The interaction of sperm with the oocyte is pivotal during the process of mammalian fertilization. The limited numbers of sperm that reach the fallopian tube as well as anatomic restrictions indicate ...that human sperm–oocyte encounter is not a matter of chance but a directed process. Chemotaxis is the proposed mechanism for re-orientating sperm toward the source of a chemoattractant and hence to the oocyte. Chemokines represent a superfamily of small (8–11 kDa), cytokine-like proteins that have been shown to mediate chemotaxis and tissue-specific homing of leukocytes through binding to specific chemokine receptors such as CCRs. Here we show that CCR6 is abundantly expressed on human sperms and in human testes. Furthermore, radioligand-binding experiments showed that CCL20 bound human sperm in a specific manner. Conversely, granulosa cells of the oocyte-surrounding cumulus complex as well as human oocytes represent an abundant source of the CCR6-specific ligand CCL20. In human ovaries, CCL20 shows a cycle-dependent expression pattern with peak expression in the preovulatory phase and CCL20 protein induces chemotactic responses of human sperm. Neutralization of CCL20 in ovarian follicular fluid significantly impairs sperm migratory responses. Conversely, analyses in infertile men with inflammatory conditions of the reproductive organs demonstrate a significant increase of CCL20/CCR6 expression in testis and ejaculate. Taken together, findings of the present study suggest that CCR6-CCL20 interaction may represent an important factor in directing sperm–oocyte interaction. Graphical Abstract Summary Sentence The chemokine CCL20 is produced by human oocytes as well as surrounding cumulus granulosa cells and induces chemotaxis of CCR6+ sperm. Infertile male donors demonstrate increased levels of CCL20 in testis and seminal fluid, which may negatively influence sperm–oocyte interaction.
Currently available treatment options for onychomycosis such as topical and systemic antifungals are often of limited efficacy, difficult to administer or associated with relevant side effects. ...Non-ablative laser therapy is proposed to represent a safe alternative without the disadvantages of drugs. Yet, to date, the efficacy of laser therapy for onychomycosis is discussed controversially. Against this background, we performed a systematic retrospective analysis of our clinical experience of 4 years of onychomycosis treatment applying a long-pulsed 1.064-nm diode laser.
We retrospectively evaluated the records of 56 patients with microscopic and culturally proven onychomycosis affecting a toenail of the hallux and other toes, who had been treated with a long-pulsed 1.064-nm diode laser (FOX, A.C.R. Laser GmbH, Nuremberg) during the time period of July 2013-December 2016 with or without concomitant topical antifungals. Thereof, 27 patients received laser treatment and 29 patients received laser treatment in combination with local antifungals. We conducted a mean of 3.9 laser treatments at 2-6-week intervals. The primary endpoint of our analysis was clinical improvement; secondary endpoints were complete remission of fungal pathogens in fungal culture and in microscopy.
Clinical improvement was achieved in 56% of patients treated with laser only after a mean of 4.5 treatments and in 69% of patients treated with laser in combination with topical antifungals after a mean of 3.6 treatments. Cultural healing was detected in 63% of patients treated with laser only after a mean of 5.4 treatments, vs. 86% of patients treated with laser and concomitant topical antifungals after a mean of 4.8 treatments. Microscopic healing (complete healing) with the absence of fungal pathogens was achieved in 11% of patients after a mean of 4.7 treatments with laser only, vs. 21% of patients treated with laser and concomitant topical antifungals after a mean of 4 treatments. No relevant adverse effects were observed.
The 1.064-nm diode laser is an effective and safe option for the treatment of onychomycosis. Of note, the combination with topical antifungals will increase overall treatment efficacy and reduce the time to healing. Particularly, patients with contraindications against systemic antifungals may benefit from this multimodal therapeutic approach. Our data, moreover, suggest that treatment efficacy is positively correlated with the total number of laser treatments.
Chronic hard-to-heal wounds generate high costs and resource use in western health systems and are the focus of intense efforts to improve healing outcomes. Here, we introduce a novel native collagen ...(90 %):alginate (10 %) wound dressing and compare it with the established oxidised dressings Method: Matrices were analysed by atomic force microscopy (AMF), scanning electron microscopy (SEM), and immunoelectron microscopy for collagen types I, III and V. Viability assays were performed with NIH-3T3 fibroblasts. Matrix metalloproteinase (MMP) binding was analysed, and the effect of the wound dressings on platelet-derived growth factor B homodimer (PDGF-BB) was investigated.
