The phosphoproteome and its physiological dynamics in Staphylococcus aureus

Phosphorylation events on proteins during growth and stress/starvation can represent crucial regulation processes inside the bacterial cell. Therefore, serine, threonine and tyrosine phosphorylation patterns were analyzed by two powerful complementary proteomic methods for the human pathogen Staphylococcus aureus. Using 2D-gel analysis with a phosphosensitive stain (Pro-Q Diamond) and gel-free titanium dioxide based phosphopeptide enrichment, 103 putative phosphorylated proteins with successfully mapped 68 different phosphorylation sites were found in the soluble proteome of S. aureus. Additionally, in a proof of concept study, 8 proteins phosphorylated on arginine residues have been identified. Most important for functional analyses of S. aureus, proteins related to pathogenicity and virulence were found to be phosphorylated: the virulence regulator SarA, the potential antimicrobial target FbaA and the elastin-binding protein EbpS. Besides newly identified phosphorylation sites we compared our dataset with existing data from literature and subsequent experiments revealed additional phosphorylation events on highly conserved localizations in FbaA. Differential analysis of phosphorylation signals on the 2D-gels showed significant changes in phosphorylation under different physiological conditions for 10 proteins. Among these, we were able to detect newly appearing signals for phosphorylated isoforms of FdaB and HchA under nitrosative stress conditions.     

Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors

We investigated the regulation of COX-2 expression and activity by adenosine receptors in rat microglial cells. The selective adenosine A_2a-receptor agonist CGS21680 and the non-selective adenosine A₁- and A₂-receptor agonist 5′-N-ethylcarboxi-amidoadenosine (NECA) induced an increase in COX-2 mRNA levels and the synthesis of prostaglandin E₂ (PGE₂). The adenosine A₁-receptor agonist cyclopentyladenosine (CPA) was less potent, and the adenosine A₃-receptor-specific agonist N⁶-2-(-aminophenylo)ethyladenosine (APNEA) showed only marginal effects. Microglia expressed adenosine A₁-, A_2a-, and A₃-, but not A_2b-receptor mRNAs, whereas astroglial cells expressed adenosine A_2b- but not A_2a-receptor mRNA. The adenosine A_2a-receptor selective antagonist (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) inhibited both CGS21680-induced COX-2 expression and PGE₂ release. CGS21680-increased PGE₂ levels were inhibited by dexamethasone, by the nonsteroidal antiinflammatory drug meloxicam, and by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536). CGS21680 and NECA both increased intracellular cAMP levels in microglial cells. Dibutyryl cAMP as well as forskolin induced the release of PGE₂. The results strongly suggest that adenosine A_2a-receptor-induced intracellular signaling events cause an up-regulation of the COX-2 gene and the release of PGE₂. Apparently, the cAMP second messenger system plays a crucial role in COX-2 gene regulation in rat microglial cells. The results are discussed with respect to neurodegenerative disorders of the CNS such as Alzheimer's disease, in which activated microglia are critically involved and COX inhibitors may be of therapeutic benefit. © 1996 Wiley-Liss, Inc.     

The global prevalence of headache: an update,with analysis of the influences of methodological factors on prevalence estimates

BackgroundAccording to the Global Burden of Disease (GBD) study, headache disorders are among the most prevalent and disabling conditions worldwide. GBD builds on epidemiological studies (published and unpublished) which are notable for wide variations in both their methodologies and their prevalence estimates.Our first aim was to update the documentation of headache epidemiological studies, summarizing global prevalence estimates for all headache, migraine, tension-type headache (TTH) and headache on ≥15 days/month (H15+), comparing these with GBD estimates and exploring time trends and geographical variations. Our second aim was to analyse how methodological factors influenced prevalence estimates.MethodsIn a narrative review, all prevalence studies published until 2020, excluding those of clinic populations, were identified through a literature search. Prevalence data were extracted, along with those related to methodology, world region and publication year. Bivariate analyses (correlations or comparisons of means) and multiple linear regression (MLR) analyses were performed.ResultsFrom 357 publications, the vast majority from high-income countries, the estimated global prevalence of active headache disorder was 52.0% (95%CI 48.9–55.4), of migraine 14.0% (12.9–15.2), of TTH 26.0% (22.7–29.5) and of H15+ 4.6% (3.9–5.5). These estimates were comparable with those of migraine and TTH in GBD2019, the most recent iteration, but higher for headache overall. Each day, 15.8% of the world’s population had headache. MLR analyses explained less than 30% of the variation. Methodological factors contributing to variation, were publication year, sample size, inclusion of probable diagnoses, sub-population sampling (e.g., of health-care personnel), sampling method (random or not), screening question (neutral, or qualified in severity or presumed cause) and scope of enquiry (headache disorders only or multiple other conditions). With these taken into account, migraine prevalence estimates increased over the years, while estimates for all headache types varied between world regions.ConclusionThe review confirms GBD in finding that headache disorders remain highly prevalent worldwide, and it identifies methodological factors explaining some of the large variation between study findings. These variations render uncertain both the increase in migraine prevalence estimates over time, and the geographical differences. More and better studies are needed in low- and middle-income countries.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01402-2.     

