Internalization of non-clustered desmoglein 1 without depletion of desmoglein 1 from adhesion complexes in an experimental model of the autoimmune disease pemphigus foliaceus

Serum antibodies against desmoglein 1 (Dsg1) are known to induce the clinical and histological manifestations of pemphigus foliaceus (PF), autoimmune bullous disease targeting skin. The basic pathophysiological phenomenon of PF blistering is the disruption of epithelial integrity in the granular layer of the epidermis due to separation of keratinocytes from one another, or acantholysis. In this report we investigate the changes in subcellular distribution of Dsg1 in response to serum of patients with PF by using an in vitro model of PF. Immunofluorescence analysis on HaCaT cells indicates that non-clustered Dsg1 is markedly internalized after exposure to serum. However, binding of PF IgG to Dsg1-rich adhesion complexes (desmosomes) does not cause disruption of such structures nor depletion of clustered Dsg1, as revealed by colocalization of PF IgG and Dsg1 in a punctate staining on cell membrane 24 hours after treatment. Furthermore, morphological studies demonstrate that the dramatic alterations induced by PF sera are not the result of apoptotic programs. Taken together, our data strongly suggest that anti-Dsg1 antibodies from PF serum could cause the internalization of non-clustered Dsg1 and perturb the formation of new desmosomes but not directly disrupt Dsg1-containing junctions when stable contacts are already formed.     

Distinguishing between neuropsychological malingering and exaggerated psychiatric symptoms in a neuropsychological setting

It is unclear whether symptom validity test (SVT) failure in neuropsychological and psychiatric domains overlaps. Records of 105 patients referred for neuropsychological evaluation, who completed the Test of Memory Malingering (TOMM), Reliable Digit Span (RDS), and Millon Clinical Multiaxial Inventory-III (MCMI-III), were examined. TOMM and RDS scores were uncorrelated with MCMI-III symptom validity indices and factor analysis revealed two distinct factors for neuropsychological and psychiatric SVTs. Only 3.5% of the sample failed SVTs in both domains, 22.6% solely failed the neuropsychological SVT, and 6.1% solely failed the psychiatric SVT. The results support a dissociation between neuropsychological malingering and exaggeration of psychiatric symptoms in a neuropsychological setting.     

Beyond zoster: sensory and immune changes in zoster-affected dermatomes: a review*

Neuroepidermal tropism of varicella-zoster virus accounts for cutaneous and nerve lesions following herpes zoster. Skin lesions heal in a few weeks and may or may not leave visible scars. Nerve lesions involve peripheral sensory fibres, sometimes causing permanent damage that results in partial denervation of the affected dermatome. The effects of the nerve injury involve the sensibility function, thus causing neuralgia, itch, allodynia, hypo- or anaesthesia, as well as the immune function that is related to neuropeptide release, thus altering immune control in the affected dermatome. The neuro-immune destabilization in the zoster-infected site paves the way for the onset of many and various immunity-related disorders along the affected dermatome.     

Behavioral alterations and changes in Ca/calmodulin kinase II levels in the striatum of connexin36 deficient mice

Gap junctions (GJ) are intercellular channels which directly connect the cytoplasm of adjacent cells. GJ allow direct cell-to-cell communication via the diffusion of ions, metabolites and second messengers such as IP₃. The connexin36 (Cx36) protein has been detected in GJ between interneurons of the hippocampus, cerebral cortex, striatum, amygdala, the inferior olive, cerebellum and other brain structures, such as the olfactory bulb. Cx36 knockout (Cx36 KO) mice display changes in synchronous network oscillations in the hippocampus, neocortex and inferior olive and exhibit impaired spatial alternation and one-trial object recognition in a Y-maze. Here, we further characterized the behavioral changes induced by Cx36 deficiency in the mouse by using different behavioral measures and experimental procedures. Additionally, we examined the effects of Cx36 deficiency on acetylcholine esterase (AChE) activity and calcium calmodulin kinase II alpha (CaMKII) protein levels in the striatum. The homozygous Cx36 KO mice displayed increased locomotion and running speed in the open-field, reduced object exploration and impaired one-trial object-place recognition. Furthermore, they exhibited more anxiety-like behavior as compared to the heterozygous controls in the light-dark box. Homozygous Cx36 KO mice exhibited reduced CaMKII levels in the striatum as compared to the heterozygous mice. AChE activity in the striatum was not significantly different between groups. The present results suggest that Cx36 deficiency in the mouse leads to reduced CaMKII levels in the striatum and behavioral changes in open-field activity, anxiety-related behavior in the light-dark box and one-trial object-place recognition.     

