The role of IL-19, IL-24, IL-21 and IL-33 in intestinal mucosa of inflammatory bowel disease: A narrative review.

Interleukins are potential therapeutic targets that can alter the prognosis and progression of inflammatory bowel disease (IBD). The roles of IL-6, IL-10, IL-17, and IL-23 have been extensively studied, setting the stage for the development of novel treatments for patients with IBD. Other cytokines have been less extensively studied. Members of the IL-20 family, mainly IL-19 and IL-24, are involved in the pathogenesis of IBD, but their exact role remains unclear. Similarly, IL-33, a newly identified cytokine, has been shown to control the Th1 effector response and the action of colonic Tregs in animal models of colitis and patients with IBD. IL-21 is involved in the Th1, Th2, and Th17 responses. Data support a promising future use of these interleukins as biomarkers of severe diseases and as potential therapeutic targets for novel monoclonal antibodies. This review aims to summarize the existing studies involving animal models of colitis and patients with IBD to clarify their role in the intestinal mucosa.

Expression of IL-21 and IL-33 in Intestinal Mucosa of Inflammatory Bowel Disease: An Immunohistochemical Study.

Interleukins are considered to be potential therapeutic targets that can alter the prognosis and disease progression of IBD. IL-21 has proven to be involved in effector Th1, Th2 and Th17 responses. Similarly, IL-33, a newly identified cytokine, has been shown to control the Th1 effector response and the action of the colonic Tregs in animal models of colitis and patients with IBD. In this retrospective study, we have studied the expression of these interleukins, using immunohistochemistry, in 121 patients with moderate to severe IBD before and after treatment with biologics. The results were statistically processed using SPSSTM. Increased IL-21 expression was found in the UC and CD groups versus the controls. The IL-33 expression was found to be increased in the post-treatment UC and CD groups, suggesting a protective role of this interleukin against bowel inflammation. The IL-33 expression post-treatment was reversely correlated with the activity index score in CD patients, suggesting a better response to treatment in patients with higher IL-33 mucosa levels. This is the first immunohistochemical study of the expression of those interleukins in bowel mucosa before and after treatment with biologics. These data support a possibly promising future use of these interleukins as biomarkers of severe disease and response to treatment and as potential therapeutic targets for novel monoclonal antibodies.

Sporadic parathyroid adenoma: an updated review of molecular genetics.

Introduction: Primary HPT (PHPT) is a common disorder, affecting approximately 1% of the general population. Parathyroid adenomas emerge as non-familial sporadic in 90% of cases. The aim of this review is to give a detailed update of molecular genetics of sporadic parathyroid adenoma reported in international literature. Methods: A bibliographic research was conducted in PubMed, Google Scholar, and Scopus. Results: Seventy-eight articles were included in our review. CaSR, MEN1, CCND1/PRAD, CDKI, angiogenic factors like VEGF, FGF, TGFß, and IGF1, and apoptotic factors are important genes in parathyroid adenomas pathogenesis that have been established by several studies. A huge list of proteins is differently expressed in parathyroid adenomas measured by Western Blotting, MALDI/TOF, MS spectrometry, and immunohistochemistry. These proteins take part in several cell processes such as cell metabolism, cytoskeleton structural stability, cell oxidative stress regulation, cell death, transcription, translation, cell connection, and cell signaling transmission, while they can be found over- or underexpressed in abnormal tissues. Conclusion: This review gives a detailed analysis of all reported data on genomics and proteomics of parathyroid adenoma. Further studies should be applied on understanding parathyroid adenoma pathogenesis and introducing new biomarkers for early detection of primary hyperparathyroidism.

Double ipsilateral parathyroid adenomas, with one supernumerary and ectopic at the same time: a case report.

BACKGROUND: Double adenomas (DA) represents a distinct clinical entity of primary hyperparathyroidism (PHPT). DA may follow various embryologic distribution patterns and could be supernumerary and/or ectopic. CASE PRESENTATION: We describe the first case of PHPT which comes as a result of double ipsilateral adenoma, of which one was both ectopic and supernumerary. A 45 year-old Greek male patient with diagnosed PHPT due to a single lower right parathyroid adenoma was admitted to our department for surgical treatment. The preoperative tests (neck US, Sestamibi scan) were conclusive for single gland disease. The patient underwent focused parathyroidectomy. The frozen section revealed a parathyroid adenoma with a slight possibility for parathyroid carcinoma. Ten minutes after the excision, intact PTH (iPTH) dropped >50% related to preoperative values and was within normal range. Right hemithyroidectomy with additional ipsilateral central neck dissection was performed, because of the possibility for parathyroid carcinoma. The final pathology report showed that the first excised tissue proved to be a parathyroid adenoma, while a second subcapsular one and a normal right upper parathyroid gland were also found. CONCLUSIONS: Preoperative localization of DA using routine imaging tests and the utility of intraoperative parathyroid hormone assay are still unreliable in detecting multiple adenomas. Furthermore, a slight possibility of a second and simultaneously supernumerary and ectopic adenoma maybe present. Therefore, it would be advisable to establish the use of more advanced imaging tests (such as 4D-CT, 4D-MRI) or other diagnostic tools when DA are suspected.

