Summary
Background
Sebaceous glands (SGs) are appendages of mammalian skin that produce a mixture of lipids known as sebum. Acne vulgaris is an exceptionally common skin condition, characterized by ...elevated sebum production, altered sebum composition, and the formation of infundibular cysts, called comedones. Comedo‐associated SGs are atrophic, suggesting that comedo formation involves abnormal differentiation of progenitor cells that generate the SG and infundibulum: the ‘comedo switch’. Understanding the biological processes that govern SG homeostasis promises to highlight potential aetiological mechanisms underlying acne and other SG‐associated skin disorders.
Results
In this review, we discuss the clinical data, genetic mouse models and in vitro research that have highlighted major hormones, paracrine factors, transcription factors and signalling pathways that control SG homeostasis. These include, but are not limited to androgens, progestogens and oestrogens; retinoids; receptor tyrosine kinases such as ErbB family receptors, fibroblast growth factor receptor 2 and insulin/insulin‐like growth factor 1 receptors; peroxisome proliferator‐activated receptor γ; aryl hydrocarbon receptor; and the Wnt signalling pathway. Where possible, the cellular and molecular mechanisms by which these regulatory factors control SG biology are indicated, along with considerations as to how they might contribute to acne pathogenesis.
Conclusions
Future research should seek to establish the relative importance, and causative relationships, of altered sebum production, sebum composition, inflammation and abnormal differentiation of sebaceous progenitors to the process of comedo formation in acne. Such an understanding will allow for therapeutic targeting of regulatory factors that control SG homeostasis, with the aim of treating acne.
What's already known about this topic?
Sebaceous glands (SGs) are skin appendages that synthesize lipids (sebum).
Several skin diseases, including acne, feature abnormal SGs.
Androgens are essential for both SG maintenance and acne.
Retinoids and oestrogens, which can be used to treat acne effectively, cause dramatic SG involution.
What does this study add?
We synthesize both historical and current literature and generate testable hypotheses regarding SG homeostasis and acne pathogenesis.
We present an up‐to‐date model of the cellular and molecular mechanisms that underpin SG homeostasis.
We discuss evidence supporting a model of comedo formation where the progenitor cells that contribute to the SG and infundibulum differentiate abnormally.
Linked Editorial: Van Steensel. Br J Dermatol 2019; 181:647–648.
We aimed to retrospectively assess treatments/outcomes, including the value of high‐dose‐chemotherapy and autologous‐stem‐cell‐rescue (HDC + AuSCR) and re‐irradiation, in a large, European ...patient‐cohort with relapsed intracranial germ‐cell‐tumors (GCTs) receiving uniform first‐line therapy, including radiotherapy as standard‐of‐care. Fifty‐eight UK/German patients (48 male/10 female) with relapsed intracranial‐GCTs 13 germinoma/45 non‐germinomatous GCT (NGGCT) treated 1996–2010 as per the SIOP‐CNS‐GCT‐96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five‐year overall‐survival (OS) for the whole‐group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard‐dose‐chemotherapy (SDC) and re‐irradiation or HDC + AuSCR with/without re‐irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non‐protocol adherence, five teratoma, five palliation). Five‐year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2–26%). By treatment received, 5‐year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0–0%) and 14% (3–36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5‐year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re‐irradiation or HDC + AuSCR with/without re‐irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa‐based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible.
What's new?
What's the optimal approach to treating a certain type of relapsed brain tumor? The authors looked at a rare type of cancer called intracranial germ cell tumors (GCTs), which fall into two categories, germinomas and non‐germinomatous tumors. They evaluated data from 58 European patients, the largest cohort of relapsed GCTs studied to date, all of whom received uniform first‐line treatment. Patients with relapsed germinoma could survive after standard‐dose chemotherapy with additional radiotherapy or high‐dose chemotherapy plus autologous‐stem‐cell‐rescue (HDC + AuSCR), with or without additional radiotherapy. Those who relapsed with non‐germinomatous GCTs had a poor prognosis; only those receiving HDC + AuSCR had any possibility of cure.
