Mucus clearance provides an essential innate defense mechanism to keep the airways and lungs free of particles and pathogens. Baseline and stimulated mucin secretion from secretory airway epithelial ...cells need to be tightly regulated to prevent mucus hypersecretion and mucus plugging of the airways. It is well established that extracellular ATP is a potent stimulus for regulated mucus secretion. Previous studies revealed that ATP acts via metabotropic P2Y
purinoreceptors on goblet cells. Extracellular ATP, however, is also a potent agonist for ionotropic P2X purinoreceptors. Expression of several P2X isoforms has been reported in airways, but cell type-specific expression and the function thereof remained elusive. With this study, we now provide evidence that P2X
is the predominant P2X isoform expressed in secretory airway epithelial cells. After IL-13 treatment of either human primary tracheal epithelial cells or mice, P2X
expression is upregulated in vitro and in vivo under conditions of chronic inflammation, mucous metaplasia, and hyperplasia. Upregulation of P2X
is strongest in MUC5AC-positive goblet cells. Moreover, activation of P2X
by extracellular ATP augments intracellular Ca
signals and mucin secretion, whereas Ca
signals and mucin secretion are dampened by inhibition of P2X
receptors. These data provide new insights into the purinergic regulation of mucin secretion and add to the emerging picture that P2X receptors modulate exocytosis of large secretory organelles and secretion of macromolecular vesicle cargo.
Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network ...layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.
Social and environmental factors such as poverty or violence modulate the risk and course of schizophrenia. However, how they affect the brain in patients with psychosis remains unclear.
We studied ...how environmental factors are related to brain structure in patients with schizophrenia and controls in Latin America, where these factors are large and unequally distributed.
This is a multicentre study of magnetic resonance imaging in patients with schizophrenia and controls from six Latin American cities. Total and voxel-level grey matter volumes, and their relationship with neighbourhood characteristics such as average income and homicide rates, were analysed with a general linear model.
A total of 334 patients with schizophrenia and 262 controls were included. Income was differentially related to total grey matter volume in both groups (P = 0.006). Controls showed a positive correlation between total grey matter volume and income (R = 0.14, P = 0.02). Surprisingly, this relationship was not present in patients with schizophrenia (R = -0.076, P = 0.17). Voxel-level analysis confirmed that this interaction was widespread across the cortex. After adjusting for global brain changes, income was positively related to prefrontal cortex volumes only in controls. Conversely, the hippocampus in patients with schizophrenia, but not in controls, was relatively larger in affluent environments. There was no significant correlation between environmental violence and brain structure.
Our results highlight the interplay between environment, particularly poverty, and individual characteristics in psychosis. This is particularly important for harsh environments such as low- and middle-income countries, where potentially less brain vulnerability (less grey matter loss) is sufficient to become unwell in adverse (poor) environments.
Surra disease is a zoonosis caused by Trypanosoma (Trypanozoon) evansi, a salivary trypanosome, originally from Africa, which affects a wide range of mammalian worldwide. Dogs are highly susceptible ...to T. evansi infection and they often exhibit strong clinical signs than can lead to death, even within weeks in untreated acute cases. The present survey is the first report through clinical, parasitological and molecular approaches, of two fatal cases of T. evansi in Colombian dogs. After analysing two presumptive cases of infection with Trypanosoma spp., in dogs by parasitological methods, we confirmed by molecular techniques the presence of T. evansi, finding clinical signs such as anaemia, thrombocytopenia and hepatosplenomegaly, with fatal outcomes within a week even after the treatment. A phylogenetic and phylogeographic analysis of both isolates from T. evansi, suggest a complex evolutionary relationship with species of Trypanozoon subgenus. Moreover, the haplotype H2 was observed for the first time in Colombia, in common areas where human cases of T. evansi infection has been reported. These findings imply a relevant problem for animal health in the country, and highlight the importance of this infection in domestic animals and the possibility of human cases.
Background and Purpose
Respiratory viral infections play central roles in the initiation, exacerbation and progression of asthma in humans. An acute paramyxoviral infection in mice can cause a ...chronic lung disease that resembles human asthma. We sought to determine whether reduction of Sendai virus lung burden in mice by stimulating innate immunity with aerosolized Toll‐like receptor (TLR) agonists could attenuate the severity of chronic asthma‐like lung disease.
Experimental Approach
Mice were treated by aerosol with 1‐μM oligodeoxynucleotide (ODN) M362, an agonist of the TLR9 homodimer, and 4‐μM Pam2CSK4 (Pam2), an agonist of the TLR2/6 heterodimer, within a few days before or after Sendai virus challenge.
