Hypertensive Crisis with Neurological Impairment Mimicking a Guillain-Barrè Syndrome: Searching for a Link.

Guillain-Barré syndrome (GBS) may be complicated by severe hypertension (HT) and in turns severe HT can occur with neurological damage mimicking a GBS, so that underlying causes should be investigated. We describe a case of a 62-year-old woman presented to the emergency department for hypertensive crisis with symmetric flaccid paralysis, hypotonia and hyporeflexia of both upper and lower limbs. Brain computed tomography, magnetic resonance imaging and lumbar puncture were normal. Laboratory investigations revealed severe hypokalemia, renal failure, liver impairment, rabdomyolysis, metabolic alkalosis, and low plasma renin and aldosterone levels. Continuous potassium replacement led to complete clinical resolution. A detailed history revealed chronic intake of 250 g/day black liquorice. Hypokalaemic muscle weakness may simulate a GBS. When serum potassium level falls below 2.5 mmol/l, rhabdomyolysis may occur. In this clinical case, an apparent mineralocorticoid excess syndrome was induced by chronic ingestion of liquorice. This latter contains the glycyrrhetic acid that inhibits the enzyme 11-ß-hydroxysteroid dehydrogenase enzyme type-2 leading an aldosterone-like effect and causing hypertension, hypokalemia, metabolic alkalosis and low renin values. The clinical presentation is similar to that observed in the primary aldosteronism, but in this syndrome plasma aldosterone levels are low rather than elevated as in primary aldosteronism. Liquorice-induced hypertension with severe hypokalemia and rhabdomyolysis is a rare condition and the initial presentation with acute muscle paralysis is still more unusual. Before performing instrumental examinations in middle-aged peoples with hypertension crisis and neurological impairment, a detailed clinical history is mandatory.

Catecholamine-Induced Chest Pain Mimicking Infarction Due to an MIBG-Negative and DOPA-Positive Succinate Dehydrogenase Syndrome Subunit B-Related Pheochromocytoma.

This 16-year-old boy presented with acute retrosternal pain possibly representing acute myocardial infarction. Cardiac enzymes were within reference ranges. There were marked increases in metanephrine to 3299 µg/24 h (reference, <400 µg/24 h), normetanephrine to 1309 µg/24 h (reference, 0-390 µg/24 h), and chromogranin A to 1605 ng/mL (reference, 0-150 µg/24 h). An incidental left adrenal mass was found during CTPA performed to exclude pulmonary embolism. I-MIBG scintigraphy was negative, and genetic screening detected SDHB (succinate dehydrogenase syndrome subunit B) gene mutation. Based on the gene mutation, F-DOPA PET/CT was performed, confirming a left-sided pheochromocytoma.

Fixed-Dose Triple Combination of Antihypertensive Drugs Improves Blood Pressure Control: From Clinical Trials to Clinical Practice.

INTRODUCTION: Blood pressure (BP) control is the main clinical goal in the management of hypertensive patients; however, BP in most of these patients remains uncontrolled, despite the widespread availability of antihypertensive drugs as free-combination therapy. This study compared the efficacy of a fixed-dose triple combination (FDTC) of antihypertensive drugs with that of a free combination of three antihypertensives in patients with uncontrolled hypertension. METHODS: Ninety-two patients (mean age 60.8 ± 12.1, 58.0% male) with uncontrolled essential hypertension (office systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg) previously treated with a renin-angiotensin-aldosterone system (RAAS) inhibitor plus hydrochlorothiazide were switched to once-daily FDTC therapy with perindopril/indapamide/amlodipine (5-10/1.25-2.5/5-10 mg). Patients were age- and sex-matched with a control group of hypertensive patients receiving free-combination therapy with three drugs including a RAAS inhibitor, a diuretic, and a calcium channel blocker. Office BP and 24-h ambulatory BP monitoring (ABPM) were evaluated at baseline and after 1 and 4 months. RESULTS: Significant reductions in ambulatory 24-h, daytime, and nighttime systolic BP, and pulse pressure (PP) were found in the FDTC group relative to reductions seen with free-combination therapy, after the first month only of follow-up. Target BP values (mean 24-h ambulatory systolic/diastolic BP < 130/80 mmHg) were reached by more recipients of FDTC than free-combination therapy (64.8% vs. 46.9%, p < 0.05) at month 4 of follow-up, despite reductions in 24-h ABPM values from baseline being similar in both groups at this time point. CONCLUSION: FDTC of perindopril/indapamide/amlodipine was effective at reducing SBP and PP in previously treated patients with uncontrolled hypertension, and well tolerated, providing support for clinicians in choosing a fixed-dose triple combination over the free-combination of a RAAS inhibitor, a diuretic, and a calcium antagonist.

Cost-benefit effectiveness of angiotensin-II receptor blockers in patients with uncomplicated hypertension: A comparative analysis.

OBJECTIVE: The treatment of hypertensive patients (HTs) requires a long-term commitment of compliance for the patient and resources by the healthcare system. This poses an economic dilemma in countries where universal healthcare is standard. The aim of this study was to evaluate the costs/health benefit and effectiveness of treatment with angiotensin-II receptor blockers (ARBs) in uncomplicated essential hypertension. DESIGN AND METHODS: The daily and annual economic commitment for treating patients with ARBs was estimated using pharmacy dispensing records and the BP-lowering effects of candesartan, irbesartan, losartan, olmesartan, telmisartan and valsartan was evaluated retrospectively. In 114 HTs (mean age 59.4±13.5year, 57.5% men), the BP-lowering effect of ARBs as in monotherapy and in fixed-dose combination (FDC) with hydrochlorothiazide at the doses commonly used in the market to reach BP control (i.e. BP <140/90mmHg) was analyzed. The BP lowering-effect was evaluated after an average of 6-month follow-up consulting medical professionals. Analysis of variance for repeated measures was provided. RESULTS: Treatment with candesartan (14.1%) and olmesartan (32,4%) versus other ARBs resulted in a significant decrease in BP as for mono- than for FDC therapy. Our studies suggest that daily (data not shown) and annual costs of olmesartan were higher than candesartan as in mono- (4577.71±1120.55 vs. 894.25±127.75 €) than for FDC therapy (5715.90±459.90 vs. 1580.45±113.15 €). CONCLUSIONS: Treatment: of BP with candesartan appears to be the most favorable option in terms of cost-effectiveness coupled with favorable health outcomes. These data have some limitations, but open the question if candesartan should be preferred to olmesartan in BP management. Further prospective studies comparing ARBs based on their effect on BP control in uncomplicated HTs are needed for validation.

Peroxisomal proliferator-activated receptor-gamma agonists induce partial reversion of epithelial-mesenchymal transition in anaplastic thyroid cancer cells.

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor characterized by marked epithelial mesenchymal transition, which leads, almost invariably, to death. Peroxisomal proliferator-activated receptor (PPAR)-gamma agonists have recently emerged as potential antineoplastic drugs. To establish whether ATC could be a target of PPAR gamma agonists, we first examined PPAR gamma protein expression in a panel of six ATC cell lines and then studied the biologic effects of two PPAR gamma agonists, ciglitazone and rosiglitazone, that belong to the class of thiazolidonediones. PPAR gamma protein was present and functional in all ATC cell lines. Both ciglitazone and rosiglitazone showed complex biological effects in ATC cells, including inhibition of anchorage-dependent and -independent growth and migration, and increased apoptosis rate. Rosiglitazone-induced growth inhibition was associated with cell cycle arrest and changes in cell cycle regulators, such as an increase of cyclin-dependent kinases inhibitors p21(cip1) and p27(kip1), a decrease of cyclin D1, and inactivation of Rb protein. Rosiglitazone-induced apoptosis was associated with a decrease of Bcl-X(L) expression and caspase-3 and -7 activation. Moreover, rosiglitazone antagonized IGF-I biological effects by up-regulating phosphatase and tensin homolog deleted from chromosome 10 with subsequent inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway. Finally, rosiglitazone increased the expression of thyroid-specific differentiation markers. In conclusions, these data suggest that PPAR gamma agonists induce a partial reversion of the epithelial mesenchymal transition in ATC cells by multiple mechanisms. PPAR gamma agonists may, therefore, have a role in the multimodal therapy currently used to slow down ATC growth and dissemination.

Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses.

The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression.Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine-phosphorylation and co-internalization with the IGF-IR. Significantly, DDR1 was critical for IGF-IR endocytosis and trafficking into early endosomes, IGF-IR protein expression and IGF-I intracellular signaling and biological effects, including cell proliferation, migration and colony formation. These biological responses were inhibited by DDR1 silencing and enhanced by DDR1 overexpression.Experiments in mouse fibroblasts co-transfected with the human IGF-IR and DDR1 gave similar results and indicated that, in the absence of IGF-IR, collagen-dependent phosphorylation of DDR1 is impaired.These results demonstrate a critical role of DDR1 in the regulation of IGF-IR action, and identify DDR1 as a novel important target for breast cancers that overexpress IGF-IR.

Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling.

We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR(+) LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy.

Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway.

Proinsulin is generally regarded as an inactive prohormone because of its low metabolic activity. However, proinsulin appears to regulate embryo development in animal models. In this study, we evaluated whether proinsulin may differentially bind to and activate the two insulin receptor (IR) isoforms (IR-A and IR-B), because IR-A is a relatively low-specificity receptor that is prevalent in fetal and cancer cells and is able to mediate the growth effects of IGF-II. Mouse R(-) fibroblasts devoid of IGF-I receptor (IGF-IR) and stably transfected with cDNA encoding either human IR-A or IR-B (R(-) /IR-A and R(-) /IR-B cells) were used. Three human cancer cell lines were also studied. We found that proinsulin stimulated phosphorylation of IR-A with an EC(50) of 4.5 ± 0.6 nm and displaced [(125)I]insulin from IR-A with a similar EC(50). In contrast, proinsulin EC(50) values for stimulation of IR-B phosphorylation and for [(125)I]insulin displacement from IR-B were approximately 7-fold higher. Proinsulin did not bind or activate IGF-IR or IR/IGF-IR hybrids. Via IR-A, proinsulin activated the ERK/p70S6K pathway to a similar degree as insulin but elicited a weaker Akt response. Despite its low metabolic activity, proinsulin was almost equipotent as insulin in inducing cell proliferation and migration in cells expressing various IR-A levels. In conclusion, proinsulin is a selective IR-A ligand and may induce biological effects through this IR isoform.

Differential signaling activation by insulin and insulin-like growth factors I and II upon binding to insulin receptor isoform A.

A variety of human malignancies overexpresses isoform A of the insulin receptor (IR-A) and produces IGFs (IGF-I and/or IGF-II). IR-A binds IGF-II with high affinity (although 4-fold lower than that for insulin), whereas it binds IGF-I with low affinity (approximately 30-fold lower than that for insulin). However, in engineered cells expressing only the IR-A, but not IGF-I receptor (R(-)/IR-A cells), IGF-II is a more potent mitogen than insulin. Herein, we investigated downstream signaling of IGF-II, IGF-I, and insulin in R(-)/IR-A cells to better understand their role in cell growth. We found that despite inducing a lower IR-A autophosphorylation than insulin, IGF-II was more potent than insulin for activating p70S6 kinase (p70S6K) and approximately equally potent in activating the early peaks of ERK1/2 and Akt. However, ERK1/2 activation persisted longer after IGF-II, whereas Akt activation persisted longer after insulin. Therefore, cells stimulated with IGF-II had a higher p70S6K/Akt activation ratio than cells stimulated with insulin. Remarkably, IGF-I also elicited a similar signaling pattern as IGF-II, despite inducing minimal IR-A autophosphorylation. ERK1/2 and protein kinase C seem to be involved in the preferential stimulation of p70S6K by IGFs. In conclusion, our study has identified a novel complex role of IR-A, which not only elicits a unique signaling pattern after IGF-II binding but also induces substantial downstream signaling upon binding to the low-affinity ligand IGF-I. These results underline the role of IR-A in physiology and disease.