Chronic inflammatory demyelinating polyradiculopathy (CIDP) is a common, but often misdiagnosed disease of the peripheral nervous system with assumed autoimmune pathogenesis. While current concepts ...of CIDP postulate a pathogenetic role of B cells and (auto)antibodies, the relevance of CD8 T cells present in the biopsies is still elusive. Thus, we asked whether nervous tissue infiltrating and blood-derived lymphocytes in CIDP are clonally expanded to evaluate the involvement of T cells in the pathogenesis of the disease.
We characterized the clonal composition of the T-cell receptor repertoire in sural nerve biopsies (n = 25) and matching peripheral blood (n = 12) of patients with CIDP using PCR-based CDR3 spectratyping and subsequent DNA sequencing. As controls we used inflammatory myopathies (dermatomyositis, inclusion body myositis) and nonpathologic control biopsies. Immunohistochemistry was employed to visualize expanded CD8+ T-cell populations in sural nerve biopsies.
In contrast to controls, T cells in CIDP biopsies showed strong monoclonal and oligoclonal restrictions in their T-cell receptor repertoire. Strikingly, clonal expansions found in the biopsies were reflected in the CD8+ T-cell pool of patients' peripheral blood. Clones overlapping between blood and biopsy could be confirmed by CDR3 sequencing. Finally, the predominance of expanded nerve-infiltrating CD8+ T-cell clones was visualized by immunohistochemistry.
Together, these data provide strong evidence for an antigen-driven, major histocompatibility complex class I restricted, CD8+ T-cell-mediated attack against peripheral nerve tissue components contributing to the pathogenesis of CIDP.
NeuLAND (New Large-Area Neutron Detector) is the next-generation neutron detector for the R3B (Reactions with Relativistic Radioactive Beams) experiment at FAIR (Facility for Antiproton and Ion ...Research). NeuLAND detects neutrons with energies from 100 to 1000 MeV, featuring a high detection efficiency, a high spatial and time resolution, and a large multi-neutron reconstruction efficiency. This is achieved by a highly granular design of organic scintillators: 3000 individual submodules with a size of 5 × 5 × 250 cm3 are arranged in 30 double planes with 100 submodules each, providing an active area of 250 × 250 cm2 and a total depth of 3 m. The spatial resolution due to the granularity together with a time resolution of σt≤ 150 ps ensures high-resolution capabilities. In conjunction with calorimetric properties, a multi-neutron reconstruction efficiency of 50% to 70% for four-neutron events will be achieved, depending on both the emission scenario and the boundary conditions allowed for the reconstruction method. We present in this paper the final design of the detector as well as results from test measurements and simulations on which this design is based.
Employing the Bonn–Gatchina partial wave analysis framework (PWA), we have analyzed HADES data of the reaction p(3.5 GeV)+p→pK+Λ. This reaction might contain information about the kaonic cluster ...“ppK−” (with quantum numbers JP=0− and total isospin I=1/2) via its decay into pΛ. Due to interference effects in our coherent description of the data, a hypothetical K‾NN (or, specifically “ppK−”) cluster signal need not necessarily show up as a pronounced feature (e.g. a peak) in an invariant mass spectrum like pΛ. Our PWA analysis includes a variety of resonant and non-resonant intermediate states and delivers a good description of our data (various angular distributions and two-hadron invariant mass spectra) without a contribution of a K‾NN cluster. At a confidence level of CLs=95% such a cluster cannot contribute more than 2–12% to the total cross section with a pK+Λ final state, which translates into a production cross-section between 0.7 μb and 4.2 μb, respectively. The range of the upper limit depends on the assumed cluster mass, width and production process.
