Relative Adrenal Insufficiency is Associated with the Clinical Outcome in Patients with Stable Decompensated Cirrhosis.

BACKGROUND: The clinical impact of relative adrenal insufficiency (AI) on patients with stable decompensated cirrhosis (DeCi) has not been yet elucidated. AIM: Explore the association between AI and outcome [death or liver transplantation (LT)] in patients with DeCi. MATERIAL AND METHODS: Patients with DeCi presenting no active complication have been included. Clinical and laboratory data, including serum levels of corticosteroid-binding globulin (CBG), interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNFα) were recorded in each participant. Salivary cortisol (SC) and serum total cortisol (STC) were assessed at (T0) and 1 h (T60) after intravenous injection of 250 µg corticotropin. RESULTS: 113 consecutive patients were totally tested. Median SC was 3.9 ng/mL and 15.5 ng/mL and median STC was 10.7 µg/dL and 22.7 µg/dL at T0 and T60 respectively. The patients with AI [group 1, n = 34 (30%)] had significantly lower systolic blood pressure (106 ± 12 vs. 113 ± 13 mmHg, p = 0.05), serum sodium (133 ± 7 vs. 137 ± 12 mEq/ L, p = 0.04), HDL (29.9 ± 14 vs. 38.6 ± 18 mg/dL, p = 0.034) and albumin (2.7 ± 0.5 vs. 3.1 ± 0.5 g/dL, p = 0.002), but higher direct bilirubin (median: 1.6 vs. 0.8 mg/dL, p = 0.029) compared to those without AI [group 2, n = 79 (70%)]. Moreover, group 1 patients presented more frequently past history of spontaneous bacterial peritonitis (SBP) [10/34 (29.4%) vs. 6/79 (7.5%), p = 0.002]. AI was significantly associated with death [HR = 2.65, 95% C.I.: 1.55 - 4.52, p = 0.003 over a follow up period of 12 (6-48) months.] Conclusions. The presence of AI in patients with stable DeCi predispose to obvious clinical implications since it is associated with circulatory dysfunction, previous history of SBP and worse survival.

Increased susceptibility of melanin-concentrating hormone-deficient mice to infection with Salmonella enterica serovar Typhimurium.

Melanin-concentrating hormone (MCH) was initially identified in mammals as a hypothalamic neuropeptide regulating appetite and energy balance. However, the wide distribution of MCH receptors in peripheral tissues suggests additional functions for MCH which remain largely unknown. We have previously reported that mice lacking MCH develop attenuated intestinal inflammation when exposed to Clostridium difficile toxin A. To further characterize the role of MCH in host defense mechanisms against intestinal pathogens, Salmonella enterocolitis (using Salmonella enterica serovar Typhimurium) was induced in MCH-deficient mice and their wild-type littermates. In the absence of MCH, infected mice had increased mortality associated with higher bacterial loads in blood, liver, and spleen. Moreover, the knockout mice developed more-severe intestinal inflammation, based on epithelial damage, immune cell infiltrates, and local and systemic cytokine levels. Paradoxically, these enhanced inflammatory responses in the MCH knockout mice were associated with disproportionally lower levels of macrophages infiltrating the intestine. Hence, we investigated potential direct effects of MCH on monocyte/macrophage functions critical for defense against intestinal pathogens. Using RAW 264.7 mouse monocytic cells, which express endogenous MCH receptor, we found that treatment with MCH enhanced the phagocytic capacity of these cells. Taken together, these findings reveal a previously unappreciated role for MCH in host-bacterial interactions.

IGF Bioregulation System in Benign and Malignant Thyroid Nodular Disease: A Systematic Review.

BACKGROUND/AIM: The insulin-like growth factor bioregulation system is implicated in cancer biology. Herein, we aim to review the evidence on the expression of the insulin-like growth factor 1 and 2 (IGF1 and IGF2), their receptors (IGF-Rs) and IGF-binding proteins (IGFBPs) in thyroid tissue and their possible association with benign and malignant thyroid nodular diseases. MATERIALS AND METHODS: We systematically reviewed Pubmed and Scopus databases up to May 2020. A total of 375 articles were retrieved and analyzed. RESULTS: Among 375 articles, 45 were included in this systematic review study. IGF1 was investigated in 31 studies, IGF2 in 1, IGF1 receptor in 15 and IGF-binding proteins in 13 articles. IGF1 expression in humans was dependent on the number and compound of benign nodules as well as the method of measurement. In differentiated thyroid carcinoma, a positive correlation between IGF1 and immunohistological stage was documented in some studies while in others only a positive trend was observed. IGF-1R and IGFBPs expression was higher in malignant rather than benign lesions. There was only a positive trend for increased IGF2 expression in malignancy, while IGFBPs were in most studies statistically increased in various cancer types compared to benign nodular disease. CONCLUSION: The present data demonstrate that in most studies there is statistically positive expression of IGF-1 and less of IGF-2 in thyroid cancer compared to normal thyroid tissue.

