A Literature Review and a Proposed Classification of the Relationships between Ovulatory Infertility and Lifestyle Factors Based on the Three Groups of Ovulation Disorders Classified by WHO.

Ovulatory infertility is a serious clinical problem whose direct causes are still largely unknown. In addition to pathologies that make it impossible for a couple to establish a pregnancy, there are a number of other factors that have a bearing on fertility, including lifestyle factors, and particularly diet. Although numerous studies have been performed linking such factors to ovulatory infertility, most of them lack the necessary clinical significance, instead focusing on observational data and suggesting or establishing associative relationships. This article consists of a literature review focusing on connections between lifestyle factors such as diet, physical exercise, oxidative stress, sleep, and supplementation, and ovulatory infertility. Special emphasis was given to issues such as obesity and insulin resistance and their mutual relationship with other factors linked to ovulatory infertility. In addition, based on the conclusions of the literature review, the authors have proposed a classification of relationships between ovulation disorders and lifestyle factors in ovulatory infertility within the framework of the WHO classification of ovulation disorders. Furthermore, areas that merit further research have been indicated as well as those that do not. WHO Group II disorders gained prominence in the results of the study as the number of links with lifestyle factors and ovulatory infertility found in the course of the review greatly exceeded those for Groups I and III. The data presented in the article show that the issues of proper diet and physical exercise are those that could benefit from robust clinical studies focused specifically on ovulation infertility, while studies concerning the relationship between oxidative stress, sleep, and supplementation and ovulatory infertility do not seem to be promising directions as far as clinical significance is concerned.

Three-Dimensional Primary Cell Culture: A Novel Preclinical Model for Pancreatic Neuroendocrine Tumors.

Molecular mechanisms underlying the development and progression of pancreatic neuroendocrine tumors (PanNETs) are still insufficiently understood. Efficacy of currently approved PanNET therapies is limited. While novel treatment options are being developed, patient stratification permitting more personalized treatment selection in PanNET is yet not feasible since no predictive markers are established. The lack of representative in vitro and in vivo models as well as the rarity and heterogeneity of PanNET are prevailing reasons for this. In this study, we describe an in vitro 3-dimensional (3-D) human primary PanNET culture system as a novel preclinical model for more personalized therapy selection. We present a screening platform allowing multicenter sample collection and drug screening in 3-D cultures of human primary PanNET cells. We demonstrate that primary cells isolated from PanNET patients and cultured in vitro form islet-like tumoroids. Islet-like tumoroids retain a neuroendocrine phenotype and are viable for at least 2 weeks in culture with a high success rate (86%). Viability can be monitored continuously allowing for a per-well normalization. In a proof-of-concept study, islet-like tumoroids were screened with three clinically approved therapies for PanNET: sunitinib, everolimus and temozolomide. Islet-like tumoroids display varying in vitro response profiles to distinct therapeutic regimes. Treatment response of islet-like tumoroids differs also between patient samples. We believe that the presented human PanNET screening platform is suitable for personalized drug testing in a larger patient cohort, and a broader application will help in identifying novel markers predicting treatment response and in refining PanNET therapy.

Biomarkers for PVR in rhegmatogenous retinal detachment.

PURPOSE: Various profibrotic and proinflammatory cytokines have been found upregulated in uncomplicated primary retinal detachment (pRD), but without providing a uniform picture. Here, we compare the cyto- and chemokine profiles in pRD with and without proliferative vitreoretinopathy (PVR) in an attempt to unravel relevant differences not in single cytokines, but in the cytokine profiles at diagnosis. METHODS: Undiluted vitreous fluid (VF) was obtained at the beginning of surgery from 174 eyes with pRD without relevant PVR (maximally grade B; group 1; n = 81) and with moderate or advanced PVR requiring a gas tamponade (group 2; n = 49) or silicon oil filling (group 3; n = 44). VF of eyes undergoing macular hole (MH) surgery served as controls (group 4; n = 26). Forty-three cytokines were quantified in parallel using a multiplex cytokine analysis system (Bioplex). For all comparisons we applied Holm's correction to control for multiple comparisons. RESULTS: 44.9% of group 2 eyes presented grade C1 and 55.1% C2-C3, whereas 86.4% of group 3 eyes exhibited a PVR grade of C2-D. CCL19 was the only cytokine that displayed higher concentrations in the vitreous of eyes with PVR C1 compared to lower PVR grades. Eyes with PVR C2-D showed higher levels of CCL27, CXCL6, IL4, IL16, CXCL10, CCL8, CCL22, MIG/CXCL9, CCL15, CCL19, CCL 23 and CXCL12 compared to controls. Interestingly, no difference of cytokine levels was detected between C1 and C2-D PVR. CONCLUSIONS: CCL19 may represent a potential biomarker for early PVR progression that holds promise for future diagnostic and therapeutic applications.

