Frailty as a predictor of postoperative outcomes in neurosurgery: a systematic review.

INTRODUCTION: Baseline frailty status has been utilized to predict a wide range of outcomes and guide preoperative decision making in neurosurgery. This systematic review aims to analyze existing literature on the utilization of frailty as a predictor of neurosurgical outcomes. EVIDENCE ACQUISITION: We conducted a systematic review following PRISMA guidelines. Studies that utilized baseline frailty status to predict outcomes after a neurosurgical intervention were included in this systematic review. Studies that utilized sarcopenia as the sole measure of frailty were excluded. PubMed, EMBASE, and Cochrane library was searched from inception to March 1st, 2023, to identify relevant articles. EVIDENCE SYNTHESIS: Overall, 244 studies met the inclusion criteria. The 11-factor modified frailty index (mFI-11) was the most utilized frailty measure (N.=91, 37.2%) followed by the five-factor modified Frailty Index (mFI-5) (N.=80, 32.7%). Spine surgery was the most common subspecialty (N.=131, 53.7%), followed by intracranial tumor resection (N.=57, 23.3%), and post-operative complications were the most reported outcome (N.=130, 53.2%) in neurosurgical frailty studies. The USA and the Bowers author group published the greatest number of articles within the study period (N.=176, 72.1% and N.=37, 15.2%, respectively). CONCLUSIONS: Frailty literature has grown exponentially over the years and has been incorporated into neurosurgical decision making. Although a wide range of frailty indices exist, their utility may vary according to their ability to be incorporated in the outpatient clinical setting.

Transmigration of macrophages through primary adult rat Sertoli cells.

The blood testis barrier (BTB) is often studied with isolated immature Sertoli cells (SCs), transepithelial resistance (TER) measurements and FITC dextran diffusion assays. Recently, it was found that even in the absence of SCs, only few immune cells enter the seminiferous tubules. Thus, in this study, we evaluated the testicular immunological barrier (TIB) in vitro by transmigration of macrophages through SCs with and without peritubular cells (PCs) and with or without matrigel (MG). Primary PCs were isolated from adult rat testis and kept in mono- or co-cultures with the conditionally reprogrammed primary adult Sertoli cell line (PASC1) from rat that has been recently generated by our group. Rat monocytes isolated from fresh blood were differentiated into M0 macrophages, and after polarization to M1 or M2 macrophages characterized by gene expression of CXCL11 and TNF-α for M1, or CCL17 and CCL22 for M2. Transmigration of LeukoTracker-labeled M0, M1, and M2 macrophages through mono- and co-cultures of PCs/SCs with and without MG demonstrated that SCs are the main constituent of the TIB in vitro with only a negligible contribution of PCs or MG. Moreover, M2 macrophages showed less migration activity compared to M0 or M1. Treatment of SCs with testosterone (T) showed positive effects on the barrier in contrast to negative effects by interleukin-6 (IL-6) or tumor necrosis factor-α (TNF-α). The new transmigration model is suitable to evaluate transmigration of macrophages through a barrier consisting of testicular cells and can be applied to study the integrity of testicular barriers with respect to immunological aspects.

Analysis of Membrane Type-1 Matrix Metalloproteinase (MT1-MMP, MMP14) in Eutopic and Ectopic Endometrium and in Serum and Endocervical Mucus of Endometriosis.