IGF-IEc Expression Is Associated With Advanced Differentiated Thyroid Cancer.

BACKGROUND/AIM: Recent knowledge implicates a differential expression of the insulin-like growth factor-I (IGF-I) mRNA splice variants (i.e., IGF-IEa, IGF-IEb and IGF-IEc) in cancerous tissues, implying possible specific roles of the encoded IGF-I protein isoforms in cancer biology. In particular, there is growing evidence that the IGF-IEc isoform may play a distinct biological role in various types of cancers. The present study investigated whether IGF-IEc expression is associated with a particular type of thyroid cancer. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue specimens of different types of thyroid cancers from 92 patients were assessed for IGF-IEc expression by immunohistochemistry. In addition, thyroid cancer biopsies of different TNM staging histological types were evaluated for mRNA expression of the IGF-IEc transcript by real-time polymerase chain reaction (PCR). RESULTS: From the total number of 92 samples, 2 were anaplastic, 10 medullary, 4 hyperplasias of C-cells, 11 follicular, 5 hurtle cell carcinomas, 2 poorly differentiated, 5 nodular hyperplasias, 1 lymphoma and 52 were papillary thyroid cancers. The age of cancer diagnosis or tumor size did not significantly affect the IGF-IEc expression. Among all types of cancers, IGF-IEc was expressed in papillary differentiated thyroid cancer. Its expression/localization was mainly cytoplasmic and significantly associated with TNM staging and the presence of muscular and capsule cancerous invasion (p<0.05). Similarly, a differential profile was revealed regarding the mRNA expression of the IGF-IEc transcript, that exhibited a higher expression in aggressive compared to the non-aggressive papillary cancers. CONCLUSION: IGF-IEc isoform expression in thyroid cancer is positively associated with more advanced stages of papillary thyroid cancer.

Procalcitonin: A New Biomarker for Medullary Thyroid Cancer? A Systematic Review.

Medullary thyroid cancer (MTC) is a rare but aggressive thyroid malignancy. The gold-standard biomarker for its diagnosis and follow-up is calcitonin (CT); however, it has a variable half-life dependent on its circadian variability. It has been suggested that a more stable hormone, procalcitonin (PCT), may overcome these problems and its introduction to routine practice may give more accurate results in the diagnosis and follow-up of MTC. We systematically reviewed Pubmed, Scopus, Biosis Previews and Embase databases up to March 2016. A total of 15 out of 184 articles were retrieved and analyzed. Of these 15 studies, 3 were case reports. In these 15 studies, the values of CT and PCT were assessed in both patients with MTC and patients that were either healthy volunteers or with benign/malignant thyroid nodular disease or with bacterial infection. Our search suggests that PCT seems to be a useful biomarker for the diagnosis and follow-up of MTC when used in conjunction with CT, particularly in a small proportion of tumors that are CT-negative or secrete low levels of CT. So far, there has not been enough data to suggest a specific threshold for normal PCT. However, most studies indicate a value of 0.1 ng/ml as an acceptable cut-off in everyday clinical practice. At present, CT should continue to be the primary biomarker in MTC with the addition of PCT in some patient groups. Nevertheless, larger patient series need to be conducted in order to provide safer and more accurate results.

Pituitary abscess: a case report and review of the literature.

UNLABELLED: Pituitary abscess is a rare life-threating entity that is usually misdiagnosed as a pituitary tumor with a definite diagnosis only made postoperatively. Over the last several decades, advances in healthcare have led to a significant decrease in morbidity and mortality due to pituitary abscess. We report a case of a 34-year-old woman who was admitted to our department for investigation of a pituitary mass and with symptoms of pituitary dysfunction, headaches and impaired vision. During her admission, she developed meningitis-like symptoms and was treated with antibiotics. She eventually underwent transsphenoidal surgery for excision of the pituitary mass. A significant amount of pus was evident intraoperatively; however, no pathogen was isolated. Six months later, the patient was well and had full recovery of the anterior pituitary function. Her menses returned, and she was only on treatment with desmopressin for diabetes insipidus that developed postoperatively. LEARNING POINTS: Pituitary abscess is a rare disease and the reported clinical features vary mimicking other pituitary lesions.The diagnosis of pituitary abscess is often very difficult to make and rarely included in the differential.The histological findings of acute inflammatory infiltration confirm the diagnosis of pituitary abscess.Medical and surgical treatment is usually recommended upon diagnosis of a pituitary abscess.