The quality of life of people with dementia and their family carers

Background: We aimed to identify factors associated with the quality of life (QoL) of 'persons with dementia' (PWDs) and their family carers. Method: Two-hundred and thirty dyads of PWDs and their family carers were included. The PWDs were assessed with the Neuropsychiatric Inventory (NPI-Q), two Activities of Daily Living (ADL) scales, the Cornell Scale and the QoL-Alzheimer's Disease scale (QoL-AD; self- and proxy-reported scores). The carers were assessed with the QoL-AD and the Geriatric Depression Scale. Results: Factors associated with self-reported QoL were depression (β = -0.26, p < 0.001) and impaired ADL (β = -0.26, p < 0.001) and with proxy-rated QoL were NPI (β = -0.18, p = 0.02), depression (β = -0.32, p < 0.001) and impaired ADL (β = -0.43, p < 0.001). Factors associated with QoL in carers living together with the PWDs were depression (β = -0.56, p < 0.001) and having a hobby (β = 0.19, p = 0.01), whereas depression was associated with QoL in those who lived separately from the PWD (β = -0.60, p < 0.001). Conclusion: Depression and impaired ADL were associated with the self- and proxy-rated QoL of the PWDs, whereas depression in the carers negatively affected their QoL.     

The effect of coping on the burden in family carers of persons with dementia

Objectives: This study explores the association between coping, measured by the extent of locus of control, and the burden of care on family carers of persons with dementia (PWD).

Method: Two hundred thirty PWD living at home and their family carers were recruited from 20 Norwegian municipalities. The carers’ burden was assessed by the Relatives’ Stress Scale (RSS) and coping by the Locus of Control Behaviour Scale. The PWD were assessed by the Neuropsychiatric Inventory (NPI-Q), the Physical Self-Maintenance Scale (PSMS), the Instrumental Activities of Daily Living (IADL) scale, and the Mini Mental Status Examination (MMSE).

Results: Locus of control (LoC) was found to be the most important factor associated with the burden on carers of PWD, even when we had controlled for the PWD variables, such as the NPI-Q score. The LoC and the carer's use of hours per day to assist the PWD were the only two variables the carers found that affected the extent of the burden. The NPI-Q was the most important variable in the PWD that affected the burden on the carers.

Conclusion: Carers who believe that what happens to them is the consequence of their own actions are likely to be less burdened than carers not expecting to have control. This finding gives a possibility to identify carers with a high risk of burden.     

Primary primitive neuroectodermal tumor of the spinal cord: case report and review of the literature.

We present the clinical, radiological, and pathological features of a primary primitive neuroectodermal tumor (PNET) that occurred in the thoracic spinal cord of a 69-year-old man. Magnetic resonance imaging (MRI) demonstrated on T1-weighted images a 2x1x5 cm isointense intraspinal mass with homogeneous contrast enhancement extending from the C7 to the Th3 level. There was no clinical or radiological evidence for the existence of an intracranial tumor. Histological examination revealed a small round cell tumor with rosette formation and immunohistochemical characteristics of a PNET. The patient is the oldest among the 20 cases with this rare spinal cord neoplasm reported so far in the literature; the previously published cases are briefly reviewed.     

Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = ?0.164 to ?0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = ?0.173 to ?0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.     

Total-body 3D magnetic resonance angiography influences the management of patients with peripheral arterial occlusive disease

High-resolution total-body 3D MR angiography (MRA) has recently become available, revealing additional clinically relevant disease in patients with peripheral arterial occlusive disease (PAOD). However, the actual impact of total-body MRA on patient management in patients with PAOD has not been investigated so far. Two hundred forty-nine consecutive patients with angiographically proven PAOD were prospectively examined by means of contrast-enhanced total-body 3D MRA on a 1.5-T MR scanner. All correlative imaging studies performed within 60 days of total-body MRA were included in the efficacy analysis. Additional clinically relevant disease (luminal narrowing >50%, aneurysmal changes or dissections) was found in 73 segments (52 patients), including the renal arteries (36 segments), carotid arteries (28 segments), subclavian arteries (four segments) and abdominal aortic aneurysms (AAA) (five segments). Of the 73 segments, 36 were deemed necessary for further investigation by means of focused MRA examinations; the diagnosis was confirmed in all cases. Within the 60-day follow-up period, interventional or surgical therapy outside the peripheral arterial tree was performed in nine patients (11 segments), including carotid endatherectomy and renal artery angioplasty. The outlined total-body 3D MRA approach permits a comprehensive evaluation of the arterial system in patients with atherosclerosis and does indeed have an impact on patient management in patients with PAOD.     

Liver X receptors downregulate 11beta-hydroxysteroid dehydrogenase type 1 expression and activity

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) converts inactive corticosteroids into biologically active corticosteroids, thereby regulating the local concentration of active glucocorticoids, such as cortisol. 11beta-HSD-1 is particularly expressed in adipocytes and liver and appears to be causally linked to the development of type 2 diabetes and the metabolic syndrome. Liver X receptor (LXR)-alpha and -beta are nuclear oxysterol receptors whose key role in lipid metabolic regulation has recently been established. In this study, we show that treatment of adipocytes derived from 3T3-L1 cells and mouse embryonic fibroblasts in vitro with synthetic or natural LXR agonists decreases mRNA expression of 11beta-HSD-1 by approximately 50%, paralleled by a significant decline in 11beta-HSD-1 enzyme activity. Downregulation of 11beta-HSD-1 mRNA by LXRs started after a lag period of 8 h and required ongoing protein synthesis. Moreover, long-term per os treatment with a synthetic LXR agonist downregulated 11beta-HSD-1 mRNA levels by approximately 50% in brown adipose tissue and liver of wild-type but not of LXRalpha(-/-)beta(-/-) mice and was paralleled by downregulation of hepatic PEPCK expression. In conclusion, LXR ligands could mediate beneficial metabolic effects in insulin resistance syndromes including type 2 diabetes by interfering with peripheral glucocorticoid activation.