BACKGROUND: Membrane type-matrix metalloproteinases (MT-MMPs) are a subgroup of the matrix metalloproteinases (MMPs) family and are key molecules in the degradation of the extracellular matrix. Membrane type-1 matrix metalloproteinase (MT1-MMP, MMP14) is often deregulated in different cancer tissues and body fluids of human cancer patients; however, MT1-MMP levels in endometriosis and adenomyosis patients are currently unknown. MATERIALS AND METHODS: Tissue samples from patients with and without endometriosis or adenomyosis were analyzed with immunohistochemistry for the localization of MT1-MMP. Serum and endocervical mucus samples from patients with and without endometriosis or adenomyosis were investigated with MT1-MMP ELISAs. RESULTS: MT1-MMP was localized preferentially in the glands of eutopic and ectopic endometrium. MT1-MMP protein levels are significantly reduced in ovarian endometriosis (HSCORE = 31) versus eutopic endometrium (HSCORE = 91) and adenomyosis (HSCORE = 149), but significantly increased in adenomyosis (HSCORE = 149) compared to eutopic endometrium (HSCORE = 91). Similarly, analysis of the levels of MT1-MMP using enzyme-linked immune assays (ELISAs) demonstrated a significant increase in the concentrations of MT1-MMP in the serum of endometriosis patients (1.3 ± 0.8) versus controls (0.7 ± 0.2), but not in the endocervical mucus. Furthermore, MT1-MMP levels in the endocervical mucus of patients with endometriosis were notably reduced in patients using contraception (3.2 ± 0.4) versus those without contraception (3.8 ± 0.2). CONCLUSIONS: Taken together, our findings showed an opposite regulation of MT1-MMP in the tissue of ovarian endometriosis and adenomyosis compared to eutopic endometrium without endometriosis but increased serum levels in patients with endometriosis.

Predictive Model for the Non-Invasive Diagnosis of Endometriosis Based on Clinical Parameters.

OBJECTIVES: Are other pain symptoms in addition to dysmenorrhea, dyspareunia, dyschezia, dysuria, and chronic pelvic pain correlated to endometriosis and suitable for a clinical prediction model? METHODS: We conducted a prospective study from 2016 to 2022, including a total of 269 women with numerous pain symptoms and other parameters. All women filled out two questionnaires and were examined by palpation and transvaginal ultrasound (TVUS). In cases of suspected deep endometriosis, magnetic resonance imaging (MRI) was performed. After the operation, endometriosis was diagnosed by histological examination. RESULTS: All in all, 30 significant parameters and 6 significant numeric rating scale (NRS) scores associated with endometriosis could be identified: 7 pain adjectives, 8 endometriosis-associated pain symptoms, 5 pain localizations, 6 parameters from the PainDETECT, consumption of analgesics, and allergies. Furthermore, longer pain duration (before, during, and after menstruation) was observed in women with endometriosis compared to women without endometriosis (34.0% vs. 12.3%, respectively). Although no specific pain for endometriosis could be identified for all women, a subgroup with endometriosis reported radiating pain to the thighs/legs in contrast to a lower number of women without endometriosis (33.9% vs. 15.2%, respectively). Furthermore, a subgroup of women with endometriosis suffered from dysuria compared to patients without endometriosis (32.2% vs. 4.3%, respectively). Remarkably, the numbers of significant parameters were significantly higher in women with endometriosis compared to women without endometriosis (14.10 ± 4.2 vs. 7.75 ± 5.8, respectively). A decision tree was developed, resulting in 0.904 sensitivity, 0.750 specificity, 0.874 positive predictive values (PPV), 0.802 negative predictive values (NPV), 28.235 odds ratio (OR), and 4.423 relative risks (RR). The PPV of 0.874 is comparable to the positive prediction of endometriosis by the clinicians of 0.86 (177/205). CONCLUSIONS: The presented predictive model will enable a non-invasive diagnosis of endometriosis and can also be used by both patients and clinicians for surveillance of the disease before and after surgery. In cases of positivety, as evaluated by the questionnaire, patients can then seek advice again. Similarly, patients without an operation but with medical therapy can be monitored with the questionnaire.

Larval midgut modifications associated with Bti resistance in the yellow fever mosquito using proteomic and transcriptomic approaches.

