Neural origins of human sickness in interoceptive responses to inflammation

BACKGROUND: Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning. RESULTS: Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions. CONCLUSIONS: These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states. PMID:19409533[PubMed - indexed for MEDLINE] PMCID: PMC2885492Free PMC Articl

BMI and All-Cause Mortality in a Population-Based Cohort in Rural South Africa

OBJECTIVE: This study evaluates the association between BMI and all-cause and cause-specific mortality in South Africa. METHODS: Prospective, population-based observational cohort data from rural South Africa were analyzed. BMI was measured in 2010. Demographic characteristics were recorded and deaths were verified with verbal autopsy interview. The InterVA-5 tool was used to assign causes of death. HIV testing was conducted annually. Cox proportional hazards models were fit to estimate the effect of BMI on all-cause and cause-specific mortality, accounting for the competing risk of death from other causes. Models were adjusted for sociodemographic characteristics and HIV status, and inverse probability weighting for survey nonparticipation was used. RESULTS: The cohort consisted of 9,728 individuals. In adjusted models, those with BMI of 25.0 to 29.9 kg/m2 or 30.0 to 34.9 kg/m2 had a lower hazard of death (adjusted hazard ratio: 0.80; 95% CI: 0.69-0.92 and adjusted hazard ratio: 0.75; 95% CI: 0.60-0.93, respectively) compared with those with BMI of 18.5 to 24.9 kg/m^{2}. CONCLUSIONS: Individuals in South Africa who meet clinically defined criteria for overweight or obesity had a lower risk of all-cause mortality than those with a normal BMI. These findings were stronger for women and communicable conditions

Frailty and physical performance in the context of extreme poverty: a population-based study of older adults in rural Burkina Faso [version 1; peer review: 2 approved]

Background: Little is known about the prevalence of frailty and about normal values for physical performance among older individuals in low-income countries, in particular those in sub-Saharan Africa. We describe the prevalence of phenotypic frailty, and values and correlates of several physical performance measures in a cohort of middle-aged and older people living in rural Burkina Faso, one of the world’s poorest communities. Methods: We analysed data collected from participants aged over 40 in Nouna district, Burkina Faso. We measured handgrip strength, four metre walk speed, chair rise time, and derived the Fried frailty score based on grip strength, gait speed, body mass index, self-reported exhaustion, and physical activity. Frailty and physical performance indicators were then correlated with health and sociodemographic variables including comorbid disease, marital status, age, sex, wealth and activity impairment. Results: Our sample included 2973 individuals (1503 women), mean age 54 years. 1207 (43%) were categorised as non-frail, 1324 (44%) as prefrail, 212 (7%) as frail, and 167 (6%) were unable to complete all five frailty score components. Lower grip strength, longer chair stand time, lower walk speed and prevalence of frailty rose with age. Frailty was more common in women than men (8% vs 6%, p=0.01) except in those aged 80 and over. Frailty was strongly associated with impairment of activities of daily living and with lower wealth, being widowed, diabetes mellitus, hypertension, and self-reported diagnoses of tuberculosis or heart disease. With the exception of grip strength, which was higher in women than prior international normative values, women had greater deficits than men in physical performance. Conclusions: Phenotypic frailty and impaired physical performance were associated as expected with female sex, co-morbidities, increasing age and impaired activities of daily living. These results support the use of frailty measurements for classification of ageing related syndromes in this setting

Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity

BACKGROUND: Inflammatory cytokines are implicated in the pathophysiology of depression. In rodents, systemically administered inflammatory cytokines induce depression-like behavior. Similarly in humans, therapeutic interferon-alpha induces clinical depression in a third of patients. Conversely, patients with depression also show elevated pro-inflammatory cytokines. OBJECTIVES: To determine the neural mechanisms underlying inflammation-associated mood change and modulatory effects on circuits involved in mood homeostasis and affective processing. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Mood questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed an implicit emotional face perception task during functional magnetic resonance imaging. Analyses focused on neurobiological correlates of inflammation-associated mood change and affective processing within regions responsive to emotional expressions and implicated in the etiology of depression. RESULTS: Typhoid but not placebo injection produced an inflammatory response indexed by increased circulating interleukin-6 and significant mood reduction at 3 hours. Inflammation-associated mood deterioration correlated with enhanced activity within subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotional face processing. Furthermore, inflammation-associated mood change reduced connectivity of sACC to amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6. CONCLUSIONS: Inflammation-associated mood deterioration is reflected in changes in sACC activity and functional connectivity during evoked responses to emotional stimuli. Peripheral cytokine