Key Results
Treatment with ODN/Pam2 caused ~75% reduction in lung Sendai virus burden 5 days after challenge. The reduction in acute lung virus burden was associated with marked reductions 49 days after viral challenge in eosinophilic and lymphocytic lung inflammation, airway mucous metaplasia, lumenal mucus occlusion and hyperresponsiveness to methacholine. Mechanistically, ODN/Pam2 treatment attenuated the chronic asthma phenotype by suppressing IL‐33 production by type 2 pneumocytes, both by reducing the severity of acute infection and by down‐regulating Type 2 (allergic) inflammation.
Conclusion and Implications
These data suggest that treatment of susceptible human hosts with aerosolized ODN and Pam2 at the time of a respiratory viral infection might attenuate the severity of the acute infection and reduce initiation, exacerbation and progression of asthma.
This paper assesses the potential cohesion effect of a physical activity (PA) school-based intervention potentiated using text messages (SMS) through analyzing longitudinally the friendship network ...structure and the mechanisms of the formation and dissolution of friendships. Three schools (n = 125 participants) in Bogotá, Colombia, were randomly assigned into three groups: Modulo Activo Recreo Activo (MARA) + SMS (networks 1 and 2), MARA (networks 3 and 4), and control (no intervention: networks 5–7). We collected socio-economic, health-related, network structure, and intervention satisfaction variables in the baseline and after 10 weeks on July–November 2013. For each classroom network, we conducted four models using a temporal and static network approach to assess (1) temporal social network changes, (2) friendship homophily, (3) friendship formation and dissolution mechanisms, and (4) effect of SMS on the networks’ cohesion. We found that (1) social cohesion emerged in the four intervened networks that were measured over time with transitivity and homophily driven by clustering, (2) the intervention affected the mechanisms of friendship formation and dissolution, and (3) MARA + SMS on average created more social cohesion and 3.8 more friendships than the program alone. Potentially, school-based interventions with information and communication technologies (ICT) such as MARA + SMS could encourage social cohesion among children. The particular characteristics of each school network need to be considered when developing school-based interventions.
The onset of deformation in the northern Andes is overprinted by subsequent stages of basin deformation, complicating the examination of competing models illustrating potential location of earliest ...synorogenic basins and uplifts. To establish the width of the earliest northern Andean orogen, we carried out field mapping, palynological dating, sedimentary, stratigraphic and provenance analyses in Campanian to lower Eocene units exposed in the northern Eastern Cordillera of Colombia (Cocuy region) and compare the results with coeval succession in adjacent basins. The onset of deformation is recorded in earliest Maastrichtian time, as terrigenous detritus arrived into the basin marking the end of chemical precipitation and the onset of clastic deposition produced by the uplift of a western source area dominated by shaly Cretaceous rocks. Disconformable contacts within the upper Maastrichtian to middle Palaeocene succession document increasing supply of quartzose sandy detritus from Cretaceous quartzose rocks exposed in eastern source areas. The continued unroofing of both source areas produced a rapid shift in depositional environments from shallow marine in Maastrichtian to fluvial‐lacustrine systems during the Palaeocene‐early Eocene. Supply of immature Jurassic sandstones from nearby western uplifts, together with localized plutonic and volcanic Cretaceous rocks, caused a shift in Palaeocene sandstones composition from quartzarenites to litharenites. Supply of detrital sandy fragments, unstable heavy minerals and Cretaceous to Ordovician detrital zircons, were derived from nearby uplifted blocks and from SW fluvial systems within the synorogenic basin, instead of distal basement rocks. The presence of volcanic rock fragments and 51–59 Ma volcanic zircons constrain magmatism within the basin. The Maastrichtian–Palaeocene sequence studied here documents crustal deformation that correlates with coeval deformation farther south in Ecuador and Peru. Slab flattening of the subducting Caribbean plate produced a wider orogen (>400 km) with a continental magmatic arc and intra‐basinal deformation and magmatism.
The Maastrichtian ‐ Paleocene sequence studied in the Cocuy area and adjacent basins documents crustal intra‐basinal deformation since Maastrichtian. Slab flattening of the subducting Caribbean plate produced a wider orogen (>400 km) with a continental magmatic arc and intra‐basinal deformation and magmatism.
Geographical variations in mood and psychotic disorders have been found in upper-income countries. We looked for geographic variation in these disorders in Colombia, a middle-income country. We ...analyzed electronic health records from the Clínica San Juan de Dios Manizales (CSJDM), which provides comprehensive mental healthcare for the one million inhabitants of Caldas.
We constructed a friction surface map of Caldas and used it to calculate the travel-time to the CSJDM for 16,295 patients who had received an initial diagnosis of mood or psychotic disorder. Using a zero-inflated negative binomial regression model, we determined the relationship between travel-time and incidence, stratified by disease severity. We employed spatial scan statistics to look for patient clusters.