Cytokine profiles of phakic and pseudophakic eyes with primary retinal detachment.

PURPOSE: To compare the cytokine profiles of phakic (p) and pseudophakic (ps) eyes with primary rhegmatogenous retinal detachment (RD) to eyes with macular holes (MH) and to identify differences in the specific cytokine profiles. METHODS: Aqueous humour (AH) and vitreous fluid (VF) were obtained from patients with primary RD without proliferative vitreoretinopathy undergoing vitrectomy. AH and VF of patients with macular holes (MH) served as controls. Forty-three different cytokines were quantified using multiplex cytokine analysis. Intergroup and intragroup comparisons were performed. To control for multiple comparisons, Holm's correction was applied. RESULTS: VF and AH samples of 71 eyes with RD (pRD N = 38; psRD N = 33) and 26 eyes with MH were included. Cytokine levels in psRD and pRD were similar (none with >10-fold difference). The levels of 39 of 43 cytokines in the VF were significantly higher in eyes with RD than in those with MH (>10-fold: CXLC5, CCL26, CCL1, IL-6, CXCL11, CCL7, CCL13, MIG/CXCL9, CCL19 and TGF-ß1). In the AH, 23 of 43 cytokines were significantly higher compared to MH (>10-fold: CXCL5, IL-4, IL-6, IL-8/CXCL8 and CCL7). CONCLUSION: A complex, but nonspecific cytokine environmental response seems to initiate immunological and profibrotic processes following RD. Relevant differences in the cytokine profiles of eyes with pRD and psRD were not identified, whereas cytokine differences between AH and VF in RD could be explained by upregulation in the vitreous, a higher turn around in the anterior chamber, or differences in inflammatory cascades in both compartments.

Comparison of cytokine profiles in the aqueous humor of eyes with pseudoexfoliation syndrome and glaucoma.

PURPOSE: To compare the cyto- and chemokine profiles in the aqueous humor of PEXS eyes in the absence or presence of secondary glaucoma with or without luxation of the intraocular lens (IOL). METHODS: Samples of aqueous humor were collected intraoperatively from 20 healthy controls and from 73 eyes with PEX-syndrome, which was manifested in the absence of any other local or systemic desease. The latter group was sub-devided into eyes with an early form of PEX-syndrome in the absence of complications (PEX, n = 33), those with a late form of PEX-syndrome and glaucoma (PEXG, n = 30), and those with a late form of PEX-syndrome with luxation of the IOL that required surgery (PEXL, n = 10). The samples were analyzed in parallel after storage at -80°C. The levels of 40 cytokines were simultaneously quantified using the Bio-Plex® multiplex beads system. The inter-group data were statistically compared using the Kruskal-Wallis test (p ≤ 0.01). RESULTS: PEX and PEXG were comparable in their cytokine profiles for all 40 cytokines, whereas the cytokine profile in PEXL-eyes revealed higher levels of all but 5 cytokines (CXCL13, CCL27, IL-2, CCL3, CCL20; p ≤ 0.01). This latter finding is indicative of a non-specific inflammatory reaction in the context of IOL-luxation. The concentrations of 6 cytokines lay below the detection limit in all groups. CONCLUSIONS: The local up-regulation of 85% of the detectable cytokines in the aqueous humor of PEXL-eyes may be linked either with a progression of the disease or a breakdown of the antero-posterior barrier in the context of IOL-luxation.