BACKGROUND: Bacillus thuringiensis var. israelensis (Bti) is a natural larval mosquito pathogen producing pore-forming toxins targeting the midgut of Diptera larvae. It is used worldwide for mosquito control. Resistance mechanisms of an Aedes aegypti laboratory strain selected for 30 generations with field-collected leaf litter containing Bti toxins were investigated in larval midguts at two levels: 1. gene transcription using DNA microarray and RT-qPCR and 2. differential expression of brush border membrane proteins using DIGE (Differential In Gel Electrophoresis). RESULTS: Several Bti Cry toxin receptors including alkaline phosphatases and N-aminopeptidases and toxin-binding V-ATPases exhibited altered expression levels in the resistant strain. The under-expression of putative Bti-receptors is consistent with Bt-resistance mechanisms previously described in Lepidoptera. Four soluble metalloproteinases were found under-transcribed together with a drastic decrease of metalloproteinases activity in the resistant strain, suggesting a role in resistance by decreasing the amount of activated Cry toxins in the larval midgut. CONCLUSIONS: By combining transcriptomic and proteomic approaches, we detected expression changes at nearly each step of the ingestion-to-infection process, providing a short list of genes and proteins potentially involved in Bti-resistance whose implication needs to be validated. Collectively, these results open the way to further functional analyses to better characterize Bti-resistance mechanisms in mosquitoes.

Claudin-10 Expression Is Increased in Endometriosis and Adenomyosis and Mislocalized in Ectopic Endometriosis.

Claudins, as the major components of tight junctions, are crucial for epithelial cell-to-cell contacts. Recently, we showed that in endometriosis, the endometrial epithelial phenotype is highly conserved, with only minor alterations. For example, claudin-11 is strongly expressed; however, its localization in the endometriotic epithelial cells was impaired. In order to better understand the role of claudins in endometrial cell-to-cell contacts, we analyzed the tissue expression and localization of claudin-10 by immunohistochemistry analysis and two scoring systems. We used human tissue samples (n = 151) from the endometrium, endometriosis, and adenomyosis. We found a high abundance of claudin-10 in nearly all the endometrial (98%), endometriotic (98−99%), and adenomyotic (90−97%) glands, but no cycle-specific differences and no differences in the claudin-10 positive endometrial glands between cases with and without endometriosis. A significantly higher expression of claudin-10 was evident in the ectopic endometrium of deep-infiltrating (p < 0.01) and ovarian endometriosis (p < 0.001) and in adenomyosis in the cases with endometriosis (p ≤ 0.05). Interestingly, we observed a shift in claudin-10 from a predominant apical localization in the eutopic endometrium to a more pronounced basal/cytoplasmic localization in the ectopic endometria of all three endometriotic entities but not in adenomyosis. Significantly, despite the impaired endometriotic localization of claudin-10, the epithelial phenotype was retained. The significant differences in claudin-10 localization between the three endometriotic entities and adenomyosis, in conjunction with endometriosis, suggest that most of the aberrations occur after implantation and not before. The high similarity between the claudin-10 patterns in the eutopic endometrial and adenomyotic glands supports our recent conclusions that the endometrium is the main source of endometriosis and adenomyosis.

Role of Betaglycan in TGF-ß Signaling and Wound Healing in Human Endometriotic Epithelial Cells and in Endometriosis.

Endometriosis is characterized by the presence of ectopic endometrium most often in the pelvis. The transforming growth factor-beta (TGF-ß) superfamily is also involved in the pathogenesis; however, betaglycan (BG, syn. TGF-ß type III receptor) as an important co-receptor was not studied. We analyzed mainly BG ectodomain shedding because released soluble BG (sBG) often antagonizes TGF-ß signaling. Furthermore, we studied the role of TGF-ßs and BG in wound healing and evaluated the suitability of BG measurements in serum and endocervical mucus for non-invasive diagnosis of endometriosis. Evaluation of the BG shedding and signaling pathways involved as well as wound healing was performed with enzyme-linked immune assays (ELISAs), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), small interfering RNA (siRNA) knockdown, and scratch assays with human endometriotic epithelial cells. TGF-ß1/2 stimulation resulted in a significant dose-dependent reduction in BG shedding in endometriotic cells, which was TGF-ß/activin receptor-like kinase-5 (ALK-5)/mother against decapentaplegic homolog3 (SMAD3)- but not SMAD2-dependent. Inhibition of matrix metalloproteinases (MMPs) using the pan-MMP inhibitor GM6001 and tissue inhibitor of MMPs (TIMP3) equally attenuated BG shedding, signifying the involvement of MMPs in shedding. Likewise, recombinant BG moderately reduced the secretion of TGF-ß1/2 and wound healing of endometriotic cells. TGF-ß1 significantly enhanced the secretion of MMP2 and MMP3 and moderately promoted wound healing. In order to evaluate the role of BG in endometriosis, serum (n = 238) and mucus samples (n = 182) were analyzed. Intriguingly, a significant reduction in the levels of sBG in endocervical mucus but not in the serum of endometriosis patients compared to controls was observed. Collectively, these observations support a novel role for BG in the pathophysiology of endometriosis.

