Macrophages and lipid metabolism

Distinct macrophage populations throughout the body display highly heterogeneous transcriptional and epigenetic programs. Recent research has highlighted that these profiles enable the different macrophage populations to perform distinct functions as required in their tissue of residence, in addition to the prototypical macrophage functions such as in innate immunity. These 'extra' tissue-specific functions have been termed accessory functions. One such putative accessory function is lipid metabolism, with macrophages in the lung and liver in particular being associated with this function. As it is now appreciated that cell metabolism not only provides energy but also greatly influences the phenotype and function of the cell, here we review how lipid metabolism affects macrophage phenotype and function and the specific roles played by macrophages in the pathogenesis of lipid-related diseases. In addition, we highlight the current questions limiting our understanding of the role of macrophages in lipid metabolism

Macrophage subsets in obesity, aligning the liver and adipose tissue

The increasing prevalence of obesity is accompanied by a rising incidence in metabolic syndrome and related pathologies such as non-alcoholic fatty liver disease. Macrophages are hypothesized to play central roles in these diseases, through their role as inflammatory mediators and as such are thought to be potential targets for future therapies. Recently, single cell technologies have revealed significant heterogeneity within the macrophage pool in both liver and adipose tissue in obesity. Thus current efforts are focused on dissecting this heterogeneity and understanding the distinct functions of the individual subsets. In this review, we discuss the current knowledge regarding macrophage heterogeneity, ontogeny and functions in the context of obese adipose tissue and fatty liver disease and attempt to align the distinct populations described to date

Relationship between antipsychotic blood levels and treatment failure during the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study

Objective: Antipsychotic blood levels (ABLs) may help identify patients at risk for treatment failure. Reference ranges (RR) for plasma concentrations of ABLs that account for between-patient variability were developed for risperidone and olanzapine based on population pharmacokinetic models. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) collected clinical outcomes and ABLs, allowing testing of the relationship of ABLs with outcomes. Methods: ABLs from 694 patients who were randomized to olanzapine or risperidonewere compared to the 80% RRs and were assessed as below or within/above the RR. Treatment failure was defined per any of these criteria: (1) emergency roomvisit for psychiatric reasons, (2) hospitalization for psychiatric reasons, (3) adverse event of completed suicide, suicidal ideation, or suicide attempt, (4) assaultive behavior, (5) arrested or jailed, (6) 2-point increase from baseline in Clinical Global Impression-Severity score, (7) 25% increase in Positive and Negative Syndrome Scale total score. Patients assessedwith treatment failure within 100 days of drug concentration measurement were analyzed. Results: Treatment failure occurred in 126 of 323 patients. The proportion of patients with ABLs below RR was 18.3% (59/323) compared to 10% expected in a fully adherent population. Among the 59 with ABLs below RR, 50.8% had treatment failure (compared to 36.4% for the 264 with ABLswithin/above RR). The difference between groups was significant (odds ratio=1.810; 95% CI = 1.025, 3.197; p= 0.0408). Conclusions: Analysis of CATIE data showed that ABLswithin the context of RRs may identify patientswith higher risk of relapse