Incretin-Based Antidiabetic Agents for the Management of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and is more prevalent in patients with type 2 diabetes mellitus (T2DM). Incretin-based antidiabetic agents (glucagonlike peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors) are used in the treatment of T2DM but it is unclear whether they may also play a role in the management of NAFLD. We systematically reviewed the PubMed and Scopus database up to October 2014 and also hand-searched the references of the retrieved articles for studies evaluating the effects of these agents on NAFLD. In animal studies, both GLP-1 receptor agonists and DPP-4 inhibitors reduced transaminase activity and steatosis but their effects on liver inflammation were inconsistent and fibrosis was not assessed. In clinical studies, both agents consistently reduced transaminase activity and steatosis as assessed non-invasively. There are very limited data on the effects of incretin-based treatments on liver histology. In conclusion, GLP-1 receptor agonists and DPP-4 inhibitors appear to hold promise in patients with NAFLD but larger controlled studies with histological and clinical endpoints are needed to evaluate their effects in this population.

Adrenal insufficiency in patients with decompensated cirrhosis.

Adrenal reserve depletion and overstimulation of the hypothalamus-pituitary-adrenal (HPA) axis are causes for adrenal insufficiency (AI) in critically ill individuals. Cirrhosis is a predisposing condition for AI in cirrhotics as well. Both stable cirrhotics and liver transplant patients (early and later after transplantation) have been reported to present AI. The mechanisms leading to reduced cortisol production in cirrhotics are the combination of low cholesterol levels (the primary source of cortisol), the increased cytokines production that overstimulate and exhaust HPA axis and the destruction of adrenal glands due to coagulopathy. AI has been recorded in 10%-82% cirrhotics depending on the test used to evaluate adrenal function and in 9%-83% stable cirrhotics. The similarity of those proportions support the assumption that AI is an endogenous characteristic of liver disease. However, the lack of a gold standard method for AI assessment and the limitation of precise thresholds in cirrhotics make difficult the recording of the real prevalence of AI. This review aims to summarize the present data over AI in stable, critically ill cirrhotics and liver transplant recipients. Moreover, it provides information about the current knowledge in the used diagnostic tools and the possible effectiveness of corticosteroids administration in critically ill cirrhotics with AI.

Compliance with once-daily versus twice or thrice-daily administration of antibiotic regimens: a meta-analysis of randomized controlled trials.

OBJECTIVE: To investigate whether compliance of patients to antibiotic treatment is better when antibiotics are administered once than multiple times daily. METHODS: We performed a systematic search in PubMed and Scopus databases. Only randomized controlled trials were considered eligible for inclusion. Compliance to antibiotic treatment was the outcome of the meta-analysis. RESULTS: Twenty-six studies including 8246 patients with upper respiratory tract infections in the vast majority met the inclusion criteria. In total, higher compliance was found among patients treated with once-daily treatment than those receiving treatment twice, thrice or four times daily [5011 patients, RR=1.22 (95% CI, 1.11, 1.34]. Adults receiving an antibiotic once-daily were more compliant than those receiving the same antibiotic multiple times daily [380 patients, RR=1.09 (95% CI, 1.02, 1.16)]. Likewise, children that received an antibiotic twice-daily were more compliant than those receiving the same antibiotic thrice-daily [2118 patients, RR=1.10 (95% CI, 1.02, 1.19)]. Higher compliance was also found among patients receiving an antibiotic once compared to those receiving an antibiotic of different class thrice or four times daily [395 patients, RR=1.20 (95% CI, 1.12, 1.28)]. The finding of better compliance with lower frequency daily was consistent regardless of the study design, and treatment duration. CONCLUSION: This meta-analysis showed that compliance to antibiotic treatment might be associated with higher when an antibiotic is administered once than multiple times daily for the treatment of specific infections and for specific classes of antibiotics.

Inflammation-induced functional connectivity of melanin-concentrating hormone and IL-10.

