Evolutionary History of Lake Tanganyika's Predatory Deepwater Cichlids

Hybridization among littoral cichlid species in Lake Tanganyika was inferred in several molecular phylogenetic studies. The phenomenon is generally attributed to the lake level-induced shoreline and habitat changes. These allow for allopatric divergence of geographically fragmented populations alternating with locally restricted secondary contact and introgression between incompletely isolated taxa. In contrast, the deepwater habitat is characterized by weak geographic structure and a high potential for gene flow, which may explain the lower species richness of deepwater than littoral lineages. For the same reason, divergent deepwater lineages should have evolved strong intrinsic reproductive isolation already in the incipient stages of diversification, and, consequently, hybridization among established lineages should have been less frequent than in littoral lineages. We test this hypothesis in the endemic Lake Tanganyika deepwater cichlid tribe Bathybatini by comparing phylogenetic trees of Hemibates and Bathybates species obtained with nuclear multilocus AFLP data with a phylogeny based on mitochondrial sequences. Consistent with our hypothesis, largely congruent tree topologies and negative tests for introgression provided no evidence for introgressive hybridization between the deepwater taxa. Together, the nuclear and mitochondrial data established a well-supported phylogeny and suggested ecological segregation during speciation

IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection.

Type 2 immune responses are essential in protection against intestinal helminth infections. In this study we show that IL-22, a cytokine important in defence against bacterial infections in the intestinal tract, is also a critical mediator of anti-helminth immunity. After infection with Nippostrongylus brasiliensis, a rodent hookworm, IL-22-deficient mice showed impaired worm expulsion despite normal levels of type 2 cytokine production. The impaired worm expulsion correlated with reduced goblet cell hyperplasia and reduced expression of goblet cell markers. We further confirmed our findings in a second nematode model, the murine whipworm Trichuris muris. T.muris infected IL-22-deficient mice had a similar phenotype to that seen in N.brasiliensis infection, with impaired worm expulsion and reduced goblet cell hyperplasia. Ex vivo and in vitro analysis demonstrated that IL-22 is able to directly induce the expression of several goblet cell markers, including mucins. Taken together, our findings reveal that IL-22 plays an important role in goblet cell activation, and thus, a key role in anti-helminth immunity

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis

Background Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis. Methods From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested. Results Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39). Conclusions The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification

Rehabilitation goals of people with spinal cord injuries can be classified against the International Classification of Functioning, Disability and Health Core Set for spinal cord injuries

Objectives: To establish whether inter-professional rehabilitation goals from people with non-traumatic spinal cord injury (SCI) can be classified against the International Classification of Functioning, Disability and Health (ICF) SCI Comprehensive and Brief Core Sets early postacute situation. Setting: Neurological rehabilitation unit. Methods: Rehabilitation goals of 119 patients with mainly incomplete and non-traumatic SCIs were classified against the ICF SCI Core Sets following established linking rules. Results: A total of 119 patients generated 1509 goals with a mean (and s.d.) of 10.5 (9.1) goals per patient during the course of their inpatient rehabilitation stay. Classifying the 1509 rehabilitation goals against the Comprehensive ICF Core Set generated 2909 ICF codes. Only 69 goals (4.6%) were classified as ‘not definable (ND)’. Classifying the 1509 goals against the Brief ICF Core Set generated 2076 ICF codes. However, 751(49.8%) of these goals were classified as ‘ND’. In the majority of goals (95.7%), the ICF code description was not comprehensive enough to fully express the goals set in rehabilitation. In particular, the notion of quality of movement or specificity and measurability aspects of a goal (usually described with the criteria and acronyms SMART) could not be expressed through the ICF codes. Conclusion: Inter-professional rehabilitation goals can be broadly described by the ICF Comprehensive Core Set for SCI but not the Brief Core Set

Patterns of Multimorbidity in the Aged Population. Results from the KORA-Age Study