Abstract Background/objective Dalfampridine is the extended-release formulation of 4-aminopyridine and is approved for the symptomatic treatment of impaired mobility in patients with multiple ...sclerosis. Our aim was to examine the short- and long-term effects of treatment with dalfampridine on motoric and cognitive assessment parameters of multiple sclerosis (MS) patients over 9–12 months. Methods Fifty-two patients with MS with an EDSS between 4.0 and 7.0 and impaired mobility were evaluated for parameters of walking ability, MSFC, cognitive and motor fatigue and evoked potentials at treatment initiation with dalfampridine as well as 2 weeks and after 9–12 months later. Results Thirty out of fifty-two patients (~ 60%) were still on treatment after 9–12 months. Two weeks after treatment initiation, significant ameliorations could be found for T25FW, maximum walking distance as well as motoric and cognitive fatigue which still persisted after 9–12 months. In contrast significant effects for velocity were observed only after 2 weeks, for improvement in PASAT only after 9–12 months. A tendency for improvement of somatosensory evoked potentials was found in a subset of patients. Conclusion Dalfampridine shows positive short- and long-term effects on motoric and cognitive assessment parameters in an open-label observational study in a cohort of patients with MS.
Cognitive impairment (CI) is a critical feature for patients with childhood or juvenile multiple sclerosis (MS).
To promote the understanding of CI and to address the impact of different ...pharmacological treatment strategies on cognitive performance in this patient group.
A cohort of 19 patients with therapy-naïve or ß-Interferon-treated juvenile MS completed a comprehensive neuropsychological assessment at initial presentation (baseline) and on average 2.5 years later (follow-up). The assessments were complemented with a neuropaediatric examination and conventional cerebral magnetic resonance imaging (MRI).
9 patients (47%) were impaired in at least one test at baseline (z-score <-1.645 compared with age-adjusted normative data), with the highest impairment frequency in the domains processing speed and attention & executive functions. At follow-up a higher impairment frequency was prominent in those patients whose therapy had not been escalated (N = 13, 69% impaired in at least one test), while cognition was preserved or ameliorated in patients whose treatment had been escalated to highly effective drugs (N = 6, 0% impaired) during the observational period. These group differences at follow-up were not attributable to differences regarding demographics, MRI metrics or cognitive performance at baseline.
Our findings confirm that paediatric MS is associated with considerable CI already in early disease stages. Early administration of highly effective treatment may protect from cognitive decline or alleviate CI in juvenile MS, but larger controlled trials are warranted to confirm these preliminary results.
•Paediatric patients with MS underwent longitudinal cognitive assessments.•Certain patients were escalated to second-line disease modifying drugs.•These patients showed significantly less cognitive impairment at follow-up.•Highly effective disease modifying drugs may alleviate cognitive impairment.•But larger, placebo-controlled studies are warranted.
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The HADES data from p + Nb collisions at a center-of-mass energy of
GeV are analyzed employing a statistical hadronization model. The model can successfully describe the production yields of the ...identified hadrons
,
,
,
K
0
s
,
with parameters
MeV and
MeV, which fit well into the chemical freeze-out systematics found in heavy-ion collisions. In addition, we reanalyze our previous HADES data from Ar + KCl collisions at
GeV with an updated version of the model. We address equilibration in heavy-ion collisions by testing two aspects: the description of yields and the regularity of freeze-out parameters from a statistical model fit as a function of colliding energy and system size. Despite its success, the model fails to describe the observed
yields in both, p + Nb and Ar + KCl . Special emphasis is put on feed-down contributions from higher-lying resonance states as a possible explanation for the observed excess.
The evolution of the traditional nuclear magic numbers away from the valley of stability is an active field of research. Experimental efforts focus on providing key spectroscopic information that ...will shed light into the structure of exotic nuclei and understanding the driving mechanism behind the shell evolution. In this work, we investigate the Z=6 spin-orbit shell gap towards the neutron dripline. To do so, we employed NA(p,2p)CA−1 quasi-free scattering reactions to measure the proton component of the 21+ state of 16,18,20C. The experimental findings support the notion of a moderate reduction of the proton 1p1/2−1p3/2 spin-orbit splitting, at variance to recent claims for a prevalent Z=6 magic number towards the neutron dripline.
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