Melanin-concentrating hormone (MCH) was identified in mammals as a hypothalamic neuropeptide regulating appetite and energy balance. However, similarly to most of the brain peptides, MCH is also produced in the gastrointestinal system and can act locally as an immunomodulator. We have previously reported high expression of MCH and its receptor MCHR1 in the affected mucosa of patients with inflammatory bowel disease. Furthermore, MCH deficiency in mice attenuated experimental colitis, pointing to MCH as a mediator of intestinal inflammation. In the present study, in order to gain further insights into the underlying mechanisms of such effects of MCH, we treated mice with established experimental colitis due to IL-10 deficiency with a MCHR1 antagonist (DABA-822). While treatment with the same drug was successful in attenuating TNBS-induced colitis in previous studies, it offered no benefit to the IL-10 knockout mouse model, suggesting that perhaps IL-10 is a downstream target of MCH. Indeed, in experiments focusing on monocytes, we found that treatment with MCH inhibited LPS-mediated IL-10 upregulation. Conversely, in the same cells, exogenous IL-10 prevented LPS-induced MCHR1 expression. Taken together, these findings indicate a functional cross-talk between MCH and IL-10 which prevents resolution of inflammation.

Intestinal upregulation of melanin-concentrating hormone in TNBS-induced enterocolitis in adult zebrafish.

BACKGROUND: Melanin-concentrating hormone (MCH), an evolutionarily conserved appetite-regulating neuropeptide, has been recently implicated in the pathogenesis of inflammatory bowel disease (IBD). Expression of MCH is upregulated in inflamed intestinal mucosa in humans with colitis and MCH-deficient mice treated with trinitrobenzene-sulfonic acid (TNBS) develop an attenuated form of colitis compared to wild type animals. Zebrafish have emerged as a new animal model of IBD, although the majority of the reported studies concern zebrafish larvae. Regulation MCH expression in the adult zebrafish intestine remains unknown. METHODS: In the present study we induced enterocolitis in adult zebrafish by intrarectal administration of TNBS. Follow-up included survival analysis, histological assessment of changes in intestinal architecture, and assessment of intestinal infiltration by myeloperoxidase positive cells and cytokine transcript levels. RESULTS: Treatment with TNBS dose-dependently reduced fish survival. This response required the presence of an intact microbiome, since fish pre-treated with vancomycin developed less severe enterocolitis. At 6 hours post-challenge, we detected a significant influx of myeloperoxidase positive cells in the intestine and upregulation of both proinflammatory and anti-inflammatory cytokines. Most importantly, and in analogy to human IBD and TNBS-induced mouse experimental colitis, we found increased intestinal expression of MCH and its receptor in TNBS-treated zebrafish. CONCLUSIONS: Taken together these findings not only establish a model of chemically-induced experimental enterocolitis in adult zebrafish, but point to effects of MCH in intestinal inflammation that are conserved across species.

Reduced intestinal tumorigenesis in APCmin mice lacking melanin-concentrating hormone.

BACKGROUND: Melanin-concentrating hormone (MCH) is an evolutionary conserved hypothalamic neuropeptide that in mammals primarily regulates appetite and energy balance. We have recently identified a novel role for MCH in intestinal inflammation by demonstrating attenuated experimental colitis in MCH deficient mice or wild type mice treated with an anti-MCH antibody. Therefore, targeting MCH has been proposed for the treatment of inflammatory bowel disease. Given the link between chronic intestinal inflammation and colorectal cancer, in the present study we sought to investigate whether blocking MCH might have effects on intestinal tumorigenesis that are independent of inflammation. METHODOLOGY: Tumor development was evaluated in MCH-deficient mice crossed to the APCmin mice which develop spontaneously intestinal adenomas. A different cohort of MCH-/- and MCH+/+ mice in the APCmin background was treated with dextran sodium sulphate (DSS) to induce inflammation-dependent colorectal tumors. In Caco2 human colorectal adenocarcinoma cells, the role of MCH on cell survival, proliferation and apoptosis was investigated. RESULTS: APCmin mice lacking MCH developed fewer, smaller and less dysplastic tumors in the intestine and colon which at the molecular level are characterized by attenuated activation of the wnt/beta-catenin signaling pathway and increased apoptotic indices. Form a mechanistic point of view, MCH increased the survival of colonic adenocarcinoma Caco2 cells via inhibiting apoptosis, consistent with the mouse studies. CONCLUSION: In addition to modulating inflammation, MCH was found to promote intestinal tumorigenesis at least in part by inhibiting epithelial cell apoptosis. Thereby, blocking MCH as a therapeutic approach is expected to decrease the risk for colorectal cancer.