Impaired Expression of Membrane Type-2 and Type-3 Matrix Metalloproteinases in Endometriosis but Not in Adenomyosis.

Matrix metalloproteinases (MMPs) play an important role in menstruation and endometriosis; however, the membrane-type matrix metalloproteinases (MT-MMPs) are not well studied in endometriosis and adenomyosis. We analyzed MT2-MMP (MMP15) and MT3-MMP (MMP16) in eutopic endometrium with and without endometriosis and with and without adenomyosis and ectopic endometrium of deep infiltrating endometriosis (DIE), peritoneal endometriosis (PE), and ovarian endometriosis (Ov) by immunohistochemistry. Preferential expression of both proteins was observed in the glandular and luminal epithelial cells of the eutopic endometrium of patients with and without endometriosis with a ~2.5-fold stronger expression of MT3-MMP compared to MT2-MMP. We did not observe any differences during menstrual cycling and in eutopic endometrium of patients with and without endometriosis. Similarly, eutopic endometrium and adenomyotic tissue with and without endometriosis showed similar protein levels of MT2-MMP and MT3-MMP. In contrast, MT2-MMP and MT3-MMP protein was decreased in ectopic compared to eutopic endometrium and adenomyosis. The similar expression of MT2-MMP and MT3-MMP in eutopic endometrium in patients with and without endometriosis in contrast to the impaired expression in ectopic endometrium suggests that alterations occur after and not before endometrial implantation possibly by distinct interactions with the different environments. The differential protein expression of MT2/3-MMP in adenomyosis compared to endometriosis might suggest a different pathogenesis pathway for the two diseases.

Activin A Modulates Betaglycan Shedding via the ALK4-SMAD3-Dependent Pathway in Endometriotic Cells.

The TGF-ß superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in endometriosis. Herein, we investigated the modulation of the TGF-ß type III receptor (betaglycan or BG) by activin A and inhibin A in endometriosis in vitro. Often, BG undergoes ectodomain shedding releasing soluble BG (sBG) which frequently antagonizes TGF-ß signaling. The effects of activin A on BG shedding and signaling pathways involved were evaluated with the inhibitors LY364947 and SIS3, siRNA knockdown in human endometrial cells (12Z, THESC, Ishikawa, and primary stromal cells) and were quantified with BG ELISAs. The effects of activin A and inhibin A on the secretion of MMP2 and MMP3 were analyzed using ELISAs. The effects of activin A on the BG expression were analyzed using RT-qPCR and western blot. The CCK-8 and BrdU assays were used to evaluate the effects of the recombinant BG on cell viability and proliferation. Activin A stimulation resulted in a significant time- and dose-dependent reduction in BG shedding, which was found to be activin A/ALK-4/SMAD3- but not SMAD2-dependent. Activin A increased the BG mRNA expression but had no effect on the protein expression. Likewise, inhibin A was found to block BG shedding. Activin A, but not inhibin A, significantly enhanced the secretion of MMP2 and MMP3. The recombinant BG had no effect on the viability and proliferation of endometriotic cells. Together, these observations support a novel role for activin A with BG in modulating the TGF-ß superfamily ligands in endometrial cells in vitro.

