Increased production of inflammatory cytokines by circulating monocytes in mesial temporal lobe epilepsy: A possible role in drug resistance.

We analyzed peripheral blood mononuclear cells (PBMCs) and serum inflammatory biomarkers in patients with mesial temporal lobe epilepsy (drug-resistant - DR, vs. drug-sensitive - DS). Patients with epilepsy showed higher levels of serum CCL2, CCL3, IL-8 and AOPP, and lower levels of FRAP and thiols compared to healthy controls (HC). Although none of the serum biomarkers distinguished DR from DS patients, when analysing intracellular cytokines after in vitro stimulation, DR patients presented higher percentages of IL-1ß and IL-6 positive monocytes compared to DS patients and HC. Circulating innate immune cells might be implicated in DR epilepsy and constitute potential new targets for treatments.

Mesangiogenic Progenitor Cells and musculoskeletal tissue regeneration: differences between adipose-derived and bone marrow-derived cells?

Mesangiogenic Progenitor cells (MPCs) have been isolated from human bone marrow mononuclear cells (hBM-MNCs) and attracted particular attention for their ability to efficiently differentiate into exponentially growing mesenchymal stromal cells (MSCs) and toward endothelial lineage, suggesting the term "mesangiogenic". Coupling mesengenesis and angiogenis, MPCs has been hypothesized retaining a great tissue regenerative potential in musculoskeletal tissues regeneration. Bone marrow and adipose tissue (AT) represent most promising adult multipotent cell sources attempting to repair bone and cartilage, with controversial results regarding advantages applying BM- or AT-derived cells. As different culture determinants as well as tissue of origins, could strongly affect regenerative potential of cell preparations, we hypothesize that MPCs counterpart could have a role in defining efficacy of applying a cell-based medicinal product in musculoskeletal tissue repair. Here we present convincing data demonstrating that the ex vivo progenitors of MPCs are tissue specific and can be detected exclusively in hBM-MNCs.

Modulation of the Emotional Response to Viewing Strabismic Children in Mothers-Measured by fMRI.

PURPOSE: Strabismus influences not only the individual with nonparallel eyes but also the observer. It has previously been demonstrated by fMRI that adults viewing images of strabismic adults have a negative reaction to the images as demonstrated by limbic activation, especially activation of the left amygdala. The aim of this study was to see if mothers would have a similar reaction to viewing strabismic children and whether or not that reaction would be different in mothers of strabismic children. METHODS: Healthy mothers of children with strabismus (n = 10, Group I) and without strabismus (n = 15, Group II) voluntarily underwent fMRI at 3T. Blood oxygen level dependent signal responses to viewing images of strabismic and non-strabismic children were analyzed. RESULTS: Group II, while viewing images of strabismic children, showed significantly increased activation of the limbic network (p < 0.05) and bilateral amygdala activation. Group I showed considerably less limbic activation, compared to the group II, and had no amygdala activation. Both groups revealed statically significant activation in the FEF (frontal eye field) when they were viewing images of strabismic children as compared to when they were viewing children with parallel eyes. The activated FEF area for Group II was much larger than for group I. CONCLUSION: Mothers of non-strabismic children showed similar negative emotional fMRI patterns as adults did while viewing strabismic adults. Strabismus is an interpersonal organic issue for the observer, which also impacts the youngest members of our society.

Relationship between the optic nerve sheath diameter and lumbar cerebrospinal fluid pressure in patients with normal tension glaucoma.

PurposeTo investigate on the relationship between the optic nerve sheath diameter (ONSD) and the lumbar cerebrospinal fluid pressure (CSF-p) in Caucasian patients with normal tension glaucoma (NTG).Patients and methodsRetrospective analysis of medical records of patients with open-angle glaucoma in the period from 2005 to 2015 from the Ophthalmology Department, Cantonal Hospital Aarau, Switzerland was performed. A total of 38 patients (mean age 68.6±11.3 years, 21 females and 17 males) fulfilled the diagnostic criteria of NTG and underwent computed tomography (CT) of the orbit and lumbar puncture (LP). In total, 38 age- and gender-matched Caucasian subjects (mean age: 68.9±10.9 years) without known ON diseases served as controls for ONSD measurements. ONSDs were measured at a distance of 3 mm from the posterior globe and lumbar CSF-p was related to the measurements. Statistical analysis was performed by using the independent two-tailed t-test and the non-parametric Spearman's correlation test.ResultsThe mean ONSD in NTGs measured 6.4±0.9 mm and in controls 5.4±0.6 mm. The difference between NTGs and controls showed statistical significance (t-test: P<0.000). The mean CSF-p in NTG was 11.6±3.7 mm Hg. There was no statistical significant correlation between ONSD and CSF-p (Spearman's correlation coefficient ρ=0.06, P=0.72).ConclusionsThis study demonstrates enlarged ONSDs and normal lumbar CSF-p in 38 Caucasian NTG patients. As enlarged ONSDs generally are associated with increased intracranial CSF-p, these results can be explained by a disturbed communication of CSF-p between the intracranial and intraorbital subarachnoid spaces.

Regulation of A1 adenosine receptor functioning induced by P2Y1 purinergic receptor activation in human astroglial cells.

