The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway

In autoimmune hepatitis (AIH), liver-damaging CD4 T cell responses are associated with defective CD4(pos) CD25(pos) regulatory T cells (T-regs). Galectin-9 (Gal9), a β-galactosidase-binding protein expressed by T-regs, is key to their function, inhibiting T helper 1 immune responses by binding T cell immunoglobulin and mucin domain 3 (Tim-3) on CD4 effector cells. We investigated whether impaired immunoregulation in AIH results from reduced expression of Gal9 in T-regs and/or Tim-3 on CD4 effector cells. Circulating Gal9(pos) CD4(pos) CD25(pos) and Tim-3(pos) CD4(pos) CD25(neg) T cell phenotype was assessed by flow cytometry in 75 AIH patients. To evaluate whether Tim-3 expression renders CD4(pos) CD25(neg) T cells amenable to T-reg control, purified CD4(pos) CD25(neg) Tim-3(pos) (Tim-3(pos)) and CD4(pos) CD25(neg) Tim-3(neg) (Tim-3(neg)) cells were cocultured with T-regs. To determine whether Gal9 expression is essential to function, T-regs were treated with small interfering RNA (siRNA) to repress Gal-9 translation; T-reg suppressor function was assessed by proliferation. In AIH, Tim-3(pos) cells within CD4(pos) CD25(neg) cells and their T-bet(pos) and RORC(pos) subsets were fewer and contained higher numbers of interferon-γ (IFNγ)(pos) and interleukin (IL)-17(pos) cells than healthy subjects (HS). In AIH and HS, Tim-3(pos) cells proliferated less vigorously and were more susceptible to T-reg control than Tim-3(neg) cells. In AIH, Gal9(pos) T-regs were fewer and contained less FOXP3(pos), IL-10(pos), and transforming growth factor β(pos) and more IFNγ(pos) and IL-17(pos) cells than HS. siRNA treatment of Gal-9(pos) T-regs drastically reduced T-reg ability to suppress CD4(pos) CD25(neg) and Tim-3(pos) cell proliferation in AIH and HS. Tim-3(pos) cell percentage correlated inversely with aminotransferase and CD25(neg) T-bet(pos) cell values. CONCLUSION: Reduced levels of Tim-3 on CD4(pos) CD25(neg) effector cells and of Gal9 in T-regs contribute to impaired immunoregulation in AIH by rendering effector cells less prone to T-reg control and T-regs less capable of suppressing.     

Nigral involvement and nigrostriatal dysfunction in Huntington's disease: Evidences from an MRI and SPECT study

BackgroundHuntington disease (HD) is pathologically characterized by a selective neurodegeneration of vulnerable populations of neurons, with an early marked neuronal loss and atrophy in the neostriatum. Dopaminergic innervations of neostriatal neurons originate in the substantia nigra pars compacta. Few studies investigated the neuronal loss and the functional role of the substantia nigra in modulating clinical features in HD.Methods12 patients and 12 age-matched controls underwent SPECT scans with ¹²³I-FP-CIT and a 1.5 T MRI scan with inversion recovery technique. The association between both clinical and neuropsychological features and striatal uptake and volume of substantia nigra was explored.ResultsStriatal (p < 0.05), caudate (p < 0.05), and putaminal (p < 0.01) uptake was significantly lower in patients with respect to controls. Further, the volume of substantia nigra was reduced in HD when compared to controls (p < 0.01). No relationship between the volume of SN and tracer striatal uptake was found as well as between clinical and neuropsychological features with the SPECT and MRI results.ConclusionsOur results confirm that the degeneration of nigrostriatal pathway may occur in symptomatic HD patients. If confirmed by larger studies, the lack of any kind of correlation between clinical and neuropsychological features with striatal uptake and volume of substantia nigra suggests that motor and cognitive aspects in HD are not directly related to nigrostriatal degeneration.     

Magical ideation is related to questionnaire but not behavioural measures of handedness

Magical ideation has repeatedly been shown to be related to handedness, with mixed-handers exhibiting higher levels of magical thinking. However, most previous research has assessed hand preference with a questionnaire measure, leaving open the possibility that the correlation reflects some aspect of questionnaire-taking behaviour and not an underlying neuropsychological relationship. The present study addressed this issue by administering the Magical Ideation Scale (Eckblad & Chapman, 1983), the Waterloo Handedness Questionnaire-Revised (Elias, Bryden, & Bulman-Fleming, 1998), and a manual dot-filling task (Tapley & Bryden, 1985) as a behavioural measure of handedness to an undergraduate student sample. The expected relationship between magical ideation and handedness as assessed by the questionnaire was observed. However, magical ideation was not related to the behavioural measure of handedness. Results cast doubt on a neuropsychological interpretation of the relationship between handedness and magical ideation in sub-clinical populations.     