Long-Term Maintenance of Viable Adult Rat Sertoli Cells Able to Establish Testis Barrier Components and Function in Response to Androgens.

A protocol for the isolation and long-term propagation of adult rat Sertoli cells (SCs) using conditional reprogramming (CR) was developed and the formation of tight junctions as an in vitro model for the blood testis barrier (BTB) was studied. Three pure primary SC lines were isolated successfully and maintained for several months without significant changes in expression levels of SC-typical markers such as SRY-box transcription factor 9 (SOX9), transferrin, clusterin, androgen receptor (AR), and GATA binding protein 1 (GATA1). In addition to AR expression, the tight junction proteins, zonula occludens-1 (ZO-1) and the junctional adhesion molecule-3 (JAM-3), were upregulated and the SC barrier integrity was enhanced by testosterone. Peritubular/myoid cells did not increase the tightness of the SC. The cytokines, interleukin-6 (IL-6), bone morphogenetic protein-2 (BMP2), and transforming growth factor beta-3 (TGF-ß3), negatively affected the tightness of the SC barrier. We have established a protocol for the isolation and long-term propagation of highly pure primary adult rat SCs, which are able to respond to androgen treatments, to form tight junctions and to maintain the mRNA expression of SC-specific genes. By applying this new method, adult SCs can now be analyzed in more detail and might serve as an in vitro model for the study of many SC functions.

The Importance of Stromal Endometriosis in Thoracic Endometriosis.

Thoracic endometriosis (TE) is a rare type of endometriosis, where endometrial tissue is found in or around the lungs and is frequent among extra-pelvic endometriosis patients. Catamenial pneumothorax (CP) is the most common form of TE and is characterized by recurrent lung collapses around menstruation. In addition to histology, immunohistochemical evaluation of endometrial implants is used more frequently. In this review, we compared immunohistochemical (CPE) with histological (CPH) characterizations of TE/CP and reevaluated arguments in favor of the implantation theory of Sampson. A summary since the first immunohistochemical description in 1998 until 2019 is provided. The emphasis was on classification of endometrial implants into glands, stroma, and both together. The most remarkable finding is the very high percentage of stromal endometriosis of 52.7% (CPE) compared to 10.2% (CPH). Chest pain, dyspnea, right-sided preference, and diaphragmatic endometrial implants showed the highest percentages in both groups. No significant association was found between the recurrence rate and the various appearances of endometriosis. Sometimes in CPE (6.8%) and CPH (30.6%) no endometrial implants were identified underlining the importance of sensitive detection of endometriosis during and after surgery. We suggest that immunohistochemical evaluation should become mandatory and will improve diagnosis and classification of the disease.

Epithelial-Mesenchymal Transition in Endometriosis-When Does It Happen?

Epithelial-mesenchymal transition (EMT) is an important process of cell remodeling characterized by the gradual loss of the epithelial phenotype and progressive gain of a mesenchymal phenotype. EMT is not an all-or-nothing process, but instead a transition of epithelial to mesenchymal cells with intermediate cell states. Recently, EMT was described in endometriosis, and many EMT-specific pathways like Twist, Snail, Slug, Zinc finger E-box-binding homeobox 1/2 (ZEB1/2), E/N-cadherin, keratins, and claudins are involved. However, as pointed out in this review, a comparison of the eutopic endometrium of women with and without endometriosis yielded only subtle changes of these EMT markers. Furthermore, only very few alterations in cell-cell contacts could be found but without changes in the epithelial phenotype. This suggests only a partial EMT which is not a prerequisite for the detachment of endometrial cells and, thus, not critical for the first step(s) in the pathogenesis of endometriosis. In contrast, the majority of changes in the EMT-related marker expression were found in the ectopic endometrium, especially in the three endometriotic entities, ovarian, peritoneal, and deep infiltrating endometriosis (DIE), compared with the eutopic endometrium. In this review, we examine the most important EMT pathways described in endometriosis and propose that partial EMT might result from the interaction of endometrial implants with their surrounding microenvironment.