Frank Siebenhaar

p53 Involvement in the Control of Murine Hair Follicle Regression

p53 is a transcription factor mediating a variety of biological responses including apoptotic cell death. p53 was recently shown to control apoptosis in the hair follicle induced by ionizing radiation and chemotherapy, but its role in the apoptosis-driven physiological hair follicle regression (catagen) remains to be elucidated. Here, we show that p53 protein is strongly expressed and co-localized with apoptotic markers in the regressing hair follicle compartments during catagen. In contrast to wild-type mice, p53 knockout mice show significant retardation of catagen accompanied by significant decrease in the number of apoptotic cells in the hair matrix. Furthermore, p53 null hair follicles are characterized by alterations in the expression of markers that are encoded by p53 target genes and are implicated in the control of catagen (Bax, Bcl-2, insulin-like growth factor binding protein-3). These data suggest that p53 is involved in the control of apoptosis in the hair follicle during physiological regression and imply that p53 antagonists may be useful for the management of hair growth disorders characterized by premature entry into catagen, such as androgenetic alopecia, alopecia areata, and telogen effluvium.

Noggin overexpression inhibits eyelid opening by altering epidermal apoptosis and differentiation

Contact of developing sensory organs with the external environment is established via the formation of openings in the skin. During eye development, eyelids first grow, fuse and finally reopen, thus providing access for visual information to the retina. Here, we show that eyelid opening is strongly inhibited in transgenic mice overexpressing the bone morphogenetic protein (BMP) antagonist noggin from the keratin 5 (K5) promoter in the epidermis. In wild‐type mice, enhanced expression of the kinase‐inactive form of BMPR‐IB mediated by an adenovirus vector also inhibits eyelid opening. Noggin overexpression leads to reduction of apoptosis and retardation of cell differentiation in the eyelid epithelium, which is associated with downregulation of expression of the apoptotic receptors (Fas, p55 kDa TNFR), Id3 protein and keratinocyte differentiation markers (loricrin, involucrin). BMP‐4, but not EGF or TGF‐α, accelerates opening of the eyelid explants isolated from K5‐Noggin transgenic mice when cultured ex vivo. These data suggest that the BMP signaling pathway plays an important role in regulation of genetic programs of eyelid opening and skin remodeling during the final steps of eye morphogenesis.

High Prevalence of Mental Disorders and Emotional Distress in Patients with Chronic Spontaneous Urticaria.

Quality of life, which is impaired in patients with chronic spontaneous urticaria (CSU), is influenced by comorbid mental disorders. The aim of this study was to assess the prevalence and spectrum of mental disorders and to determine levels of emotional distress in patients with CSU. One hundred patients with CSU were investigated for mental disorders (by specialized diagnostic interviews and psychometric instruments), levels of emotional distress (by the Global Severity Index of the Symptom Check List; SCL-90R GSI) and underlying causes of their urticaria (by dermatological assessment). Forty-eight percent of patients with CSU were diagnosed with one or more psychosomatic disorders; most common were anxiety disorders (especially phobias), followed by depressive and somatoform disorders. The use of psychometric instruments confirmed these findings. Levels of emotional distress were significantly higher and more commonly increased in patients with CSU with mental disorders. In conclusion, patients with CSU frequently experience anxiety, depression, and somatoform disorders, and these disorders are linked to increased emotional distress. These findings call for screening of patients with CSU for mental disorders in routine clinical practice as well as for controlled clinical trials.

Fas Signaling Is Involved in the Control of Hair Follicle Response to Chemotherapy

Chemotherapeutic agents induce p53-dependent apoptosis in the hair follicle (HF) resulting in hair loss, a common side effect of cancer therapy. Here, we show that Fas as a p53 target plays important role in the HF response to cyclophosphamide. Specifically, we demonstrate that Fas is up-regulated in HF keratinocytes after cyclophosphamide treatment, Fas ligand–neutralizing antibody partially inhibits HF response to cyclophosphamide in wild-type mice, and Fas knockout mice show significant retardation of cyclophosphamide-induced HF involution associated with reduced Fas-associated death domain and caspase-8 expression. These data raise a possibility to explore blockade of Fas signaling as a part of complex local therapy for inhibiting keratinocyte apoptosis and hair loss induced by chemotherapy.

Cardioprotective C-kit⁺ bone marrow cells attenuate apoptosis after acute myocardial infarction in mice - in-vivo assessment with fluorescence molecular imaging.

Cardiomyocyte loss via apoptosis plays a crucial role in ventricular remodeling following myocardial infarction (MI). Cell-based therapy approaches using bone marrow derived c-kit+ pluripotent cells may attenuate apoptosis following ischemic injury. We therefore thought to examine the early course of apoptosis following myocardial infarction - in-vivo - and non-invasively determine the effect of c-kit+ bone marrow cells on post-MI remodeling. We studied apoptosis in wild-type Kit+/+, c-kit mutant KitW/KitW-v and KitW/KitW-v mice after cell therapy with bone-marrow derived c-kit+ cells after ischemia-reperfusion injury. Mice were followed by hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography (FMT-XCT) at 6h, 24h and 7 days after ischemia-reperfusion injury using an Annexin V-based fluorescent nanosensor targeting phosphatidylserine. KitW/KitW-v mice showed increased and prolonged apoptosis compared to control Kit+/+ mice while c-kit cell therapy was able to attenuate the altered apoptosis rates. Increased apoptosis was accompanied by severe decline in heart function, determined by cardiac Magnetic Resonance Imaging, and cell therapy was able to rescue the animals from deleterious heart failure. Post-mortem cryoslicing and immunohistochemistry localized the fluorescence signal of the Annexin V sensor within the infarcted myocardium. Flow cytometry of digested infarct specimens identified apoptotic cardiomyocytes as the major source for the in-vivo Annexin V signal. In-vivo molecular imaging using hybrid FMT-XCT reveals increased cardiomyocyte apoptosis in KitW/KitW-v mice and shows that c-kit+ cardioprotective cells are able to attenuate post-MI apoptosis and rescue mice from progressive heart failure.

Chronic urticaria - What does the new guideline tell us?: CME Article

Patients with chronic urticaria experience significant impairment, and require an effective treatment. Such treatment is preceded by a thorough diagnostic workup and measurement of disease activity, disease burden and disease control using well‐established tools. Treatment is subsequently adjusted according to patient needs and therapeutic response, based on the tenet “as much as necessary, as little as possible” (in that order). Once disease control has been achieved, it is recommended that intermittent attempts at medication withdrawal be made in order to identify spontaneous disease remission. Chronic urticaria should be treated until spontaneous remission occurs.

Chronische Urtikaria - Was bringt die neue Leitlinie?: CME Article

Patienten mit chronischer Urtikaria sind durch ihre Erkrankung erheblich beeinträchtigt und bedürfen einer wirksamen Therapie. Dies wird durch ein gründliches diagnostisches Vorgehen vorbereitet und erfolgt nach und unter der Bestimmung der Krankheitsaktivität, ‐last und ‐kontrolle mit etablierten Instrumenten. Die Therapie wird im Verlauf den Bedürfnissen des Patienten und dem Ansprechen angepasst – so viel wie nötig, so wenig wie möglich – in dieser Reihenfolge. Bei erreichter Therapiekontrolle empfehlen sich Auslassversuche, um eine Spontanremission zu erkennen. Eine chronische Urtikaria sollte so lange behandelt werden bis Spontanremission auftritt.