Orexin-A exerts equivocal role in atherosclerosis process depending on the duration of exposure : in vitro study

Orexin-A is a peptide hormone that plays a crucial role in feeding regulation and energy homeostasis. Diurnal intermittent fasting (DIF) has been found to increase orexin-A plasma levels during fasting hours, while Ramadan fasting which resembles DIF, has led to beneficial effects on endothelial function. Herein, we aimed to investigate the effects of orexin-A on the expression of molecules involved in the atherogenesis process: Monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase-1 and 2 (TIMP-1 and TIMP-2), in human aortic endothelial cells (HAECs). HAECs were incubated with orexin-A at concentrations of 40 ng/mL, 200 ng/mL and 400 ng/mL for 6, 12 and 24 h. The mRNA levels of MCP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 and orexin-1 receptor were measured by real-time qPCR. We also evaluated the MMP-2, p38, phospho-p38, NF-κΒ/p65 as well as TIMP-1 protein levels by Western blot and ELISA, respectively. MMP-2 activity was measured by gelatin zymography. Short-term 6-h incubation of HAECs with orexin-A at a high concentration (400 ng/mL) decreased MCP-1, MMP-2 expression, MMP-2/TIMP-1 ratio (p < 0.05), and MMP-2 activity, while incubation for 24 h increased MCP-1, MMP-2 expression (p < 0.05), MMP-2/TIMP-1 and MMP-2/TIMP-2 ratio (p < 0.01 and p < 0.05, respectively) as well as MMP-2 activity. The dual effects of orexin-A are mediated, at least in part, via regulation of p38 and NF-κΒ pathway. Orexin-A may have an equivocal role in atherosclerosis process with its effects depending on the duration of exposure

Synergistic Gravity and the Role of Resonances in GRS-Inspired Braneworlds

We consider 5D braneworld models of quasi-localized gravity in which 4D gravity is reproduced at intermediate scales while the extra dimension opens up at both the very short and the very long distances, where the geometry is flat. Our main interest is the interplay between the zero mode of these models, whenever a normalizable zero mode exists, and the effects of zero energy graviton resonant modes coming from the contributions of massive KK modes. We first consider a compactified version of the GRS model and find that quasi-localized gravity is characterized by a scale for which both the resonance and the zero mode have significant contribution to 4D gravity. Above this scale, gravity is primarily mediated by the zero mode, while the resonance gives only minor corrections. Next, we consider an asymmetric version of the standard non-compact GRS model, characterized by different cosmological constants on each AdS side. We show that a resonance is present but the asymmetry, through the form of the localizing potential, can weaken it, resulting in a shorter lifetime and, thus, in a shorter distance scale for 4D gravity. As a third model exhibiting quasi-localization, we consider a version of the GRS model in which the central positive tension brane has been replaced by a configuration of a scalar field propagating in the bulk.Comment: 18 pages, 3 figures, added 1 figure, revised version as published in Class. Quant. Gra

Paraneoplastic hypoglycaemia secondary to IGF-2 secretion from a metastatic gastrointestinal stromal tumour

We report the case of a 79-year-old male with previous history of non-Hodgkin's lymphoma in remission, who presented acutely to the Accident and Emergency department with recurrent episodes of hypoglycaemia. At the time of presentation, a random glucose was low at 1.4 mmol/l, which upon correction resolved his symptoms. In hindsight, the patient recalled having had similar episodes periodically over the past 2 months to which he did not give much notice. While hospitalized, he continued having episodes of symptomatic hypoglycaemia, requiring treatment with intravenous dextrose and per os steroids. Once stable, he was discharged on oral prednisolone and dietary advice. A computed tomography scan performed during inpatient stay showed multiple deposits in the abdomen. An ultrasound guided biopsy of one of the liver deposits was performed. Immunohistochemistry supported the diagnosis of a gastrointestinal stromal tumour (GIST) positive for CD34 and CD117. The diagnosis of non-islet cell tumour hypoglycaemia (NICTH) secondary to an IGF2 secreting GIST was confirmed with further biochemical investigations (IGF2=105.9 nmol/l; IGF2:IGF1 ratio 23, Upper Level of Normal (ULN) <10). Targeted cytoreductive treatment with Imatinib mesylate following assessment of the tumour's mutational status was successful in preventing hypoglycaemia over a 21-month follow-up observation period

A new medication-based prediction score for postoperative delirium in surgical patients: development and proof of feasibility in a retrospective patient cohort