Unlike oxidised regenerated cellulose (ORC)/collagen matrix and ovine forestomach matrix (OFM), the three-dimensional structure of the native collagen matrix (NCM) was found to be analogous to intact, native, dermal collagen. Fibroblasts seeded on the NCM showed exponential growth whereas in ORC/collagen matrix or OFM, very low rates of proliferation were observed after 7 days. MMP sequestration was effective and significant in the NCM. In addition, the NCM was able to significantly stabilise PDGF-BB in vitro.
We hypothesise that the observed microstructure of the NCM allows for an effective binding of MMPs and a stabilisation and protection of growth factors and also promotes the ingrowth of dermal fibroblasts, potentially supporting the re commencement of healing in previously recalcitrant wounds.
This work was supported by BSN Medical, Hamburg, Germany.
Hyaluronidase is a hyaluronic acid (HA) metabolizing enzyme, which is approved as an adjuvant for infiltration anesthesia. The "off-label" use of hyaluronidase is regarded as gold standard for the ...management of HA-filler-associated complications. Yet, up to date there are only few studies that have systematically assessed the degradability of different HA-fillers by hyaluronidase.
To analyze the interactions of HA-fillers and hyaluronidase in a time-dependent manner using a novel standardized in vitro approach.
Comparable HA-fillers, Belotero Balance Lidocaine (BEL; Merz), Emervel classic (EMV; Galderma) and Juvederm Ultra 3 (JUV; Allergan), were incubated with a fluorescent dye and bovine hyaluronidase (HYAL; Hylase "Dessau", Riemser) or control (NaCl) and monitored by time-lapse videomicroscopy. The degradation of HA-fillers was assessed as decrease in fluorescence intensity of HA-filler plus hyaluronidase vs. HA-filler plus control, quantified by computer-assisted image analysis (ImageJ).
Hyaluronidase showed a significant degradation of the HA-fillers BEL and EMV. Degradation was measurable at 5 h (BEL) and 7 h (EMV), respectively; significance was reached at 14 h (BEL) and 13 h (EMV). No effect of hyaluronidase was observed for JUV.
Time-lapse microscopy enables systematically, standardized, comparative in vitro analyses of the interactions of hyaluronidase and HA-fillers.
Insulin-like growth factor (IGF)-1, -2 and Insulin like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated, if the ...IGF-system can serve as a tumor marker in neoplasms.
In our prospective study 163 patients with colorectal cancer (22), prostate cancer (21), head and neck tumors (17), lymphomas (20), lung cancer (34) and other entities (49) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared to 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared.
The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected.
The IGF-system cannot serve as a new tumor marker. The detected differences are very small, sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.
Background
An earlier published series of neoadjuvant radiochemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. ...Long-term outcome data and predictive factors for pathologic complete response (pCR) were analyzed.
Patients and methods
During 1991–1998, 315 LABC patients (cT1-cT4/cN0-N1) were treated with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or—in case of breast conservation—a 10-Gy interstitial boost with
192
Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow-up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX, and the time interval between end of RT and surgery were examined in multivariate terms with pCR and overall survival as end point.
Results
The total pCR rate after neoadjuvant RT-CHX reached 29.2%, with LABC breast conservation becoming possible in 50.8% of cases. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1.17 95% CI 1.05–1.31, p < 0.01). However, in large tumors (T3–T4) a significantly reduced pCR rate (HR 0.89 95% CI 0.80–0.99, p = 0.03) was obtained. Importantly, pCR was the strongest prognostic factor for long-term survival (HR 0.28 95% CI 0.19–0.56, p < 0.001).
Conclusion
pCR identifies patients with a significantly better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of pCR after NRT-CHX.
Antiseptics are frequently used for the prophylaxis and treatment of local infections of chronic wounds. Whereas local antiseptics in general have a positive effect on wound healing an uncritical use ...may impair wound healing due to toxic side effects.
We sought to assess the vascular irritation potential of different antiseptic solutions and ointments commonly used for short and long term application as a measure of tissue toxicity.
The vascular irritation was evaluated by the hen's egg test (HET) on the chorioallantoic membrane (CAM). The effects on the vessels of a mucous membrane were directly assessed by stereomicroscopic observation in vivo.