Intra-hospital Transport of Brain-Injured Patients: A Prospective, Observational Study

Introduction

Discrepant data exist regarding the incidence and severity of clinical problems related to intra-hospital transport of brain-injured patients and no consensus exists whether modern-day intra-hospital transport represents a safe or potentially problematic environment for neurointensive care unit (NICU) patients.

Methods

We examined the incidence of clinical complications and physiological derangements that occurred in 160 neurologically injured patients (90 males, 70 females, mean age 57 ± 17 years) who underwent intra-hospital transport (288 cases, 237 scheduled, 51 unscheduled) for computed tomography scans.

Results

Our findings indicate that (1) at least one significant complication (predominantly hemodynamic) occurred in over one-third (36 %) of all transports (p = n.s scheduled vs. unscheduled) necessitating the deployment of interventions designed to treat changes in arterial pressure (2) despite the presence of trained medical personnel and availability of specialized equipment, intra-cranial pressure was not adequately monitored during transports (especially in patients with intra-cranial hypertension prior to transport) (3) intra-hospital transfer was associated with minor but statistically significant clinical changes, including a reduction in arterial partial pressure of oxygen ( $ {\text{Pa}}_{{{\text{O}}_{ 2} }} $ )/inspired oxygen fraction ( $ {\text{Fi}}_{{{\text{O}}_{ 2} }} $ ) (only in the scheduled transport population), decreased arterial lactate levels (scheduled transport population), lowered body temperature (scheduled transport population), and increased arterial partial pressure of carbon dioxide ( $ {\text{Pa}}_{{{\text{CO}}_{ 2} }} $ ) (scheduled transport population).

Conclusions

Intra-hospital transport of brain-injured NICU patients may present some hazards even if performed by skilled personnel with specialized equipment. In Trauma Centers such as ours, an improvement in the frequency of neuromonitoring [intra-cranial pressure (ICP) and end-tidal CO₂ ( $ {\text{ET}}_{{{\text{CO}}_{ 2} }} $ )] during transport is recommended.     

“CADASIL coma” in an Italian homozygous CADASIL patient: comparison with clinical and MRI findings in age-matched heterozygous patients with the same G528C NOTCH3 mutation

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by mutations in the NOTCH3 gene, with a striking variability in phenotypic expression. To date, only two homozygous patients have been reported, with divergent phenotypic features. We describe an Italian CADASIL patient, homozygous for G528C mutation, in whom early manifestation of the disease was migraine, but whose clinical evolution was characterized by a reversible acute encephalopathy followed by full recovery (“CADASIL coma”). Clinical evaluation, MR scan, neuropsychological and neurophysiological investigation did not reveal substantial differences between our homozygous patient and her heterozygous relatives sharing the same mutation, or between our patient and a group of heterozygous individuals with the same mutation but from different families. Skin biopsy identified peculiar features in the homozygous patient, with cytoplasmic pseudoinclusions likely containing granular osmiophilic material (GOM) in the vascular smooth muscle cells, but further studies are necessary to substantiate their possible relationships with CADASIL homozygosis. “CADASIL coma” did not seem to be specific of patient’s homozygosis, since it was observed in one of her heterozygous relatives, whereas its pathogenesis seems to be related to peculiar constellations of unknown predisposing factors. The present study demonstrated that CADASIL conforms to the classical definition of dominant diseases, according to which homozygotes and heterozygotes for a defect are phenotypically indistinguishable.     

Effect of water contamination on the shear bond strength of self-ligating brackets

PurposeThe aim of the present study is to evaluate the effect of water contamination on the shear bond strength (SBS) and adhesive remnant index (ARI) score of self-ligating brackets.Materials and methodsOne conventional bracket and three different self-ligating brackets were bonded onto 160 bovine permanent mandibular incisors, divided randomly into 8 groups. For each type of bracket, 20 samples were bonded on dry enamel and 20 after water contamination. After 24 h, all specimens were tested for SBS using an Instron Universal Testing Machine, and ARI scores were evaluated.ResultsAll groups showed clinically adequate SBSs. Quick brackets bonded onto dry enamel showed significantly higher SBSs than all other groups tested, whereas the lowest shear strength values were recorded for Step, Quick, and Damon 3MX brackets bonded onto contaminated enamel and for Damon 3MX onto dry enamel. Frequency distribution of ARI Scores showed a prevalence of ARI “2” and “3” for all the groups tested.ConclusionsWater contamination reduces the SBS of self-ligating brackets, but significant differences have been found only for Quick brackets. All groups showed a significant higher frequency of ARI Score of “2” and “3”.