CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28null CD4 T cells

Androgen Receptor Drives Cellular Senescence

The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor

A HISTOLOGICAL COMPARISON OF MYELINATED NERVE FIBERS BETWEEN THE EXTERNAL AND EXTREME CAPSULES IN HUMAN BRAIN

Introduction: To recognize the myelinated nerve fibers of the external and extreme capsules in human brain. Materials and Methods: 10 adult and normal brains (20 hemispheres) from both sexes were studied using 15 mm serial secions in all three cardinal planes after fixation and processing. These sections were stained by Klüver – Barrera and Heidenhin – Woelcke methods. Results: Some fibers from different parts of the cortex through corona radiata entered the dorsal border of the external capsule, These fibers moved ventraly and ventrocaudaly toward the ventral border of the external capsule, and most of them entered the cerebral peduncles trans -, sub-, or retrolenticularly. Some fibers passed through dorsal part of putamen and connected the external capsule with posterior limb of the internal capsule. Some fibers passed between rostrum of corpus callosum and venteral part of the external capsule. Some fibers traced from the external capsule to posterior bundle of the anterior commissure; some of them entered the commissure but others terminated in nucleus basalis (Meynert) neurons. Some fibers passed through rostral part of the external and extreme capsules.Most of the fibers of the extreme capsule interconnected the temporal and frontoparietal operculi with the insular gyri, or with each other. A group of the extreme capsule fibers connected the adjacent insular gyri with each other. Some fibers exchanged between the extreme capsule and the claustrum. There were fibers which went between the external and extreme capsules through the dorsal claustrum. Conclusion: It is concluded that the external capsule contains all three groups of fibers, but it is mainly projectional; on the other hand, the extreme capsule is mainly associational. Thus, in our opinion, these two capsules should be classified in different groups

Frequency of hematologic and solid malignancies in the family history of 50 patients with acute myeloid leukemia - a single center analysis.

Background and objectiveThe revised World Health Organization classification of 2016 for myeloid neoplasms and acute leukemia added a section of myeloid neoplasms with germline predisposition. The main objective of our study was to evaluate the frequency of hematologic and solid malignancies in the family history of patients with acute myeloid leukemia (AML) by using a systemic pedigree interview. The family history was taken of 50 patients between 24 and 80 years.Findings8/50 (16%) patients with AML had family members with hematologic malignancies. 2/50 (4%) patients had family members of first degree with hematologic malignancies. Furthermore in 42/50 (84%) of AML patients solid malignancies were documented in family members of any degree and in 31/50 (62%) in family members of first degree. The most commonly occurring malignancies in our cohort were breast and colorectal cancer. We analyzed the pedigrees for cancer syndromes that can be associated with acute leukemia like Li-Fraumeni syndrome, Lynch syndrome and hereditary breast cancer. 2/50 (4%) patients fulfilled the criteria for familial breast and ovarian cancer from the German consortium and 1/50 (2%) patients fulfilled the Bethesda Guidelines criteria for hereditary nonpolyposis colorectal cancer. No pedigree met the criteria for Li-Fraumeni syndrome. In 29 cases we compared the patient history obtained in the routine work-up with our data. The accuracy of the obtained family history was 23%, outlining that in the clinical routine information about family histories often escapes notice.ConclusionOur study shows that though generally considered a sporadic disease, the presence of hematologic and solid malignancies in the family history of AML patients is relatively high. One should keep in mind that cancer syndromes like hereditary breast cancer are associated with a higher incidence of leukemia. These data are relevant in the context of family donor search for allogeneic stem cell transplantation, genetic counseling and testing as well as cancer prevention

Ein schwerer Fall von Lipoidproteinose des Larynx mit Dysphonie und Dyspnoe

Hintergrund: Die Lipoidproteinose (Urbach-Wiethe-Syndrom) ist eine sehr seltene autosomal-rezessiv vererbte Haut- und Schleimhauterkrankung. Es zeigen sich proteinreiche Plaques in Haut- und Schleimhäuten, die vielfältige Symptome machen können, das Leitsymptom ist eine von Kindheit an bestehende Heiserkeit.Material und Methoden: Eine 46-jährige Patientin mit schwerer Heiserkeit und Atemnot bei Lipoidproteinose wird vorgestellt. Spiegelbefundlich zeigten sich weißliche höckrige Plaques im Bereich der Mundhöhle, des Oro- und Hypopharynx und Larynx.Ergebnisse: Die Resektion der larynxeinengenden Strukturen mittels CO2-Laser und Mikroinstrumenten ist Therapie der Wahl bei Dyspnoe, seit dem Eingriff vor 1,5 Jahren ist der Befund stabil, die Dysphonie besserte sich jedoch langfristig nicht.Diskussion: Bei derzeit fehlender ursächlicher Therapie ist die symptomatische Therapie der Erkrankung vorrangig. Diese beinhaltet ggf. Resektion von raumfordernden Lipoidproteinablagerungen, v.a. bei Dyspnoe, Schleimhautpflege und ggf. genetische Beratung und Untersuchung der Familie im Falle von Kinderwunsch.Fazit: Bei histologisch proteinreichen und makroskopisch sichtbaren Ablagerungen in der Schleimhaut des Oro-, Hypopharynx und Larynx mit Dysphonie und ggf. Dyspnoe muss an eine Lipoidproteinose gedacht werden. Diese wird dann mit einer ECM1-Gendiagnostik gesichert. Die Therapie erfolgt bisher ausschließlich symptomatisch