Increased adhesive properties of platelets in sickle cell disease: roles for αIIbβ3‐mediated ligand binding,diminished cAMP signalling and increased phosphodiesterase 3A activity

Whilst high pro‐coagulant activity is reported in sickle cell disease (SCD), the precise role of platelets (PLTs) in SCD inflammatory and vaso‐occlusive processes is unclear. Adhesion of PLTs from healthy controls (CON), SCD individuals (SCD) and SCD patients on hydroxycarbamide (SCDHC) to fibrinogen (FB) was compared using static adhesion assays. PLT adhesion molecules and intraplatelet cyclic adenosine monophosphate (icAMP) were observed by flow cytometry and enzyme‐linked immunosorbent assay. SCD‐PLTs demonstrated significantly greater adhesion than CON‐PLTs to FB. Participation of the α_IIbβ₃‐integrin in SCD‐PLT adhesion was implicated by increased α_IIbβ₃ activation and data showing that an α_IIbβ₃‐function‐inhibiting antibody significantly diminished SCD‐PLT adhesion to FB. Platelet activation was potentated by reductions in icAMP; cAMP levels were decreased in SCD‐PLTs, being comparable to those of thrombin‐stimulated CON‐PLTs. Furthermore, SCD‐PLT adhesion to FB was significantly reduced by cilostazol, an inhibitor of cAMP‐hydrolyzing phosphodiesterase 3A (PDE3A). Both α_IIbβ₃‐integrin activation and icAMP correlated significantly with fetal haemoglobin in SCD. Accordingly, hydroxycarbamide therapy was associated with lower PLT adhesion and higher icAMP. SCD‐PLTs may be capable of adhering to proteins encountered on the inflamed vascular wall and, potentially, participate in vaso‐occlusive processes. Hydroxycarbamide and, speculatively, nitric oxide donor or cyclic‐nucleotide‐targeted therapies may aid in the reversal of PLT adhesive properties in SCD.     

Gastroprotective effect of lupeol on ethanol-induced gastric damage and the underlying mechanism

The effect of lupeol, a natural pentacyclic triterpene on ethanol-induced gastric damage in mice was evaluated. The gastroprotection was assessed by determination of changes in mean gastric lesion area, quantification of mucosal non-protein sulfhydryls (NP-SH), and characterized using drugs that influence the endogenous prostaglandins, α₂-adrenoceptors, nitric oxide, K_ATP-channels, and intracellular calcium. Orally administered lupeol (3, 10, and 30 mg/kg) significantly and dose-dependently attenuated the ethanol-induced gastric damage by 39–69%, whereas the positive control N-acetylcysteine (NAC, 300 mg/kg, i.p.) afforded 32% protection. Both lupeol and NAC restored the NP-SH depleted by ethanol but the lupeol effect was only marginal. Lupeol gastroprotection was attenuated by indomethacin and L-NAME, the respective COX and NO-synthase inhibitors and was weakly sensitive to α₂-adrenergic antagonist yohimbine and K_ATP-channel blocker glibenclamide, but more profoundly to calcium blocker verapamil. These pharmacological effects of lupeol may synergistically contribute to alleviating the ethanol-associated gastric damage, which is multifactorial.     

Cushing’s syndrome as a cause of secondary obesity and metabolic syndrome: a case report

We describe the case of a woman affected by morbid obesity associated to type 2 diabetes mellitus (T2DM), hyperlipidaemia and hypertension, configuring a picture of metabolic syndrome (MS). Hormonal investigations revealed that her MS was secondary to the presence of a cortisol-producing left adrenal adenoma. After monolateral adrenalectomy, the MS subsided. Excessive and sustained hypercortisolism gives rise to the entire spectrum of MS. As some clinical manifestations of MS and Cushing’s syndrome (CS) overlap, it is important to consider CS as a possible cause of secondary MS, in order to avoid a delay in diagnosis and proper treatment, which exposes the patient to an increased risk of morbidity and mortality.     

