Adiponectin,biomarkers of inflammation and changes in cardiac autonomic function: Whitehall II study

Background

Biomarkers of inflammation and adiponectin are associated with cardiovascular autonomic neuropathy (CAN) in cross-sectional studies, but prospective data are scarce. This study aimed to assess the associations of biomarkers of subclinical inflammation and adiponectin with subsequent changes in heart rate (HR) and heart rate variability (HRV) in non-diabetic and diabetic individuals.

Methods

Data are based on up to 25,050 person-examinations for 8469 study participants of the Whitehall II cohort study. Measures of CAN included HR and several HRV indices. Associations between baseline serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra) and adiponectin and 5-year changes in HR and six HRV indices were estimated using mixed-effects models adjusting for age, sex, ethnicity, body mass index (BMI), metabolic covariates and medication. A modifying effect of diabetes was tested.

Results

Higher levels of IL-1Ra were associated with higher increases in HR. Additional associations with measures of HRV were observed for hsCRP, IL-6 and IL-1Ra, but these associations were explained by BMI and other confounders. Associations between adiponectin, HR and HRV differed depending on diabetes status. Higher adiponectin levels were associated with more pronounced decreases in HR and increases in three measures of HRV reflecting both sympathetic and vagal activity, but these findings were limited to individuals with type 2 diabetes.

Conclusions

Higher IL-1Ra levels appeared as novel risk marker for increases in HR. Higher adiponectin levels were associated with a more favourable development of cardiovascular autonomic function in individuals with type 2 diabetes independently of multiple confounders.

     

Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome

Context

Patients with chronic fatigue syndrome and those with orthostatic intolerance share many symptoms, yet questions exist as to whether CFS patients have physiological evidence of orthostatic intolerance.

Objective

To determine if some CFS patients have increased rates of orthostatic hypotension, hypertension, tachycardia, or hypocapnia relative to age-matched controls.

Design

Assess blood pressure, heart rate, respiratory rate, end tidal CO2 and visual analog scales for orthostatic symptoms when supine and when standing for 8 minutes without moving legs.

Setting

Referral practice and research center.

Participants

60 women and 15 men with CFS and 36 women and 4 men serving as age matched controls with analyses confined to 62 patients and 35 controls showing either normal orthostatic testing or a physiological abnormal test.

Main outcome measures

Orthostatic tachycardia; orthostatic hypotension; orthostatic hypertension; orthostatic hypocapnia or combinations thereof.

Results

CFS patients had higher rates of abnormal tests than controls (53% vs 20%, p < .002), but rates of orthostatic tachycardia, orthostatic hypotension, and orthostatic hypertension did not differ significantly between patients and controls (11.3% vs 5.7%, 6.5% vs 2.9%, 19.4% vs 11.4%, respectively). In contrast, rates of orthostatic hypocapnia were significantly higher in CFS than in controls (20.6% vs 2.9%, p < .02). This CFS group reported significantly more feelings of illness and shortness of breath than either controls or CFS patients with normal physiological tests.

Conclusion

A substantial number of CFS patients have orthostatic intolerance in the form of orthostatic hypocapnia. This allows subgrouping of patients with CFS and thus reduces patient pool heterogeneity engendered by use of a clinical case definition.

     

The association of fecal microbiota and fecal,blood serum and urine metabolites in myalgic encephalomyelitis/chronic fatigue syndrome

Introduction

The human gut microbiota has the ability to modulate host metabolism. Metabolic profiling of the microbiota and the host biofluids may determine associations significant of a host–microbe relationship. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term disorder of fatigue that is poorly understood, but has been linked to gut problems and altered microbiota.

Objectives

Find changes in fecal microbiota and metabolites in ME/CFS and determine their association with blood serum and urine metabolites.

Methods

A workflow was developed that correlates microbial counts with fecal, blood serum and urine metabolites quantitated by high-throughput ¹H NMR spectroscopy. The study consists of thirty-four females with ME/CFS (34.9?±?1.8 SE years old) and twenty-five non-ME/CFS female (33.0?±?1.6 SE years old).

Results

The workflow was validated using the non-ME/CFS cohort where fecal short chain fatty acids (SCFA) were associated with serum and urine metabolites indicative of host metabolism changes enacted by SCFA. In the ME/CFS cohort a decrease in fecal lactate and an increase in fecal butyrate, isovalerate and valerate were observed along with an increase in Clostridium spp. and a decrease in Bacteroides spp. These differences were consistent with an increase in microbial fermentation of fiber and amino acids to produce SCFA in the gut of ME/CFS patients. Decreased fecal amino acids positively correlated with substrates of gluconeogenesis and purine synthesis in the serum of ME/CFS patients.