Unexplained infertility patients present the mostly impaired levels of progesterone receptors: Prospective observational study.

PROBLEM: Τo assess the endometrial expression of progesterone receptors in various subgroups of infertile women during implantation window. ΜETHODS: A prospective observational study was performed during March 2013-February 2017. Infertile women were categorized to those with tubal factor, ovarian failure, endometriosis or unexplained infertility. Endometrial biopsy was obtained on 7th-8th postovulatory day. Total progesterone receptors' PR(A + B) and type-B receptors' (PR-B) expression were compared between all categories of infertile and fruitful controls. RESULTS: There were overall 30 patients with tubal factor infertility (group 1), 30 with ovarian failure (group 2), 20 with endometriosis (group 3) and 20 with unexplained infertility (group 4). The control group consisted of 30 fertile patients. Patients with unexplained infertility presented the lowest levels of epithelial endometrial expression both regarding PR(A + B) and PR-B receptors. PgR(A + B) h-score in luminal epithelial cells was 106.4 ± 14.7 for cases with unexplained infertility vs 219.7 ± 15.8 for controls (P < .001). Similarly, PgR(A + B) h-score in glandular epithelial cells was 109.7 ± 13.9 vs 220.1 ± 17.2 (P < .001). Relative remarks were made for type-B progesterone receptors. CONCLUSION: Εndometrial expression of progesterone receptors is impaired in women with unexplained infertility. Therapeutic strategies targeting on improving progesterone receptors' expression may significantly affect final reproductive outcome.

LIF endometrial expression is impaired in women with unexplained infertility while LIF-R expression in all infertility sub-groups.

The main objective of our study was to study LIF and LIF-R endometrial expression during the implantation window in the various sub-groups of infertile women according to infertility cause. A prospective observational case-control study was performed from March 2013 to February 2016. Infertile women consisted of the patients' group (group 2) while fertile women were the control group (group 1). Infertile women were divided according to infertility cause in women with tubal factor (group 2a), poor ovarian reserve (group 2b), endometriosis (group 2c) and unexplained infertility (group 2d). Endometrial biopsy was performed on 7th-8th postovulatory menstrual day. Leukemia Inhibitory Factor (LIF) and LIF-Receptor (LIF-R) expression in epithelial and stromal cells were assessed with Immunohistochemistry (IHC). There were 20 infertile with poor ovarian reserve, 15 with tubal factor, 10 with endometriosis and 15 with unexplained infertility included in the analysis. LIF expression in patients with unexplained infertility was significantly compared with controls (P=0.006). No significant difference was observed between patients with tubal factor, poor ovarian reserve and endometriosis compared with control group (P=0.78, P=0.44 and P=0.56 respectively). Analysis of LIF-R expression in sub-categories of infertility indicated that expression was significantly decreased in all sub-groups of infertility. Our study indicated impaired LIF expression levels only in women with unexplained infertility, while LIF-R expression was impaired in all sub-groups of infertile women. Further multicenter prospective studies should be performed in order to assess the exact etiopathogenetic role of these cytokines in the molecular background of infertility.

LIF and LIF­R expression in the endometrium of fertile and infertile women: A prospective observational case­control study.