Improving internal communication via channel optimization

This report provides an analysis and evaluation of the information flow within Verstraete IML. Open communication is one of Verstraete IML’s core values. The managerial team attaches great importance to this value as it allows a flow of energy and creativity throughout the company. Today, not all messages catch the attention of those interested. Investing in the optimization of the communication strategy will benefit Verstraete IML, as research has shown that effective employee communication is a leading indicator of financial performance and a driver of employee engagement. Research methods include internal focus groups with operators, white-collar workers, team coaches, process owners and management. The focus groups’ aim was to uncover the pain points regarding internal communication experienced by the different parties. Additionally, an external benchmark was performed to check on the communication tools used by other production companies. Multiple researchers have defined internal communications in a different way. To enable the use of one definition in the data collection, a simplified version of literature has been adopted: “internal communication can be seen as the sharing of information horizontally and vertically within the organization”. Unfortunately, literature does not yet provide a specific framework on how to organize internal communication. In general, a lot of opportunities exist to supplement prior research in this field of study. Analyzing the data gathered in the focus groups, resulted in three key findings. Firstly, there is a commonly shared negative perspective on the fact that there is no clear overview on which channel to consult, when in need of discovering information on a certain topic. Secondly, the lack of consistency in the usage of communication channels was pointed out. A third key finding concerns the suggestions for improvement made by the interviewees. The creation of a clearly structured portfolio of appropriate channels and guidelines on how to use them, is the first improvement opportunity. The second opportunity for improvement is related to changing the attitude of the employees consulting the tools. As for the external benchmark, the overall conclusion is that, compared to the companies interviewed (Ontex, Renson, TVH and Aleris), Verstraete IML is a pioneer in internal communication. At some points, Verstraete IML could fine tune its communication strategy learning from Aleris. The most important recommendation to optimize the communication practices at Verstraete IML, includes the appointment of an internal communication manager keeping a helicopter view over the various communication channels. This individual will stimulate communication throughout the company and become the point of contact for employees. The appointment of this internal communication manager will also be vital for the successful completion of the second recommendation, namely the centralization of information within the organization. To enable this centralization, three new channels can be installed. Firstly, a customized SharePoint communication site will offer easy access to news topics and events. Secondly, installing an internal social medium, Yammer, will create higher connectivity throughout the company. It allows to share opinions and ideas on a central location. Lastly, implementing communication boards in production will prevent the sense of information overload. A third recommendation concerns the retention of printed communication to address the production departments. Inevitably, this research carries some limitations as well. Collecting data through the use of focus groups is, according to literature, the best way to assess the employees’ needs and expectations. Downsides to this research method are that on the one hand shy employees might be hesitant in sharing their true opinion, on the other hand ‘group thinking’ could occur. In this research project, this effect is countered by a small survey at the end of each focus group, and by the usage of multiple moderators paying attention to non-verbal communication. As analyzing a focus groups is fairly labor intensive, the number of focus groups is limited. In addition, by solely selecting enthusiastic employees willingly to engage in the project, a bias could occur. Another limitation is linked to the scope of the project. As the scope of this research project is limited, suggestions related to for example personal feedback could not be addressed. Overall, this report offers a new communication strategy and plan for a growing company. All channels have been reviewed and optimized to enable better information sharing throughout the company. Following this plan will allow Verstraete IML to take communication to a next level

A one-year prospective study of the safety, tolerability and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia

<p>Abstract</p> <p>Background</p> <p>There are no previous reports of paliperidone palmitate's (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period.</p> <p>Methods</p> <p>In this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scale's total score ≤ 70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B.</p> <p>Results</p> <p>Of the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent (≥ 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients' psychoses remained stable.</p> <p>Conclusions</p> <p>Safety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range.</p> <p>Trial registration no</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01150448">NCT01150448</a></p

Pharmacokinetics, Safety, and Antiviral Effects of Multiple Doses of the Respiratory Syncytial Virus (RSV) Fusion Protein Inhibitor, JNJ-53718678, in Infants Hospitalized With RSV Infection: A Randomized Phase 1b Study