Selective α7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes

AZD0328, a novel spirofuropyridine neuronal nicotinic receptor partial agonist, was used to investigate the role of α7 neuronal nicotinic receptor (NNR) activation in the modulation of midbrain dopamine neuron function, cortical dopamine release and on two behavioral tasks known to be dependent on optimal levels of cortical dopamine. In vivo recordings from area 10 (ventral tegmental area) in rat brain showed an increased firing of putative dopamine neurons in response to low (0.00138 mg/kg) doses of AZD0328. Bursting patterns of dopamine neuron activity remained largely unchanged by application of AZD0328. In vivo microdialysis in awake rats showed an increase in extracellular prefrontal cortical dopamine in response to low doses of AZD0328. Compound-stimulated dopamine release showed an inverted dose effect relation that was maximal at the lowest dose tested (0.00178 mg/kg). Peak extracellular dopamine levels were reached 2 h after dosing with AZD0328. Acquisition of operant responding with delayed reinforcement in rats was dose dependently enhanced by AZD0328 with a plateau effect measured at 0.003 mg/kg. This effect was blocked by pre-treatment of animals with the selective α7 antagonist methyllycaconitine. AZD0328 improved novel object recognition in mice over a broad range of doses (0.00178–1.78 mg/kg) and the compound effect was found to be absent in homozygous α7 KO animals. Together, these data indicate that selective interaction with α7 NNRs by AZD0328 selectively enhances midbrain dopaminergic neuronal activity causing an enhancement of cortical dopamine levels; these neurochemical changes likely, underlie the positive behavioral responses observed in two different animal models. Our results suggest selective α7 NNR agonists may have significant therapeutic utility in neurologic and psychiatric indications where cognitive deficits and dopamine neuron dysfunction co-exist.     

Probiotic properties of <Emphasis Type="Italic">Lactobacillus rhamnosus</Emphasis> and <Emphasis Type="Italic">Lactobacillus paracasei</Emphasis> isolated from human faeces

Background  

The possibility of using microbes to maintain health, and to prevent or treat disease is a topic as old as microbiology. The research of novel probiotic strains is important in order to satisfy the increasing request of the market and to obtain functional products in which the probiotic cultures are more active and with better probiotic characteristics than those already present on the market.     

Biological therapies for inflammatory bowel disease: controversies and future options

Over the last few years, advances in understanding the pathogenesis of inflammatory bowel disease, together with progress in biotechnology, have led to the availability of several biological drugs that have dramatically changed the therapeutic approach to these disorders. Indeed, several molecules targeting crucial inflammatory cytokines, blocking T-cell activation/proliferation or the recruitment of inflammatory cells into the inflamed bowel, have been discovered and commercialized. However, the increasing use of biological agents has raised some concerns regarding their short- and long-term safety. This review offers a critical evaluation of the efficacy and safety of biological agents in the management of both Crohn's disease and ulcerative colitis. In addition, promising therapeutic options are discussed.     

The hospital admission risk profile: the HARP helps to determine a patient's risk of functional decline

Older adults are at risk for losing functional ability during and after a hospitalization. It's often difficult to determine which patients are at highest risk and which might benefit from targeted interventions. The Hospital Admission Risk Profile, a simple screening tool, can be used to classify hospitalized older adults as being at low, intermediate, or high risk for losing the ability to perform activities of daily living, based on assessments of age, cognitive function, and the ability to perform independent activities of daily living. It's one of many tools profiled in Try This: Best Practices in Nursing Care to Older Adults, a series provided by the Hartford Institute for Geriatric Nursing at New York University's College of Nursing. For a free online video demonstrating the use of this tool, go to http://links.lww.com/A286.     