In the rat brain, a heteromeric association between adenosine A(1) and purinergic P2Y(1) receptors has been demonstrated. It is suggested that this association plays an important role in the control of purine-mediated responses during pathophysiological conditions. Recently, we have demonstrated that these receptors colocalize on glutamatergic synaptic and astroglial membranes in rat hippocampus and reciprocally interact, thus modulating their functional responses at the G protein coupling level. In the present work, by means of immunoprecipitation studies, we demonstrated that A(1) and P2Y(1) receptors are present in human astroglial cells (ADF) and aggregate to form a multimeric complex. P2Y(1) receptor activation by its agonist, 2-methylthio-adenosine 5'-diphosphate (MeSADP), induced a time-dependent reduction in agonist-mediated A(1) receptor functional responses, causing a drop in A(1) receptor agonist potency to promote receptor-G protein coupling and to inhibit the adenylate cyclase pathway. These effects appeared to be selectively mediated by P2Y(1) receptor activation and probably occurred as a consequence of a direct receptor-receptor interaction at the plasma membrane level. These results indicated that P2Y(1) receptor activation induces A(1) receptor heterologous desensitization. The interaction between A(1) and P2Y(1) receptors may play an important role in the purinergic signaling cascade in astrocytes, which are involved in cell-to-cell communication and in control of synaptic transmission, particularly during pathological conditions, when large amounts of purines are released.

Norepinephrine-mediated regulation of 5HT1 receptor functioning in human platelets.

Adaptive changes in serotonergic 5HT1 receptor signalling are believed to underlie the therapeutic effectiveness of antidepressant drugs. Since cells are continuously exposed to neurotransmitters/neuromodulators, spatially and temporally integrated, the responsiveness of a receptor system is dependent upon the physio-pathological state of the cell and the interaction between different neurotransmitters. In the present work, we investigated heterologous regulation of 5HT1 receptors induced by norepinephrine (NE) in human platelets. NE platelet treatment induced a time and concentration dependent 5HT1 receptor desensitisation mediated by both alpha and beta receptors through activation of intracellular protein kinases. In particular NE, through PKC activation, regulated 5HT1 receptor phosphorylation on threonine residues, causing in turn serotonin receptor-G protein uncoupling and functional responsiveness drop. These results suggest that high NE levels (released i.e. during stress disorders) may play an important role in regulating the 5HT1 responsiveness and in controlling effectiveness of drugs acting on these neurotransmitter systems.

GABA A/Bz receptor subtypes as targets for selective drugs.

The gamma-aminobutyric acid type A (GABA(A)) receptors are the major inhibitory neuronal receptors in the mammalian brain. Their activation by GABA opens the intrinsic ion channel, enabling chloride flux into the cell with subsequent hyperpolarization. Several GABA(A) receptor subunit isoforms have been cloned, the major isoform containing alpha, beta, and gamma subunits, and a regional heterogeneity associated with distinct physiological effects has been suggested. As a variety of allosteric ligands can modulate GABA-gated conductance changes through binding to distinct sites, the development of subtype-selective ligands may lead to the selective treatment of GABA system-associated pathology. In particular, the best characterized binding site is the benzodiazepine site (BzR), localized at the alpha/gamma subunit interface, in which the alpha subunit is the main determinant of BzR ligand action selectivity. The alpha1-containing BzR have been proposed to be responsible for the sedative action; the alpha2 and/or the alpha3 subtypes have been suggested to mediate the anxiolytic activity and the myorelaxation effects, and the alpha5 subtype has been associated with cognition processes. The discovery of alpha-selective subtype ligands may help in the specific treatment of anxiety, sleep disorders, convulsions and memory deficits with fewer side effects. Selectivity may be achieved by two approaches: selective affinity or selective efficacy. Selective affinity needs a compound to bind with a higher affinity to one receptor subtype compared with another, whereas subtype-selective efficacy relies on a compound binding to all subtypes, but having different efficacies at various subtypes. The status of BzR ligands, subdivided on the basis of their main chemical structural features, is reviewed in relation to structure-activity relationships which determine their affinity or efficacy selectivity for a certain BzR subtype.

Surgical informatics is a useful management tool.

BACKGROUND: Management of surgery in the largest health care system in the country depends upon readily available and valid data. Use of an administrative data base had not fulfilled these requirements. An information program based upon the computerized operating room log and scheduling program presented a possible remedy. METHODS: Data elements previously appearing in the computerized operating room log were expanded to include outcomes. Reports essential to the surgical management of VA surgery were developed through an advisory panel. Necessary changes were added to the surgical computer program and computers installed in each operating room throughout the system. RESULTS: The work load information to manage a surgical service was determined to include the total number of operations performed, both major and minor, and a description of the patient population including the American Society of Anesthesiologists (ASA) classification. The breakdown into the individual surgical specialties, information regarding index operations, extent of resident supervision, and incidence of postoperative occurrences completed the required information. CONCLUSIONS: The information provided by this report is an example of the importance of the use of surgical informatics in the management of VA surgery. The ability to obtain valid information for analysis and dissemination is a direct result of the computer-generated information taken directly from the surgical log of each of the 126 VA Medical Centers.