BACKGROUND: This phase 1b study evaluated the pharmacokinetics, safety, and antiviral effects of the respiratory syncytial virus (RSV)-specific fusion inhibitor JNJ-53718678 (JNJ-8678) in hospitalized RSV-infected patients aged > 1 to /=6 to /=3 to 1 to < 3 months) were randomized to oral JNJ-8678 or placebo once daily for 7 days. Dose increases followed data review committee recommendations (cohort 1: 2/6/8/9 mg/kg; cohort 2: 1.5/4.5/6 mg/kg; cohort 3: 1/3/5 mg/kg). Cohort 1 included a 9 mg/kg dose, as target exposures were not reached at lower doses. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modeling. Safety was assessed by adverse events (AEs), laboratory tests, and electrocardiograms. To assess antiviral effects, RSV RNA viral load from nasal swabs was quantified over time using reverse-transcription quantitative polymerase chain reaction. RESULTS: Patients received JNJ-8678 (n = 37) or placebo (n = 7). Pharmacokinetic parameters were similar at the highest doses for cohorts 1-3 (area under the plasma concentration-time curve from time of administration up to 24 hours postdosing at day 7: 35 840, 34 980, and 39 627 ng x hour/mL, respectively). Two grade 3 AEs were reported (both bronchiolitis; 1 JNJ-8678, 1 placebo), reported as serious AEs; all other AEs were grade 1 or 2. Two additional serious AEs were reported (rhinitis [JNJ-8678]; pneumonia [placebo]). No deaths, grade 4 AEs, or AEs leading to discontinuation were reported. Median RSV viral load change from baseline in JNJ-8678 vs placebo by day 3 was -1.98 vs -0.32 log10 copies/mL. CONCLUSIONS: In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed. CLINICAL TRIALS REGISTRATION: NCT02593851

Hepatic macrophage responses in inflammation, a function of plasticity, heterogeneity or both?

peer-reviewedWith the increasing availability and accessibility of single cell technologies, much attention has been given to delineating the specific populations of cells present in any given tissue. In recent years, hepatic macrophage heterogeneity has also begun to be examined using these strategies. While previously any macrophage in the liver was considered to be a Kupffer cell (KC), several studies have recently revealed the presence of distinct subsets ofhepatic macrophages, including those distinct from KCs both under homeostatic and non-homeostatic conditions. This heterogeneity has brought the concept of macrophage plasticity into question. Are KCs really as plastic as once thought, being capable of responding efficiently and specifically to any given stimuli? Or are the differential responses observed from hepatic macrophages in distinct settings due to the presence of multiple subsets of these cells? With these questions in mind, here we examine what is currently understood regarding hepatic macrophage heterogeneity in mouse and human and examine the role of heterogeneity vs plasticity in regards to hepatic macrophage responses in settings of both pathogen-induced and sterile inflammation

A20 deficiency in myeloid cells protects mice from diet-induced obesity and insulin resistance due to increased fatty acid metabolism

Obesity-induced inflammation is a major driving force in the development of insulin resistance, type 2 diabetes (T2D), and related metabolic disorders. During obesity, macrophages accumulate in the visceral adipose tissue, creating a low-grade inflammatory environment. Nuclear factor kappa B (NF-kappa B) signaling is a central coordinator of inflammatory responses and is tightly regulated by the anti-inflammatory protein A20. Here, we find that myeloid-specific A20-deficient mice are protected from diet-induced obesity and insulin resistance despite an inflammatory environment in their metabolic tissues. Macrophages lacking A20 show impaired mitochondrial respiratory function and metabolize more palmitate both in vitro and in vivo. We hypothesize that A20-deficient macrophages rely more on palmitate oxidation and metabolize the fat present in the diet, resulting in a lean phenotype and protection from metabolic disease. These findings reveal a role for A20 in regulating macrophage immunometabolism

Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver

Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs), are suggested to play important roles in the pathogenesis of MAFLD through their activation, although the exact roles played by these cells remain unclear. Here, we demonstrated that KCs were reduced in MAFLD being replaced by macrophages originating from the bone marrow. Recruited macrophages existed in two subsets with distinct activation states, either closely resembling homeostatic KCs or lipid-associated macrophages (LAMs) from obese adipose tissue. Hepatic LAMs expressed Osteopontin, a biomarker for patients with NASH, linked with the development of fibrosis. Fitting with this, LAMs were found in regions of the liver with reduced numbers of KCs, characterized by increased Desmin expression. Together, our data highlight considerable heterogeneity within the macrophage pool and suggest a need for more specific macrophage targeting strategies in MAFLD