Psoriatic arthritis is a frequent manifestation of psoriasis, and has a high level of impact on physical functioning, work ability and quality of life. However, there have been few studies of the ...epidemiology, development of and risk factors for concomitant psoriatic arthritis in patients with psoriasis. This study analysed data from a German public health insurance database of > 2 million individuals. Factors influencing the development of psoriatic arthritis were determined by descriptively analysing comorbidities and Cox regression modelling. The prevalences of psoriasis and psoriatic arthritis were 2.63% and 0.29% in adults (18+ years) and, respectively, 0.30% and 0.01% in children (0–17 years). The proportion of adult patients with incident psoriasis who developed concomitant psoriatic arthritis within five years after diagnosis of psoriasis (mean 2.3 years) was 2.6%. Cardiovascular diseases are the most frequent comorbidity in patients with psoriasis with or without concomitant psoriatic arthritis. Depression and neurosis/stress disorder were identified as indicators for the development of psoriatic arthritis.
Haploinsufficiency of the class I bHLH transcription factor TCF4 causes Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder, while common variants in the
gene have been identified as ...susceptibility factors for schizophrenia. It remains largely unknown, which brain regions are dependent on TCF4 for their development and function.
We systematically analyzed the expression pattern of TCF4 in the developing and adult mouse brain. We used immunofluorescent staining to identify candidate regions whose development and function depend on TCF4. In addition, we determined TCF4 expression in the developing rhesus monkey brain and in the developing and adult human brain through analysis of transcriptomic datasets and compared the expression pattern between species. Finally, we morphometrically and histologically analyzed selected brain structures in
-haploinsufficient mice and compared our morphometric findings to neuroanatomical findings in PTHS patients.
TCF4 is broadly expressed in cortical and subcortical structures in the developing and adult mouse brain. The TCF4 expression pattern was highly similar between humans, rhesus monkeys, and mice. Moreover,
haploinsufficiency in mice replicated structural brain anomalies observed in PTHS patients.
Our data suggests that TCF4 is involved in the development and function of multiple brain regions and indicates that its regulation is evolutionary conserved. Moreover, our data validate
-haploinsufficient mice as a model to study the neurodevelopmental basis of PTHS.
Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated ...that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus - one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.
We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.
The present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.
Abstract
Neuronal activity initiates transcriptional programs that shape long-term changes in plasticity. Although neuron subtypes differ in their plasticity response, most activity-dependent ...transcription factors (TFs) are broadly expressed across neuron subtypes and brain regions. Thus, how region- and neuronal subtype-specific plasticity are established on the transcriptional level remains poorly understood. We report that in young adult (i.e., 6–8 weeks old) mice, the developmental TF SOX11 is induced in neurons within 6 h either by electroconvulsive stimulation or by exploration of a novel environment. Strikingly, SOX11 induction was restricted to the dentate gyrus (DG) of the hippocampus. In the novel environment paradigm, SOX11 was observed in a subset of c-FOS expressing neurons (ca. 15%); whereas around 75% of SOX11+ DG granule neurons were c-FOS+, indicating that SOX11 was induced in an activity-dependent fashion in a subset of neurons. Environmental enrichment or virus-mediated overexpression of SOX11 enhanced the excitability of DG granule cells and downregulated the expression of different potassium channel subunits, whereas conditional Sox11/4 knock-out mice presented the opposite phenotype. We propose that Sox11 is regulated in an activity-dependent fashion, which is specific to the DG, and speculate that activity-dependent Sox11 expression may participate in the modulation of DG neuron plasticity.
Introduction
Hidradenitis suppurativa (HS) is a chronic, debilitating, and inflammatory skin disease. The epidemiology of HS varies greatly, with an estimated prevalence ranging from 0.03% to 4% ...worldwide. Similar to psoriasis (PsO), HS also exhibits a systemic inflammatory nature with a spectrum of systemic comorbidities. A large health insurance claims (HICs) database is analyzed to determine the demography and epidemiology of HS, PsO, and HS with concurrent PsO (HS-PsO) patients. Furthermore, the comorbidity profiles, including the comorbidity risk of these patient populations, are analyzed.
Methods
This is a noninterventional retrospective analysis of anonymized HICs data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome is the prevalence and incidence of HS, PsO, and HS-PsO. Secondary outcomes include comorbidity profiles and a comorbidity risk analysis.
Results
The prevalence and incidence of HS were 0.0681% and 0.0101%, respectively. The prevalence of HS-PsO was 0.004% (6% of the total HS population). HS patients frequently suffered from arterial hypertension (45%), nicotine dependence (46%), obesity (41%), and depression (36%), which were more common in HS-PsO patients compared with HS alone. HS patients had an increased prevalence of metabolic, psychiatric, immune-mediated, and cardiovascular diseases, e.g., overweight/obesity odds ratio (OR): 2.65, 95% confidence interval (CI) 2.37–2.96, depression (OR: 1.55, 95% CI 1.42–1.76), or seronegative rheumatoid arthritis (OR: 2.82, 95% CI 1.61–4.94) compared with the overall population. The increased risk of myocardial infarction in HS patients (OR: 4.1, 95% CI 3.5–4.8, adjusting for age/sex) was largely attributed to patient’s current smoking status (OR: 1.1, 95% CI 0.8–1.5, adjusting for smoking/age/sex).