Multimorbidity is a common problem in aged populations with a wide range of individual and societal consequences. The objective of the study was to explore patterns of comorbidity and multimorbidity in an elderly population using different analytical approaches. Data were gathered from the population-based KORA-Age project, which included 4,127 persons aged 65–94 years living in the city of Augsburg and its two surrounding counties in Southern Germany. Information on the presence of 13 chronic conditions was collected in a standardized telephone interview and a self-administered questionnaire. Patterns of comorbidity and multimorbidity were analyzed using prevalence figures, logistic regression models and exploratory tetrachoric factor analysis. The prevalence of multimorbidity (≥2 diseases) was 58.6% in the total sample. Hypertension and diabetes (Odds Ratio [OR] 2.95, 99.58% confidence interval [CI] [2.19–3.96]), as well as hypertension and stroke (OR 2.00, 99.58% CI [1.26–3.16]) most often occurred in combination. This association was independent of age, sex and the presence of other conditions. Using factor analysis, we identified four patterns of multimorbidity: the first pattern includes cardiovascular and metabolic diseases, the second includes joint, liver, lung and eye diseases, the third covers mental and neurologic diseases and the fourth pattern includes gastrointestinal diseases and cancer. 44% of the persons were assigned to at least one of the four multimorbidity patterns; 14% could be assigned to both the cardiovascular/metabolic and the joint/liver/lung/eye pattern. Further common pairs were the mental/neurologic pattern combined with the cardiovascular/metabolic pattern (7.2%) or the joint/liver/lung/eye pattern (5.3%), respectively. Our results confirmed the existence of co-occurrence of certain diseases in elderly persons, which is not caused by chance. Some of the identified patterns of multimorbidity and their overlap may indicate common underlying pathological mechanisms

Aberrant Cyclization Affords a C-6 Modified Cyclic Adenosine 5′-Diphosphoribose Analogue with Biological Activity in Jurkat T Cells

*S Supporting Information ABSTRACT: Two nicotinamide adenine dinucleotide (NAD +) analogues modified at the 6 position of the purine ring were synthesized, and their substrate properties toward Aplysia californica ADP-ribosyl cyclase were investigated. 6-N-Methyl NAD + (6-N-methyl nicotinamide adenosine 5′-dinucleotide 10) hydrolyzes to give the linear 6-N-methyl ADPR (adenosine 5′-diphosphoribose, 11), whereas 6-thio NHD + (nicotinamide 6-mercaptopurine 5′-dinucleotide, 17) generates a cyclic dinucleotide. Surprisingly, NMR correlation spectra confirm this compound to be the N1 cyclic product 6-thio N1-cIDPR (6-thio cyclic inosine 5′-diphosphoribose, 3), although the corresponding 6-oxo analogue is well-known to cyclize at N7. In Jurkat T cells, unlike the parent cyclic inosine 5′-diphosphoribose N1-cIDPR 2, 6-thio N1-cIDPR antagonizes both cADPR- and N1cIDPR-induced Ca 2+ release but possesses weak agonist activity at higher concentration. 3 is thus identified as the first C-6 modified cADPR (cyclic adenosine 5′-diphosphoribose) analogue antagonist; it represents the first example of a fluorescent N1cyclized cADPR analogue and is a new pharmacological tool for intervention in the cADPR pathway of cellular signaling

Social psychiatry and psychiatric epidemiology functional impairment among people with severe and enduring mental disorder in rural Ethiopia: a cross-sectional study

Purpose: Evidence regarding functional impairment in people with severe mental disorders (SMD) is sparse in low and middle-income countries. The aim of this study was to identify factors associated with functional impairment in people with enduring SMD in a rural African setting. Methods: A cross-sectional study was conducted at the baseline of a health service intervention trial. A total of 324 participants were recruited from an existing communityascertained cohort of people with SMD (n= 218), and attendees at the Butajira General Hospital psychiatric clinic (n= 106). Inclusion criteria defined people with SMD who had ongoing need for care: those who were on psychotropic medication, currently symptomatic or had a relapse in the preceding two years. The World Health Organization Disability Assessment schedule (WHODAS-2.0) and the Butajira Functioning Scale (BFS), were used to assess functional impairment. Multivariable negative binomial regression models were fitted to investigate the association between demographic, socio-economic and clinical characteristics, and functional impairment. Results: Increasing age, being unmarried, rural residence, poorer socio-economic status, symptom severity, continuous course of illness, medication side effects and internalized stigma were associated with functional impairment across self reported and caregiver responses for both the WHODAS and the BFS. Diagnosis per se was not associated consistently with functional impairment. Conclusion: To optimize functioning in people with chronic SMD in this setting, services need to target residual symptoms, poverty, medication side effects and internalized stigma. Testing the impact of community interventions to promote recovery will be useful. Advocacy for more tolerable treatment options is warranted