Conclusion

Increased production of SCFA by microbial fermentation in the gut of ME/CFS patients may be associated with deleterious effects on the host energy metabolism.

     

Awareness of comfort immediately after a relaxation therapy session affects future quality of life and autonomic function: a prospective cohort study on the expectations of therapy

Background

High expectations regarding therapy are reported to have positive effects on future therapeutic course and related behavior. Some individuals are aware of feelings of comfort immediately after a relaxation therapy session.

Methods

Heart rate variability biofeedback (HRV-BF) therapy using a relaxation technique called resonant breathing was administered to 44 family caregivers who felt burdened by their work caring for family members with cancer. We prospectively evaluated how the level of comfort participants were aware of immediately after an initial therapy session affected their expectations regarding the therapy, as well as future quality of life (QOL) and autonomic function. This study was a secondary analysis of a randomized, open-label study titled “Self-care system for family caregivers of cancer patients using resonant breathing with a portable home device”.

Results

Among the participants, 56.8% were aware of a feeling of comfort immediately after an initial therapy session. Participants were then divided into two groups according to the presence or absence of their awareness of comfort. Expectation levels regarding the therapy were significantly increased in the awareness group after the therapy session (P?=?0.003). No main effect between groups was observed for heart rate variability (HRV) during therapy (P?=?0.949). Four weeks after the initial therapy session, QOL improved and HRV increased in the awareness group (P?<?0.001).

Conclusions

Better outcomes in the awareness group were not associated with HRV during therapy. A feeling of comfort immediately after a therapy session may have positive effects on future QOL and autonomic function by raising participants’ expectations of the therapy.

Trial registration

UMIN000021639. Registered 27 March 2016

     

Heart rate variability after radiofrequency ablation of epicardial ganglionated plexuses on the ovine left atrium

Background

Ganglionated plexuses (GP) are terminal parts of cardiac autonomous nervous system (ANS). Radiofrequency ablation (RFA) for atrial fibrillation (AF) possibly affects GP. Changes in heart rate variability (HRV) after RFA can reflect ANS modulation.

Methods

Epicardial RFA of GP on the left atrium (LA) was performed under the general anesthesia in 15 mature Romanov sheep. HRV was used to assess the alterations in autonomic regulation of the heart. A 24???hour ECG monitoring was performed before the ablation, 2 days after it and at each of the 12 following months. Ablation sites were evaluated histologically.

Results

There was an instant change in HRV parameters after the ablation. A standard deviation of all intervals between normal QRS (SDNN), a square root of the mean of the squared differences between successive normal QRS intervals (RMSSD) along with HRV triangular index (TI), low frequency (LF) power and high frequency (HF) power decreased, while LF/HF ratio increased. Both the SDNN, LF power and the HF power changes persisted throughout the 12???month follow???up. Significant decrease in RMSSD persisted only for 3 months, HRV TI for 6 months and increase in LF/HF ratio for 7 months of the follow???up. Afterwards these three parameters were not different from the preprocedural values.

Conclusions

Epicardial RFA of GP’s on the ovine left atrium has lasting effect on the main HRV parameters (SDNN, HF power and LF power). The normalization of RMSSD, HRV TI and LF/HF suggests that HRV after epicardial RFA of GPs on the left atrium might restore over time.

     

Functioning in individuals with chronic fatigue syndrome: increased impairment with co-occurring multiple chemical sensitivity and fibromyalgia

Background

Chronic fatigue syndrome (CFS), multiple chemical sensitivity (MCS), and fibromyalgia (FM) commonly co-occur. Some propose that CFS, MCS, and FM are manifestations of the same illness based on high rates of co-occurrence and overlapping diagnostic criteria. This study seeks to differentiate these diagnoses by comparing individuals with one or more illness on functioning, psychiatric comorbidity, coping style, and in vivo physical measures.

Methods

Participants included 114 men and women who met criteria for CFS. FM was diagnosed during a physical examination, and MCS was assessed using a questionnaire. Participants were divided into four groups: CFS alone, CFS-MCS, CFS-FM, and CFS-MCS-FM. Self-report measures, a psychiatric interview, and in vivo physical measures were given.

Results

43.9% met criteria for CFS alone, 23.7% met criteria for CFS-MCS, 15.8% met criteria for CFS-FM, and 16.7% met criteria for CFS-MCS-FM. The CFS-MCS-FM group was more disabled than the CFS alone group on measures of physical functioning, general health, and bodily pain. In vivo measures did not differ, but the CFS-MCS-FM group rated exertion higher than the CFS alone group.

Conclusion

Individuals with CFS alone were the highest functioning group across several domains, such as disability, depression, and severity of symptoms. Participants with three diagnoses experienced the greatest amount of disability. While substantial co-occurrence of these illnesses was found, this study provides evidence that having more than one illness exacerbates one's disability beyond CFS alone.

     

Metabolites predict cardiovascular disease events in persons living with HIV: a pilot case–control study

Introduction

Persons living with HIV (PLWH) are at higher risk for cardiovascular disease (CVD) events than uninfected persons. Current risk-stratification methods to define PLWH at highest risk for CVD events are lacking.

Methods

Using tandem flow injection mass spectrometry, we quantified plasma levels of 60 metabolites in 24 matched pairs of PLWH [1:1 with and without known coronary artery disease (CAD)]. Metabolite levels were reduced to interpretable factors using principal components analysis.

Results

Factors derived from short-chain dicarboxylacylcarnitines (SCDA) (p?=?0.08) and glutamine/valine (p?=?0.003) were elevated in CAD cases compared to controls.

Conclusion

SCDAs and glutamine/valine may be valuable markers of cardiovascular risk among persons living with HIV in the future, pending validation in larger cohorts.

     

The Economic impact of ME/CFS: Individual and societal costs

Background

ME/CFS is characterized by debilitating fatigue in addition to other physical and cognitive symptoms. It is estimated to affect over 800,000 adults in the U.S. ME/CFS often results in diminished functionality and increased economic impact. The economic impact of an illness is generally divided into two categories: direct and indirect costs. Despite high prevalence rates and the disabling nature of the illness, few studies have examined the costs of ME/CFS at the individual and societal level. In fact, of the four studies examining the economic impact of ME/ME/CFS only two used a U. S. sample. The current study used community and tertiary samples to examine the direct costs of ME/CFS.

Methods

Using archival data, Study 1 examined the direct cost of ME/CFS in a community-based sample in Chicago. Study 2 estimated the direct cost of ME/CFS in a tertiary sample in Chicago. Both Study1 and Study 2 assessed direct costs using office visit costs, medical test costs, and medication costs.

Results

For Study 1, the annual direct total cost per ME/CFS patient was estimated to be $2,342, with the total annual direct cost of ME/CFS to society being approximately $2 billion. In Study 2, the annual direct was estimated to be $8,675 per ME/CFS patient, with the total annual direct cost of ME/CFS to society being approximately $7 billion.

Conclusion

Using ME/CFS prevalence data of 0.42 and indirect costs estimates from Reynolds et al. (2004), the direct and indirect cost of ME/CFS to society was estimated to be $18,677,912,000 for the community sample and $23,972,300,000 for the tertiary sample. These findings indicate that whether or not individuals are recruited from a community or tertiary sample, ME/CFS imposes substantial economic costs.

     

Using urine metabolomics to understand the pathogenesis of infant respiratory syncytial virus (RSV) infection and its role in childhood wheezing

Background

Respiratory syncytial virus (RSV) infection in infants causes significant morbidity and is the strongest risk factor associated with asthma. Metabolites, which reflect the interactions between host cell and virus, provide an opportunity to identify the pathways that underlie severe infections and asthma development.

Objective

To study metabolic profile differences between infants with RSV infection, and human rhinovirus (HRV) infection, and healthy infants. To compare infant metabolic differences between children who do and do not wheeze.

Methods

In a term birth cohort, urine was collected while healthy and during acute viral respiratory infection with RSV and HRV. We used ¹H-NMR to identify urinary metabolites. Multivariate and univariate statistics were used to discriminate metabolic profiles of infants with either RSV ARI, or HRV ARI, and healthy infants. Multivariable logistic regression was used to assess the association of urine metabolites with 1st-, 2nd-, and 3rd-year recurrent wheezing.

Results

Several metabolites in nicotinate and nicotinamide metabolism pathways were down-regulated in infants with RSV infection compared to healthy controls. There were no significant differences in metabolite profiles between infants with RSV infection and infants with HRV Infection. Alanine was strongly associated with reduced risk of 1st-year wheezing (OR 0.18[0.0, 0.46]) and 2nd-year wheezing (OR 0.31[0.13, 0.73]), while 2-hydroxyisobutyric acid was associated with increased 3rd-year wheezing (OR 5.02[1.49, 16.93]) only among the RSV infected subset.