Severe CAM irritation was observed after short-term applications of 1% octenidin-2HCl (Octenisept), 72% isopropanol (Cutasept), 0.35% chloroxylenol (Dettol) and 10% PVP-I ointment (Betaisodona). Medium irritations were observed for 10% PVP-I solution (Betaisodona), 3% lysosomal PVP-I ointment (Repithel), 1.8% cadexomer-iodine ointment (Iodosorb) and 1% cadexomer-iodine pellets (Iodosorb). Finally, slight irritations were observed for 1% PVP-I solution (Betaisodona), 0.1% polyhexanid plus betain (Prontosan) and 1% silver-sulfadiazine ointment (Flammazine), whereas 0.04% polyhexanid solution (Lavanid), washings from sterile maggots of Lucilia sericata and filtrated enzymes from Clostridium histolyticum (Iruxol-N) showed no effects of irritation. In the long-term approaches, no vascular irritations were found for polyhexanid, washings from Lucilia sericata and enzyme filtrations from Clostridium histolyticum.
The vascular injuries caused by the studied antiseptics are an indirect indicator of their tissue toxicity. Strikingly, even therapeutic substances, which have been regarded as safe in their application for the treatment of chronic wounds in clinical studies, showed severe irritations on the CAM. We suggest that agents with no or low irritation potential on the CAM should be preferred in the clinical practice in order to obtain optimal results.
Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting ...of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemo?radiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection.
Seasonsal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) as well as intermittent and persistent allergic rhinitis are widespread diseases. Because a combined occurrence of ...ocular and nasal symptoms is very common the summarising term allergic rhinoconjunctivitis is frequently used. SAC and PAC representing the two acute forms of allergic conjunctivitis account for more than 90% of all cases of allergic conjunctivitis. Compared to the chronic forms of allergic conjunctivitis their course of disease is milder. Nevertheless because of their high prevalence and the proven influence on patients' quality of life they possess clinical and socioeconomic relevance. Allergic rhinoconjunctivitis is caused by a type 1 IgE-mediated hypersensitivitity reaction that is provoked by aeroallergens in the majority of cases. The pathognomonic sign is itching. Besides, typical ocular findings are chemosis, conjunctival injection,watery secretion and lid swelling. Otorhinolaryngologists' findings include rhinorrhea, postnasal drip and sneezing. Problems in breathing through the nose resulting from nasal obstruction can cause impaired nighttime sleep and daytime somnolence. In addition to a reduction of allergen exposure by modification of environment and life style factors, in mild forms of SAC and PAC artificial tears are recommended. Topical antihistamines can generate rapid relief from acute symptoms and itching. Topical mast cell stabilisers however provide long-term effects. Dual action drugs that combine antihistamines and mast cell stabilisers show increased patient compliance due to reduced application frequency. Use of topical steroids should be cautious and only temporary. For prolonged treatment periods unpreserved anti-allergic eye-drops should be preferred. Combined topical antihistamines and new-generation topical nasal steroids often used by otorhinolaryngologists demonstrate a good safety profile without systemic side effects. In summary, allergic rhinoconjunctivitis represents a common disease pattern that can be treated effectively. Once it is diagnosed correctly targeted treatment results in improved patients' quality of life quickly.
Abstract Background Recent studies provided insights into the recruitment and activation pathways of leukocytes in atopic dermatitis, however, the underlying mechanisms of tissue remodeling in atopic ...skin inflammation remain elusive. Objective To identify chemokine-mediated communication pathways regulating tissue remodeling during atopic skin inflammation. Methods Analysis of the chemokine receptor repertoire of human dermal fibroblasts using flow cytometry and immunofluorescence. Quantitative real-time polymerase chain reaction and immunohistochemical analyses of chemokine expression in atopic vs. non-atopic skin inflammation. Investigation of the function of chemokine receptor CCR3 on human dermal fibroblasts through determining intracellular Ca2+ mobilization, cell proliferation, migration, and repair capacity. Results Analyses on human dermal fibroblasts showed abundant expression of the chemokine receptor CCR3 in vitro and in vivo . Among its corresponding ligands (CCL5, CCL8, CCL11, CCL24 and CCL26) CCL26 demonstrated a significant and specific up-regulation in atopic when compared to psoriatic skin inflammation. In vivo , epidermal keratinocytes showed most abundant CCL26 protein expression in lesional atopic skin. In structural cells of the skin, TH 2-cytokines such as IL-4 and IL-13 were dominant inducers of CCL26 expression. In dermal fibroblasts, CCL26 induced CCR3 signaling resulting in intracellular Ca2+ mobilization, as well as enhanced fibroblast migration and repair capacity, but no proliferation. Conclusion Taken together, findings of the present study suggest that chemokine-driven communication pathways from the epidermis to the dermis may modulate tissue remodeling in atopic skin inflammation.
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