We show that travel-times (for driving) to the CSJDM are less than 1 h for ~50% of the population and more than 4 h for ~10%. We find a distance-decay relationship for outpatients, but not for inpatients: for every hour increase in travel-time, the number of expected outpatient cases decreases by 20% (RR = 0.80, 95% confidence interval 0.71, 0.89, p = 5.67E-05). We find nine clusters/hotspots of inpatients.
Our results reveal inequities in access to healthcare: many individuals requiring only outpatient treatment may live too far from the CSJDM to access healthcare. Targeting of resources to comprehensively identify severely ill individuals living in the observed hotspots could further address treatment inequities and enable investigations to determine factors generating these hotspots.
Introduction:
Recent publications frequently introduce new indexes to measure glycemic variability (GV), quality of glycemic control, or glycemic risk; however, there is a lack of evidence supporting ...the use of one particular parameter, especially in clinical practice.
Methods:
A cohort of type 2 diabetes mellitus (T2DM) patients in ambulatory care were followed using continuous glucose monitoring sensors (CGM). Mean glucose (MG), standard deviation, coefficient of variation (CV), interquartile range, CONGA1, 2, and 4, MAGE, M value, J index, high blood glucose index, and low blood glucose index (LBGI) were estimated. Hypoglycemia incidence (<54 mg/dl) was calculated. Area under the curve (AUC) was determined for different indexes as identifiers of patients with risk of hypoglycemia (IRH). Optimal cutoff thresholds were determined from analysis of the receiver operating characteristic curves.
Results:
CGM data for 657 days from 140 T2DM patients (4.69 average days per patient) were analyzed. Hypoglycemia was present in 50 patients with 144 hypoglycemic events in total (incidence rate of 0.22 events per patient/day). In the multivariate analysis, both CV (OR 1.20, 95% CI 1.12-1.28, P < .001) and LBGI (OR 4.83, 95% CI 2.41-9.71, P < .001) were shown to have a statistically significant association with hypoglycemia. The highest AUC were for CV (0.84; 95% CI 0.77-0.91) and LBGI (0.95; 95% CI 0.92-0.98). The optimal cutoff threshold for CV as IRH was 34%, and 3.4 for LBGI.
Conclusion:
This analysis shows that CV can be recommended as the preferred parameter of GV to be used in clinical practice for T2DM patients. LBGI is the preferred IRH between glycemic risk indexes.
Severe mental illness diagnoses have overlapping symptomatology and shared genetic risk, motivating cross-diagnostic investigations of disease-relevant quantitative measures. We analysed ...relationships between neurocognitive performance, symptom domains, and diagnoses in a large sample of people with severe mental illness not ascertained for a specific diagnosis (cases), and people without mental illness (controls) from a single, homogeneous population.
In this case-control study, cases with severe mental illness were ascertained through electronic medical records at Clínica San Juan de Dios de Manizales (Manizales, Caldas, Colombia) and the Hospital Universitario San Vicente Fundación (Medellín, Antioquía, Colombia). Participants were assessed for speed and accuracy using the Penn Computerized Neurocognitive Battery (CNB). Cases had structured interview-based diagnoses of schizophrenia, bipolar 1, bipolar 2, or major depressive disorder. Linear mixed models, using CNB tests as repeated measures, modelled neurocognition as a function of diagnosis, sex, and all interactions. Follow-up analyses in cases included symptom factor scores obtained from exploratory factor analysis of symptom data as main effects.
Between Oct 1, 2017, and Nov 1, 2019, 2406 participants (1689 cases schizophrenia n=160; bipolar 1 disorder n=519; bipolar 2 disorder n=204; and major depressive disorder n=806 and 717 controls; mean age 39 years (SD 14); and 1533 female) were assessed. Participants with bipolar 1 disorder and schizophrenia had similar impairments in accuracy and speed across cognitive domains. Participants with bipolar 2 disorder and major depressive disorder performed similarly to controls, with subtle deficits in executive and social cognition. A three-factor model (psychosis, mania, and depression) best represented symptom data. Controlling for diagnosis, premorbid IQ, and disease severity, high lifetime psychosis scores were associated with reduced accuracy and speed across cognitive domains, whereas high depression scores were associated with increased social cognition accuracy.
Cross-diagnostic investigations showed that neurocognitive function in severe mental illness is characterised by two distinct profiles (bipolar 1 disorder and schizophrenia, and bipolar 2 disorder and major depressive disorder), and is associated with specific symptom domains. These results suggest the utility of this design for elucidating severe mental illness causes and trajectories.
US National Institute of Mental Health.
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