Conclusion

The metabolites associated with infant RSV infection and recurrent-wheezing are indicative of viral takeover of the cellular machinery and resources to enhance virulence, replication, and subversion of the host immune-response, highlighting metabolic pathways important in the pathogenesis of RSV infection and wheeze development.

     

Determinants of fatigue and stress

Background

Fatigue can be triggered by previous perceived stress which may lead to impairment of performance and function. The purpose of the study was to investigate the relationship between fatigue and perceived stress.

Method

Health determinants including sociodemographic factors for associations between fatigue and perceived stress in the general population (N = 2,483) are outlined. Fatigue and stress were assessed with the Chalder Fatigue Scale (CFS) and the Perceived Stress Questionnaire (PSQ).

Results

Within the general population, 25.9% of male and 34.5% of female respondents reported moderate fatigue during the last six months; 9.7% of subjects reported substantial fatigue lasting six months or longer. An adjusted regression analysis (R²corr = .28, p < .001) showed that fatigue is highest associated with perceived stress and self-perceived health status. The following factors were correlated with increased rates of fatigue and perceived stress: female gender, divorce/separation, low social class and poor health status.

Conclusion

We conclude that the two conditions overlap most in terms of socio-economic status and self-perceived health status.

     

A lost opportunity for science: journals promote data sharing in metabolomics but do not enforce it

Introduction

Data sharing is being increasingly required by journals and has been heralded as a solution to the ‘replication crisis’.

Objectives

(i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals’ policies to those that publish the most metabolomics papers.

Methods

A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications.

Results

Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data.

Conclusion

Further efforts are required to improve data sharing in metabolomics.

     

Optimization of fecal sample preparation for untargeted LC-HRMS based metabolomics

Introduction

Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.

Objectives

In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.

Methods

The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.

Results

A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.

Conclusion

The workflow generated repeatable and informative fingerprints for robust metabolome characterization.

     

A robust,single-injection method for targeted,broad-spectrum plasma metabolomics

Background

Metabolomics is a powerful emerging technology for studying the systems biology and chemistry of health and disease. Current targeted methods are often limited by the number of analytes that can be measured, and/or require multiple injections.

Methods

We developed a single-injection, targeted broad-spectrum plasma metabolomic method on a SCIEX Qtrap 5500 LC-ESI-MS/MS platform. Analytical validation was conducted for the reproducibility, linearity, carryover and blood collection tube effects. The method was also clinically validated for its potential utility in the diagnosis of chronic fatigue syndrome (CFS) using a cohort of 22 males CFS and 18 age- and sex-matched controls.

Results

Optimization of LC conditions and MS/MS parameters enabled the measurement of 610 key metabolites from 63 biochemical pathways and 95 stable isotope standards in a 45-minute HILIC method using a single injection without sacrificing sensitivity. The total imprecision (CV_total) of peak area was 12% for both the control and CFS pools. The 8 metabolites selected in our previous study (PMID: 27573827) performed well in a clinical validation analysis even when the case and control samples were analyzed 1.5 years later on a different instrument by a different investigator, yielding a diagnostic accuracy of 95% (95% CI 85–100%) measured by the area under the ROC curve.

Conclusions

A reliable and reproducible, broad-spectrum, targeted metabolomic method was developed, capable of measuring over 600 metabolites in plasma in a single injection. The method might be a useful tool in helping the diagnosis of CFS or other complex diseases.

     

Untargeted metabolomics suffers from incomplete raw data processing

Introduction

Untargeted metabolomics is a powerful tool for biological discoveries. To analyze the complex raw data, significant advances in computational approaches have been made, yet it is not clear how exhaustive and reliable the data analysis results are.

Objectives

Assessment of the quality of raw data processing in untargeted metabolomics.

Methods

Five published untargeted metabolomics studies, were reanalyzed.

Results

Omissions of at least 50 relevant compounds from the original results as well as examples of representative mistakes were reported for each study.

Conclusion

Incomplete raw data processing shows unexplored potential of current and legacy data.

     

Extraction of natural products from bark of <Emphasis Type="Italic">Betula pendula</Emphasis> using ionic liquids

Introduction

Aqueous–methanol mixtures have successfully been applied to extract a broad range of metabolites from plant tissue. However, a certain amount of material remains insoluble.

Objectives

To enlarge the metabolic compendium, two ionic liquids were selected to extract the methanol insoluble part of trunk from Betula pendula.

Methods

The extracted compounds were analyzed by LC/MS and GC/MS.

Results

The results show that 1-butyl-3-methylimidazolium acetate (IL-Ac) predominantly resulted in fatty acids, whereas 1-ethyl-3-methylimidazolium tosylate (IL-Tos) mostly yielded phenolic structures. Interestingly, bark yielded more ionic liquid soluble metabolites compared to interior wood.

Conclusion

From this one can conclude that the application of ionic liquids may expand the metabolic snapshot.

     

A methodology for elucidating regulatory mechanisms leading to changes in lipid profiles

Introduction

It is difficult to elucidate the metabolic and regulatory factors causing lipidome perturbations.

Objectives

This work simplifies this process.

Methods

A method has been developed to query an online holistic lipid metabolic network (of 7923 metabolites) to extract the pathways that connect the input list of lipids.

Results

The output enables pathway visualisation and the querying of other databases to identify potential regulators. When used to a study a plasma lipidome dataset of polycystic ovary syndrome, 14 enzymes were identified, of which 3 are linked to ELAVL1—an mRNA stabiliser.

Conclusion

This method provides a simplified approach to identifying potential regulators causing lipid-profile perturbations.

     

KniMet: a pipeline for the processing of chromatography–mass spectrometry metabolomics data

Introduction

Data processing is one of the biggest problems in metabolomics, given the high number of samples analyzed and the need of multiple software packages for each step of the processing workflow.

Objectives

Merge in the same platform the steps required for metabolomics data processing.

Methods

KniMet is a workflow for the processing of mass spectrometry-metabolomics data based on the KNIME Analytics platform.

Results

The approach includes key steps to follow in metabolomics data processing: feature filtering, missing value imputation, normalization, batch correction and annotation.

Conclusion

KniMet provides the user with a local, modular and customizable workflow for the processing of both GC–MS and LC–MS open profiling data.

     

Paroxysmal atrial fibrillation recognition based on multi-scale wavelet <Emphasis Type="Italic">α</Emphasis>-entropy

Background

This study proposed an effective method based on the wavelet multi-scale α-entropy features of heart rate variability (HRV) for the recognition of paroxysmal atrial fibrillation (PAF). This new algorithm combines wavelet decomposition and non-linear analysis methods. The PAF signal, the signal distant from PAF, and the normal sinus signals can be identified and distinguished by extracting the characteristic parameters from HRV signals and analyzing their quantification indexes. The original ECG signals for QRS detection and HRV signal extraction are first processed. The features from the HRV signals are extracted as feature vectors using the wavelet multi-scale entropy. A support vector machine-based classifier is used for PAF prediction.

Results

The performance of the proposed method in predicting PAF episodes is evaluated with 100 signals from the MIT-BIT PAF prediction database. With regard to the dynamics and uncertainty of PAF signals, our proposed method obtains the values of 92.18, 94.88, and 89.48% for the evaluation criteria of correct rate, sensitivity, and specificity, respectively.

Conclusions

Our proposed method presents better results than the existing studies based on time domain, frequency domain, and non-linear methods. Thus, our method shows considerable potential for clinical monitoring and treatment.

     

Pseudo current density maps of electrophysiological heart,nerve or brain function and their physical basis

Background

In recent years the visualization of biomagnetic measurement data by so-called pseudo current density maps or Hosaka-Cohen (HC) transformations became popular.

Methods

The physical basis of these intuitive maps is clarified by means of analytically solvable problems.

Results

Examples in magnetocardiography, magnetoencephalography and magnetoneurography demonstrate the usefulness of this method.

Conclusion

Hardware realizations of the HC-transformation and some similar transformations are discussed which could advantageously support cross-platform comparability of biomagnetic measurements.

     

Application of residual polysaccharide-degrading enzymes in dried shiitake mushrooms as an enzyme preparation in food processing

Objective

To examine the activities of residual enzymes in dried shiitake mushrooms, which are a traditional foodstuff in Japanese cuisine, for possible applications in food processing.

Results

Polysaccharide-degrading enzymes remained intact in dried shiitake mushrooms and the activities of amylase, β-glucosidase and pectinase were high. A potato digestion was tested using dried shiitake powder. The enzymes reacted with potato tuber specimens to solubilize sugars even under a heterogeneous solid-state condition and that their reaction modes were different at 38 and 50 °C.

Conclusion

Dried shiitake mushrooms have a potential use in food processing as an enzyme preparation.