The epigenetic landscape in the cardiovascular complications of diabetes.

A growing body of evidence suggests that epigenetic modifications-changes to the genome that do not involve changes in DNA sequence-may significantly derail transcriptional programs implicated in angiogenesis, oxidative stress and inflammation, thus fostering cardiovascular damage in patients with diabetes. Notably, adverse epigenetic signals acquired over the life course can be transmitted to the offspring, and may contribute to early cardiovascular phenotypes in the young generations. Hyperglycaemia and insulin resistance-key hallmarks of diabetes-induce an array of epigenetic modifications (i.e., DNA methylation, histone marks, and non-coding RNAs) which are responsible for a long-lasting impairment of vascular and cardiac function, even after intensive glycemic control. Hence, unveiling the "epigenetic landscape" in patients with diabetes may provide a post-genomic snapshot of global cardiovascular risk, and may furnish the tools to design personalized, epigenetic-based therapies to alleviate the burden of cardiovascular disease in diabetic patients. The present review aims to acquaint the scientific community with the rapidly advancing field of epigenetics and its implications in the cardiovascular complications of diabetes.

Fibroblast growth factor and endothelin-1 receptors mediate the response of human striatal precursor cells to hypoxia.

Fetal striatal transplantation has emerged as a new therapeutic strategy in Huntington's disease (HD). Hypoxia is one of the microenvironmental stress conditions to which fetal tissue is exposed as soon as it is isolated and transplanted into the diseased host brain. Mechanisms that support neuroblast survival and replenishment of damaged cells within the HD brain in the hypoxic condition have yet to be fully elucidated. This study is aimed at investigating the molecular pathways associated with the hypoxic condition in human fetal striatal neuroblasts (human striatal precursor (HSP) cells), using the hypoxia-mimetic agent cobalt chloride (CoCl2). We analyzed the effect of CoCl2 on HSP cell proliferation and on the expression of hypoxia-related proteins, such as hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). Moreover, we evaluated fibroblast growth factor 2 (FGF2; 50ng/ml) and endothelin-1 (ET-1; 100nM) proliferative/survival effects in HSP cells in normoxic and hypoxic conditions. Dose-response experiments using increasing concentrations of CoCl2 (50-750µM) showed that the HSP cell growth was unaffected after 24h, while it increased at 48h, with the maximal effect observed at 400µM. In contrast, cell survival was impaired at 72h. Hypoxic conditions determined HIF-1α protein accumulation and increased gene and protein expression of VEGF, while FGF2 and ET-1 significantly stimulated HSP cell proliferation both in normoxic and hypoxic conditions, thus counteracting the apoptotic CoCl2 effect at 72h. The incubation with selective receptor (FGFR1, endothelin receptor A (ETA) and endothelin receptor B (ETB)) inhibitors abolished the FGF2 and ET-1 neuroprotective effect. In particular, ET-1 stimulated HSP cell survival through ETA in normoxic conditions and through ETB during hypoxia. Accordingly, ETA expression was down-regulated, while ETB expression was up-regulated by CoCl2 treatment. Overall, our results support the idea that HSP cells possess the machinery for their adaptation to hypoxic conditions and that neurotrophic factors, such as FGF2 and ET-1, may sustain neurogenesis and long-term survival through complex receptor-mediated mechanisms.

New monolithic chromatographic supports for macromolecules immobilization: challenges and opportunities.

This mini-review reports on some recent advances in the field of immobilized protein employing both silica and polymer-based monoliths as supports, and their application in affinity chromatography and immobilized enzyme reactors (IMERs) developments. The major emphasis is put on some interesting challenges and opportunities related to the development of new monolithic affinity supports based on biofriendly sol-gel inorganic monoliths with entrapped proteins and on organic monolithic supports with improved hydrophilicity for IMERs development in proteomic studies. The ease of preparation of monoliths and the multitude of functionalization techniques, make monoliths interesting for an increasing number of biochemical and medical applications.

Synthesis and chromatographic evaluation of molecularly imprinted polymers prepared by the substructure approach for the class-selective recognition of glucuronides.