Structured risk screening for postoperative delirium (POD) considering prehospital medication is not established. We aimed to develop a POD-risk prediction score based on known risk factors and delirium-risk increasing drugs to be used by pharmacists during medication reconciliation at hospital admission, and to test for feasibility in a retrospective cohort of surgical patients. Therefore, established POD-risk factors and drugs were extracted from the literature and a score was generated. Following this, the score was tested for feasibility in a retrospective 3-month-cohort of surgical patients. For patients with higher scores suggesting higher probability of POD, patient charts were screened for documentation of POD. For development of the score, the following POD-risk factors were defined and points assigned for score calculation: age (≥65 years=1 point/≥75 years=2), male sex (1), renal insufficiency (RI; 1), hepatic impairment (HI; Model-of-endstage-liver-disease (MELD) 10-14=1/≥15=2), delirium-risk increasing drugs (1 point per drug class), anticholinergic drug burden (ACB; ≥3=1). In the retrospective test cohort of 1174 surgical patients these factors concerned: age ≥65 years 567 patients (48%)/≥75 years 303 (26%), male 652 (55%), RI 238 (20%), MELD 10-14 106 (9%)/≥15 65 (5%), ≥ 1 delirium-risk increasing drug 418 (36%), ACB ≥3 106 (9%). The median POD-risk prediction score was 2 (range 0-9). Of 146 patients (12%) with a score ≥ 5, POD was documented for 43 (30%), no evidence for POD for 91 (62%) and data inconclusive for 12 (8%). For scores of ≥ 7, POD was documented for 50% of the patients with sufficient POD documentation. Overall, POD documentation was poor. To summarize, we developed and successfully tested the feasibility of a POD-prediction-score assessable by pharmacists at medication reconciliation at hospital admission

Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma

BACKGROUND: Interleukin (IL) 11 is produced by human endometrium and endometrial cancer tissue. It has roles in endometrial epithelial cell adhesion and trophoblast cell invasion, two important processes in cancer progression. This study aimed to determine the levels of IL11 in uterine lavage fluid in women with endometrial cancer and postmenopausal women. It further aimed to determine the levels of IL11 protein and its signaling molecules in human endometrial cancer of varying grades, and endometrium from postmenopausal women and IL11 signalling mechanisms in endometrial cancer cell lines. METHODS: IL11 levels in uterine lavage were measured by ELISA. IL11, IL11 receptor(R) α, phosphorylated (p) STAT3 and SOCS3 were examined by immunohistochemistry in endometrial carcinomas and in control endometrium from postmenopausal women and normal cycling women. The effect of IL11 on pSTAT3/STAT3 and SOCS3 protein abundance in endometrial cancer cell lines and non-cancer endometrial epithelial cells was determined by Western blot. RESULTS: IL11 was present in uterine flushings and was significantly higher in women with Grade 1 carcinomas compared to postmenopausal women (p < 0.05). IL11 immunostaining was significantly elevated in the endometrial tumour epithelial cells from Grade 1 and 3 compared to endometrial epithelium from postmenopausal and cycling women. IL11Rα immunostaining intensity was increased in cancer epithelium in the Grades 1 and 2 tumours compared to epithelium from postmenopausal women. Both IL11 and IL11Rα localized to vascular endothelial and smooth muscle cells while IL11 also localized to subsets of leucocytes in the cancer tissues. pSTAT3 was found in both the tumour epithelial and stromal compartments but was maximal in the tumour epithelial cells, while SOCS3 was predominantly found in the tumour epithelial cells. pSTAT3 staining intensity was significantly higher in Grade 1 and 2 tumour epithelial cells compared to epithelial cells from cycling and postmenopausal women. SOCS3 staining intensity did not differ between between each tumour and postmenopausal endometrial epithelium but SOCS3 in cycling endometrium was significantly higher compared to postmonopausal and Tumour Grades 2 and 3. IL11 increased pSTAT3/STAT3 in all tumour cell lines, while SOCS3 abundance was increased only in one tumour cell line. CONCLUSIONS: The present study suggests that IL11 in uterine washings may be useful as a diagnostic marker for early stage endometrial cancer. It indicates that IL11, along with its specific receptor, IL11Rα, and downstream signalling molecules, STAT3 and SOCS3, are likely to play a role in the progression of endometrial carcinoma. The precise role of IL11 in endometrial cancer remains to be elucidated

Severe paraneoplastic hypoglycemia secondary to a gastrointestinal stromal tumour masquerading as a stroke

We report the case of a 70-year-old previously healthy female who presented acutely to the Accident and Emergency department with left-sided vasomotor symptoms including reduced muscle tone, weakness upon walking and slurred speech. Physical examination confirmed hemiparesis with VIIth nerve palsy and profound hepatomegaly. A random glucose was low at 1.7 mmol/l, which upon correction resolved her symptoms. In hindsight, the patient recalled having had similar episodes periodically over the past 3 months to which she did not give much attention. While hospitalized, she continued having episodes of symptomatic hypoglycaemia during most nights, requiring treatment with i.v. dextrose and/or glucagon. Blood tests including insulin and C-peptide were invariably suppressed, in correlation with low glucose. A Synacthen stimulation test was normal (Cort (0′) 390 nmol/l, Cort (30′) 773 nmol/l). A computed tomography scan showed multiple lobulated masses in the abdomen, liver and pelvis. An ultrasound guided biopsy of one of the pelvic masses was performed. Immunohistochemistry supported the diagnosis of a gastrointestinal stromal tumour (GIST) positive for CD34 and CD117. A diagnosis of a non islet cell tumour hypoglycaemia (NICTH) secondary to an IGF2 secreting GIST was confirmed with further biochemical investigations (IGF2=96.5 nmol/l; IGF2:IGF1 ratio 18.9, ULN <10). Treatment with growth hormone resolved the patient's hypoglycaemic symptoms and subsequent targeted therapy with Imatinib was successful in controlling disease progression over an 8-year observation period