A dynamic network approach for the study of human phenotypes

The use of networks to integrate different genetic, proteomic, and metabolic datasets has been proposed as a viable path toward elucidating the origins of specific diseases. Here we introduce a new phenotypic database summarizing correlations obtained from the disease history of more than 30 million patients in a Phenotypic Disease Network (PDN). We present evidence that the structure of the PDN is relevant to the understanding of illness progression by showing that (1) patients develop diseases close in the network to those they already have; (2) the progression of disease along the links of the network is different for patients of different genders and ethnicities; (3) patients diagnosed with diseases which are more highly connected in the PDN tend to die sooner than those affected by less connected diseases; and (4) diseases that tend to be preceded by others in the PDN tend to be more connected than diseases that precede other illnesses, and are associated with higher degrees of mortality. Our findings show that disease progression can be represented and studied using network methods, offering the potential to enhance our understanding of the origin and evolution of human diseases. The dataset introduced here, released concurrently with this publication, represents the largest relational phenotypic resource publicly available to the research community.Comment: 28 pages (double space), 6 figure

Hypertension and diabetes control along the HIV care cascade in rural South Africa

INTRODUCTION: Participation in antiretroviral therapy (ART) programmes has been associated with greater utilization of care for hypertension and diabetes in rural South Africa. The objective of this study was to assess whether people living with HIV on ART with comorbid hypertension or diabetes also have improved chronic disease management indicators. METHODS: The Health and Aging in Africa: a longitudinal study of an INDEPTH Community in South Africa (HAALSI) is a cohort of 5059 adults >40 years old. Enrollment took place between November 2014 and November 2015. The study collected population-based data on demographics, healthcare utilization, height, weight, blood pressure (BP) and blood glucose as well as HIV infection, HIV-1 RNA viral load (VL) and ART exposure. We used regression models to determine whether HIV care cascade stage (HIV-negative, HIV+ /No ART, ART/Detected HIV VL, and ART/Undetectable VL) was associated with diagnosis or treatment of hypertension or diabetes, and systolic blood pressure and glucose among those with diagnosed hypertension or diabetes. ART use was measured from drug level testing on dried blood spots. RESULTS AND DISCUSSION: Compared to people without HIV, ART/Undetectable VL was associated with greater awareness of hypertension diagnosis (adjusted risk ratio (aRR) 1.18, 95% CI: 1.09 to 1.28) and treatment of hypertension (aRR 1.24, 95% CI: 1.10 to 1.41) among those who met hypertension diagnostic criteria. HIV care cascade stage was not significantly associated with awareness of diagnosis or treatment of diabetes. Among those with diagnosed hypertension or diabetes, ART/Undetectable VL was associated with lower mean systolic blood pressure (5.98 mm Hg, 95% CI: 9.65 to 2.32) and lower mean glucose (3.77 mmol/L, 95% CI: 6.85 to 0.69), compared to being HIV-negative. CONCLUSIONS: Participants on ART with an undetectable VL had lower systolic blood pressure and blood glucose than the HIV-negative participants. HIV treatment programmes may provide a platform for health systems strengthening for cardiometabolic disease

The ART Advantage: Health Care Utilization for Diabetes and Hypertension in Rural South Africa