Two series of molecularly imprinted polymers (MIPs) for the class-selective recognition of glucuronides have been prepared by using lipophilic substructures of the target analyte as template molecule and potent host monomers against oxyanions, that are expected to establish a strong stoichiometric interaction with the single carboxylic group of the template. The polymers were tested as stationary phases in liquid chromatography for specific recognition. A preliminary investigation of the imprinting properties of eleven MIPs was carried out, by comparing the retention time of the template and of structurally related compounds on the MIP column with that on the corresponding non-imprinted polymer (NIP). The two polymers showing the best performance were selected to further test cotinine, mycophenolic acid, testosterone and their respective glucuronides as model compounds. The high specificity obtained against glucuronides and the different chemical structure of the parent drug make the two MIPs class-selective imprinted receptors, also suitable for SPE application.

IgM monoclonal gammopathy-associated neuropathies with different IgM specificity.

BACKGROUND AND PURPOSE: Antibodies directed against myelin-associated glycoprotein (MAG) are believed to be the most frequent biologic marker of the neuropathies associated with IgM monoclonal gammopathy of undetermined significance (MGUS). The objective of this study was to examine the prevalence of antiganglioside and/or sulfatide-positive patients and their clinical findings, including therapeutic response, compared to anti-MAG-positive or seronegative patients. METHODS: We prospectively followed 46 patients with MGUS who were diagnosed in our tertiary referral centers for polyneuropathy since 1997. All patients underwent nerve conduction studies and were tested for anti-MAG, gangliosides, and sulfatide antibodies. All the anagraphic and clinical data (including symptoms, disability scale, therapy, secondary malignancy development) were recorded in a database and compared between three patients' groups (anti-MAG-positive; antiganglioside/sulfatide-positive; no reactivity). RESULTS: Anti-MAG reactivity was present in 17 (37%) patients; other 17 patients (37%) had antiganglioside/sulfatide reactivity and 12 (26%) had no reactivity. Patients with antiganglioside/sulfatide positivity, although heterogeneous by a clinical and neurophysiological point of view, had the most severe neuropathic manifestations and a higher disability score at nadir (P < 0.001). These patients had a better response to both intravenous immunoglobulin therapy and rituximab. CONCLUSIONS: Our results suggest that antiganglioside/sulfatide-positive patients form a relevant portion of patients with MGUS-associated polyneuropathy seen in tertiary care centers and should be considered in future studies on treatment response.

Which patients with sexual dysfunction are suitable for testosterone replacement therapy?

According to all the consensus and statements of the major societies, hypogonadism should be considered a medical problem, termed late onset hypogonadism (LOH) or testosterone deficiency syndrome (TDS), only when symptoms are present. One of the most common symptoms of LOH/TDS is sexual dysfunction (SD). The main purpose of this review is to discuss the role of testosterone (T) in men's sexual function, including epidemiology, pathophysiology, diagnostic procedures, and treatment efficacy in patients affected by erectile dysfunction (ED). The prevalence of hypogonadism in men with ED ranges from 1.7% to 35%. In ED patients, hypogonadism is often associated with reduced sexual desire and nocturnal penile erections, while association with sex-induced erection is less evident. This is because T regulates not only cyclic guanosine monophosphate (cGMP) formation, through nitric oxide synthase (NOS) stimulation, but also its catabolism, through phosphodiesterase-5 (PDE5) activity. The androgen-dependent PDE5 expression could explain the reduced effectiveness of PDE5 inhibitors (PDE5i) in the treatment of erectile dysfunction in hypogonadal patients. Accordingly, T substitution in these subjects restores responsiveness to PDE5i. Recognising hypogonadism in patients with ED is essential in order to appropriately treat the disease. However, suspecting LOH/TDS in SD patients is not an easy task. Recently published structured inventories, such as ANDROTEST, might help physicians to recognize hypogonadism and to further pursue its appropriate diagnosis and treatment.

[Paraneoplastic syndromes of the central nervous system]. / Sindromi paraneoplastiche del sistema nervoso centrale.

Paraneoplastic syndromes of central nervous system are rare neurologic syndromes caused by cancer but not secondary to metastases. The physiopathologic mechanisms underlying these syndromes are still under debate. We report the biological and clinical features of the most frequent paraneoplastic syndromes involving the central nervous system. Their early clinical identification might be an useful marker of an otherwise unknown visceral malignancy. Furthermore, they might also be suggestive for the particular type of cancer present. Once, therefore, the diagnosis of these paraneoplastic syndromes has been established, an appropriate evaluation for the asymptomatic neoplasm in cancer-free individuals or investigation for the malignancy recurrences in oncologic patients might be performed.