Kinetics of selected di-n-butyl phthalate metabolites and fetal testosterone following repeated and single administration in pregnant rats

Human exposure to phthalic acid diesters occurs through a variety of pathways as a result of their widespread use in consumer products and plastics. Repeated doses of di-n-butyl phthalate (DBP) from gestation day (GD) 12 to 19 disrupt testosterone synthesis and male sexual development in the fetal rat. Currently little is known about the disposition of DBP metabolites, such as monobutyl phthalate (MBP) and its glucuronide conjugate (MBP-G), during gestation after repeated exposure to DBP. In order to gain a better understanding of the effect of repeated dosing on maternal and fetal metabolism and distribution, pregnant Sprague–Dawley rats were given a single dose of 500 mg/kg DBP on GD 19 or daily doses of 50, 100, and 500 mg/(kg day) from GD 12 to 19 via corn oil gavage. Dose–response evaluation revealed a non-linear increase in maternal and fetal plasma concentrations of MBP. Maternal and fetal MBP levels were slightly lower in animals after 8 days of dosing at 500 mg/(kg day). Fetal plasma MBP levels closely followed maternal plasma, while the appearance and elimination of MBP-G in fetal plasma were significantly delayed. MBP-G accumulated over time in the amniotic fluid. Inhibition of testosterone was rapid in fetal testes when exposed to DBP (500 mg/(kg day)) on GD 19. Within 24 h, the level of inhibition in the fetus was similar between animals exposed to a single or multiple daily doses of 500 mg/(kg day). Examination of testosterone time-course data indicates a rapid recovery to normal levels within 24 h post-dosing at DBP doses of 50 and 100 mg/(kg day), with a rebound to higher than normal concentrations at later time-points. MBP kinetics in fetal testes allows direct comparison of active metabolite concentrations and testosterone response in the fetal testes.     

Trauma-related risk factors for substance abuse among male versus female young adults

Clinical efforts to reduce risk for Substance Use Disorders (SUDs) among young adults rely on the empirical identification of risk factors for addictive behaviors in this population. Exposure to traumatic events and Posttraumatic Stress Disorder (PTSD) have been linked with SUDs in various populations. Emerging data, particularly from adolescent samples, suggest that traumatic event exposure increases risk for SUDs for young women, but not young men. The purpose of the current study was to examine trauma-related risk factors for alcohol and drug abuse among a national sample of young adults and compare such risk factors between men and women. Participants were 1753 young adults who participated in the 7–8 year follow-up telephone-based survey to the original National Survey of Adolescents. In the full sample, 29.1% met criteria for substance abuse. Trauma-related risk factors for alcohol and drug abuse differed for men and women. Clinical implications of these results are discussed.     

The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons

Local anesthetics (LAs) block the generation and propagation of action potentials by interacting with specific sites of voltage-gated Na(+) channels. LAs can also excite sensory neurons and be neurotoxic through mechanisms that are as yet undefined. Nonspecific cation channels of the transient receptor potential (TRP) channel family that are predominantly expressed by nociceptive sensory neurons render these neurons sensitive to a variety of insults. Here we demonstrated that the LA lidocaine activated TRP channel family receptors TRPV1 and, to a lesser extent, TRPA1 in rodent dorsal root ganglion sensory neurons as well as in HEK293t cells expressing TRPV1 or TRPA1. Lidocaine also induced a TRPV1-dependent release of calcitonin gene-related peptide (CGRP) from isolated skin and peripheral nerve. Lidocaine sensitivity of TRPV1 required segments of the putative vanilloid-binding domain within and adjacent to transmembrane domain 3, was diminished under phosphatidylinositol 4,5-bisphosphate depletion, and was abrogated by a point mutation at residue R701 in the proximal C-terminal TRP domain. These data identify TRPV1 and TRPA1 as putative key elements of LA-induced nociceptor excitation. This effect is sufficient to release CGRP, a key component of neurogenic inflammation, and warrants investigation into the role of TRPV1 and TRPA1 in LA-induced neurotoxicity.