The prevalence of diabetes and hypertension has increased in HIV-positive populations, but there is limited understanding of the role that antiretroviral therapy (ART) programs play in the delivery of services for these conditions. The aim of this study is to assess the relationship between ART use and utilization of health care services for diabetes and hypertension.Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa is a cohort of 5059 adults. The baseline study collects biomarker-based data on HIV, ART, diabetes, and hypertension and self-reported data on health care utilization. We calculated differences in care utilization for diabetes and hypertension by HIV and ART status and used multivariable logistic regressions to estimate the relationship between ART use and utilization of services for these conditions, controlling for age, sex, body mass index, education, and household wealth quintile.Mean age, body mass index, hypertension, and diabetes prevalence were lower in the HIV-positive population (all P < 0.001). Multivariable logistic regression showed that ART use was significantly associated with greater odds of blood pressure measurement [adjusted odds ratio (aOR) 1.27, 95% confidence interval (CI): 1.04 to 1.55] and blood sugar measurement (aOR 1.26, 95% CI: 1.05 to 1.51), counseling regarding exercise (aOR 1.57, 95% CI: 1.11 to 2.22), awareness of hypertension diagnosis (aOR 1.52, 95% CI: 1.12 to 2.05), and treatment for hypertension (aOR 1.63, 95% CI: 1.21 to 2.19).HIV-positive patients who use ART are more likely to have received health care services for diabetes and hypertension. This apparent ART advantage suggests that ART programs may be a vehicle for strengthening health systems for chronic care

Triatomine Infestation in Guatemala: Spatial Assessment after Two Rounds of Vector Control

In 2000, the Guatemalan Ministry of Health initiated a Chagas disease program to control Rhodnius prolixus and Triatoma dimidiata by periodic house spraying with pyrethroid insecticides to characterize infestation patterns and analyze the contribution of programmatic practices to these patterns. Spatial infestation patterns at three time points were identified using the Getis-Ord Gi*(d) test. Logistic regression was used to assess predictors of reinfestation after pyrethroid insecticide administration. Spatial analysis showed high and low clusters of infestation at three time points. After two rounds of spray, 178 communities persistently fell in high infestation clusters. A time lapse between rounds of vector control greater than 6 months was associated with 1.54 (95% confidence interval = 1.07-2.23) times increased odds of reinfestation after first spray, whereas a time lapse of greater than 1 year was associated with 2.66 (95% confidence interval = 1.85-3.83) times increased odds of reinfestation after first spray compared with localities where the time lapse was less than 180 days. The time lapse between rounds of vector control should remain under 1 year. Spatial analysis can guide targeted vector control efforts by enabling tracking of reinfestation hotspots and improved targeting of resources

Diabetes-related excess mortality in Mexico: a comparative analysis of National Death Registries between 2017-2019 and 2020

OBJECTIVE: To estimate diabetes-related mortality in Mexico in 2020 compared with 2017-2019 after the onset of the coronavirus disease 2019 (COVID-19) pandemic. RESEARCH DESIGN AND METHODS: This retrospective, state-level study used national death registries of Mexican adults aged ≥20 years for the 2017-2020 period. Diabetes-related death was defined using ICD-10 codes listing diabetes as the primary cause of death, excluding certificates with COVID-19 as the primary cause of death. Spatial and negative binomial regression models were used to characterize the geographic distribution and sociodemographic and epidemiologic correlates of diabetes-related excess mortality, estimated as increases in diabetes-related mortality in 2020 compared with average 2017-2019 rates. RESULTS: We identified 148,437 diabetes-related deaths in 2020 (177 per 100,000 inhabitants) vs. an average of 101,496 deaths in 2017-2019 (125 per 100,000 inhabitants). In-hospital diabetes-related deaths decreased by 17.8% in 2020 versus 2017-2019, whereas out-of-hospital deaths increased by 89.4%. Most deaths were attributable to type 2 diabetes (130 per 100,000 inhabitants). Compared with 2018-2019 data, hyperglycemic hyperosmolar state and diabetic ketoacidosis were the two contributing causes with the highest increase in mortality (128% and 116% increase, respectively). Diabetes-related excess mortality clustered in southern Mexico and was highest in states with higher social lag, rates of COVID-19 hospitalization, and prevalence of HbA1c ≥7.5%. CONCLUSIONS: Diabetes-related deaths increased among Mexican adults by 41.6% in 2020 after the onset of the COVID-19 pandemic, occurred disproportionately outside the hospital, and were largely attributable to type 2 diabetes and hyperglycemic emergencies. Disruptions in diabetes care and strained hospital capacity may have contributed to diabetes-related excess mortality in Mexico during 2020

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers