice without impacting blood counts or splenomegaly. Using an acute pulmonary thrombosis model in vivo, we found that NAC reduced thrombus formation to a similar extent as the irreversible platelet inhibitor aspirin. In vitro analysis of platelet activation revealed that NAC reduced thrombin-induced platelet-leukocyte aggregate formation in JAK2V617F mice. Furthermore, NAC reduced neutrophil extracellular trap formation in primary human neutrophils from patients with MPN as well as healthy controls. These results provide evidence that N-acetylcysteine inhibits thrombosis in JAK2V617F mice and provide a pre-clinical rationale for investigating NAC as a therapeutic to reduce thrombotic risk in MPN

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence

PurposeChronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN.Experimental designWe randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome.ResultsThe Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention.ConclusionsWith dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions.SignificanceDiet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes

FIGURE 2 from The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence

Patients with MPN can adopt a Mediterranean eating pattern with dietician counseling and education. A, Percentage of participants with MEDAS scores ≥8 at each timepoint with orange shaded area depicting the active intervention period. B, Participant responses to feasibility question during active intervention period, green represents a participant who met the feasibility benchmark of HEI-2015 (C) was calculated from each 24-hour diet recall, and scores for each participant were averaged for the pre-intervention (weeks 1–2), active intervention (weeks 3–12), and post-intervention (weeks 13–15) period. Data shown represent median with interquartile range.</p

Mediterranean Diet education materials from The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence

Educational materials given to MED diet group</p

FIGURE 4 from The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence

Baseline and week 9 BMI. Baseline BMI was calculated using height and weight at enrollment, with no significant differences between USDA and MED groups. Weight was followed throughout the study, no significant changes in BMI were observed in either group.</p