Conclusions
HS patients show a broad spectrum of inflammatory and metabolic syndrome-related comorbidities, with an increased risk by concurrent PsO. Important for clinical practice, the elevated cardiovascular risk of HS patients can be largely attributed to smoking.
Abstract
Objective
Psoriasis is a systemic inflammatory disease often accompanied by comorbidities, including metabolic syndrome, cardiovascular diseases and depression. Up to 41% of psoriasis ...patients develop psoriatic arthritis (PsA), making it one of the most relevant manifestations. A large health claims data set was analysed to determine the rate of PsA development in psoriasis patients. Furthermore, comorbid disease profiles of psoriasis patients with or without PsA were compared, and potential risk factors for the development of PsA were identified.
Methods
This was a non-interventional, retrospective analysis of anonymized insurance health claims data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome was the prevalence and incidence of diagnosed PsA among psoriasis patients in Germany. Risk factors for the development of PsA in psoriasis patients were determined by conditional logistic regression analysis.
Results
The cumulative percentage of patients with existing psoriasis developing concomitant PsA over 4 years was 3.44%, with a mean time to diagnosis of PsA of 1.5 years. Psoriasis patients diagnosed with acute rheumatism (odds ratio: 2.93, 95% CI = 1.76, 4.86; P < 0.001) or pain in unspecific joints (odds ratio: 1.74, 95% CI = 1.01, 2.99; P = 0.047) showed an increased risk for development of PsA later on. Interestingly, fewer than half of the patients with concomitant PsA consulted a rheumatologist.
Conclusions
Unspecific arthritic symptoms are likely to precede PsA diagnoses and can develop soon after onset of psoriasis, with accumulating risk over time. There is a high unmet need for early rheumatological assessment of psoriasis patients.
The discovery of continuous generation of functional neurons throughout life has emerged as a major contributor to plasticity in defined regions of the adult mammalian brain. Work over the past ...decades identified cellular constituents of the distinct adult neurogenic niches as well as numerous signaling pathways, transcriptional and epigenetic regulators that exert tight control over the production of new neurons from resident stem cells. Recent studies uncovered developmental stage-specific adaptations of metabolic circuits and have provided evidence for their central regulatory function in the adult neurogenic lineage. Moreover, there is increasing evidence for a regulatory impact of a wide range of systemic metabolic factors including exercise induced metabolic changes and diet on the development of adult-born neurons. Here, we will summarize current knowledge and emerging principles underlying the metabolic control of neuronal maturation in adult neurogenesis.
In addition to its high prognostic value, the involvement of axillary lymph nodes in breast cancer patients also plays an important role in therapy planning. Therefore, an imaging modality that can ...determine nodal status with high accuracy in patients with primary breast cancer is desirable. Our purpose was to investigate whether, in newly diagnosed breast cancer patients, machine-learning prediction models based on simple assessable imaging features on MRI or PET/MRI are able to determine nodal status with performance comparable to that of experienced radiologists; whether such models can be adjusted to achieve low rates of false-negatives such that invasive procedures might potentially be omitted; and whether a clinical framework for decision support based on simple imaging features can be derived from these models.
Between August 2017 and September 2020, 303 participants from 3 centers prospectively underwent dedicated whole-body
F-FDG PET/MRI. Imaging datasets were evaluated for axillary lymph node metastases based on morphologic and metabolic features. Predictive models were developed for MRI and PET/MRI separately using random forest classifiers on data from 2 centers and were tested on data from the third center.
The diagnostic accuracy for MRI features was 87.5% both for radiologists and for the machine-learning algorithm. For PET/MRI, the diagnostic accuracy was 89.3% for the radiologists and 91.2% for the machine-learning algorithm, with no significant differences in diagnostic performance between radiologists and the machine-learning algorithm for MRI (
= 0.671) or PET/MRI (
= 0.683). The most important lymph node feature was tracer uptake, followed by lymph node size. With an adjusted threshold, a sensitivity of 96.2% was achieved by the random forest classifier, whereas specificity, positive predictive value, negative predictive value, and accuracy were 68.2%, 78.1%, 93.8%, and 83.3%, respectively. A decision tree based on 3 simple imaging features could be established for MRI and PET/MRI.
Applying a high-sensitivity threshold to the random forest results might potentially avoid invasive procedures such as sentinel lymph node biopsy in 68.2% of the patients.
Surface conditions on Mars are currently cold and dry, with water ice unstable on the surface except near the poles. However, geologically recent glacierlike landforms have been identified in the ...tropics and the midlatitudes of Mars. The ice has been proposed to originate from either a subsurface reservoir or the atmosphere. We present high-resolution climate simulations performed with a model designed to simulate the present-day Mars water cycle but assuming a 45° obliquity as experienced by Mars a few million years ago. The model predicts ice accumulation in regions where glacier landforms are observed, on the western flanks of the great volcanoes and in the eastern Hellas region. This agreement points to an atmospheric origin for the ice and reveals how precipitation could have formed glaciers on Mars.
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