The aim of the present study was to determine the expression of leukemia inhibitory factor (LIF) and LIF receptor (LIF­R) in the endometrium of fertile and infertile women during the implantation window. A prospective study was conducted between March 2013 and March 2015 at Iakentro, Infertility Treatment Center (Thessaloniki, Greece) and the 3rd Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki (Thessaloniki, Greece). The patient group consisted of women diagnosed with infertility, whereas the control group consisted of women who had delivered at least one live newborn (fertile women). An endometrial biopsy was obtained using a Pipelle on day 7 or 8 post­ovulation, and the expression of LIF and LIF­R was assessed by immunohistochemistry in epithelial and stromal cells. Primary outcomes included positive cellular percentage, staining intensity and H­score. P<0.05 was considered to indicate a statistically significant difference. Overall, 45 women were included in the present analysis (15 fertile women and 30 infertile women). Mean age was 32.8±6.0 years for the fertile group, and 37.6±3.7 for the infertile group. LIF and LIF­R expression was significantly reduced in the epithelial cells of infertile women (P=0.05 and P=0.006, respectively). However, no significant differences were detected with regards to the expression of LIF in stromal cells (P=0.95). In addition, LIF­R expression was relatively higher in the stromal cells of the fertile group; however, the difference did not reach statistical significance (P=0.10). In conclusion, endometrial expression of LIF and LIF­R is significantly reduced in the epithelial cells of infertile women. Expression patterns of LIF­R in stromal cells require further research in order to achieve definitive results.

Expression of progesterone receptors is significantly impaired in the endometrium of infertile women during the implantation window: a prospective observational study.

OBJECTIVE: To compare the expression of progesterone receptors (A + B) and type-B progesterone receptors in the epithelial and stromal cells of fertile and infertile women. METHODS: Women were divided into two groups, the group of fertile controls (group 1) and the group of infertile women (group 2) and were set on regular ultrasound imaging in order to detect ovulation. An endometrial biopsy was obtained on the seventh or eighth post-ovulatory day. Immunohistochemistry was performed to measure percentage of positive nuclei, intensity of staining and h-score for progesterone receptors (PgR) (A + B) as well as type-B progesterone receptors in epithelial and stromal cells. Secondary outcomes included endometrial tissue dating, the rate of tissues being out-of-phase and endometrial thickness. RESULTS: Endometrial issue was obtained from 15 fertile and 30 infertile women. Expression of PgR (A + B) and PgR type-B was significantly lower in the epithelial cells of infertile women. PgR (A + B) h-score was 220.0 ± 18.5 for fertile versus 147.3 ± 18.0 for infertile women (p = 0.02). PgR type-B h-score in epithelial cells was 166.8 ± 30.7 for fertile versus 90.8 ± 20.6 for infertile (p = 0.04). No significant difference was observed in stromal cells. CONCLUSIONS: Expression levels of PgR (A + B) as well as type-B receptors are significantly lower in the epithelial cells of infertile women during implantation window.

Simultaneous occurrence of hyperthyroidism and fistulizing Crohn's disease complicated with intra-abdominal fistulas and abscess: a case report and review of the literature.

INTRODUCTION: Fistula formation in patients with Crohn's disease is a common complication during the course of the disease. Perianal and enteroenteric are the most common forms of fistulas, whereas the involvement of the upper gastrointestinal tract with gastrocolic and duodenocolic fistulas represents an extremely unusual condition. Moreover, hyperthyroidism in association with Crohn's disease has been rarely described. CASE PRESENTATION: We present here a rare case of a 25-year-old male with simultaneous onset of hyperthyroidism and fistulizing Crohn's disease. Crohn's disease was complicated with intra-abdominal fistulas involving the upper gastrointestinal tract (duodenocolic, gastrocolic) and an intra-peritoneal abscess formation in the lesser sac. We describe the clinical presentation and therapeutic management of the patient including both medical treatment and surgical intervention. Despite intense medical treatment with total parenteral nutrition, antibiotics, aminosalicylates and corticosteroids the clinical course of the disease was suboptimal. Finally, the patient underwent laparotomy and right hemi-colectomy with ileo-transverse anastomosis performed, with simultaneous drainage of the abdominal abscess and primary closure of the upper gastrointestinal tract openings (gastric, duodenal and jejunal) at one stage operation. Although the surgical approach definitively cured the perforating complications of the disease (fistulas and abscess), the luminal disease in the colon remnant was still active and steroid-refractory. The subsequent successful treatment with infliximab, azathioprine and mesalazine resulted in the induction and maintenance of the disease remission. Thyrotoxicosis was successfully treated with methimazole and the hyperthyroidism has definitely subsided. CONCLUSION: The management of intra-abdominal fistulas in Crohn's disease is a complex issue, requiring a multi-disciplinary approach and 'tailoring' of the treatment to the individual patient's needs. Probably, a sensible approach involves early surgical intervention with prior optimization of the patient's general condition when feasible. Common autoimmune mechanisms are probably involved in thyroid dysfunction associated with Crohn's disease. Moreover, diagnosis and treatment of coexisting thyroid disorder in patients with Crohn's disease has a favorable impact in disease prognosis.