Intranasally applied L-DOPA alleviates parkinsonian symptoms in rats with unilateral nigro-striatal 6-OHDA lesions

l-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective drug for therapy of Parkinson's disease. However, the current clinical route of L-DOPA administration is variable and unreliable because of problems with drug absorption and first-pass metabolism. Administration of drugs via the nasal passage has been proven an effective alternate route for a number of medicinal substances. Here we examined the acute behavioral and neurochemical effects of intranasally (IN) applied L-DOPA in rats bearing unilateral lesions of the medial forebrain bundle, with severe depletion (97%) of striatal dopamine. Turning behavior in an open field, footslips on a horizontal grid and postural motor asymmetry in a cylinder were assessed following IN L-DOPA or vehicle administration with, or without, benserazide pre-treatment. IN L-DOPA without benserazide pre-treatment mildly decreased ipsilateral turnings and increased contralateral turnings 10-20 min after the treatment. IN L-DOPA with saline pre-treatment reduced contralateral forelimb-slips on the grid while no effects were evident in the cylinder test. These results support the hypothesis that L-DOPA can bypass the blood-brain barrier by the IN route and alleviate behavioral impairments in the hemiparkinsonian animal model.     

Low-dose intravenous cyclophosphamide in systemic sclerosis: an open prospective efficacy study in patients with early diffuse disease

OBJECTIVE: To investigate the efficacy of a treatment with low-dose intravenous cyclophosphamide (CYC) and low-dose prednisone in early diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Patients with dcSSc and a disease duration <24 months consecutively admitted to a tertiary centre underwent a prospective 1-year study. They were treated with i.v. CYC 500 mg/pulses, 10 mg prednisone equivalent, and supportive therapy. Modified Rodnan skin score (mRss), Health Assessment Questionnaire-Disability Index (HAQ-DI), forced vital capacity (FVC), and diffusing lung capacity for CO (DLCO) were assessed as outcome measures. In addition, the nine Medsger severity scale scores were evaluated. RESULTS: mRss and DLCO significantly improved at both 6 (p = 0.002 and 0.012, respectively) and 12 months (p = 0.002 and 0.003, respectively). HAQ-DI showed a nearly significant reduction at 12 months (p = 0.06). Medsger's severity scores also improved for general condition (p = 0.001), peripheral vascular (p = 0.05), skin (p = 0.02), joint/tendon (p = 0.001), muscle (p = 0.05), and lung (p = 0.02). No treatment interruption was needed. CONCLUSIONS: This preliminary study suggests a role for low-dose i.v. CYC in the treatment of early dcSSc. Controlled studies are warranted.     

Cerinolactone, a hydroxy-lactone derivative from Trichoderma cerinum

A novel metabolite, 3-hydroxy-5-(6-isopropyl-3-methylene-3,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl)dihydrofuran-2-one, trivially named cerinolactone (1), has been isolated from culture filtrates of Trichoderma cerinum together with three known butenolides containing the 3,4-dialkylfuran-2(5H)-one nucleus, harzianolide (2), T39butenolide (3), and dehydroharzianolide (4). The structure of 1 was determined by spectroscopic methods, including UV, MS, and 1D and 2D NMR analyses. In vitro tests with the purified compound exhibited activity against Pythium ultimum, Rhizoctonia solani, and Botrytis cinerea.     

Thalamic metabolic abnormalities in patients with Huntington's disease measured by magnetic resonance spectroscopy

Huntington''s disease (HD) is a neurologic disorder that is not completely understood;its fundamental physiological mechanisms and chemical effects remain somewhatunclear. Among these uncertainties, we can highlight information about theconcentrations of brain metabolites, which have been widely discussed. Concentrationdifferences in affected, compared to healthy, individuals could lead to thedevelopment of useful tools for evaluating the progression of disease, or to theadvance of investigations of different/alternative treatments. The aim of this studywas to compare the thalamic concentration of metabolites in HD patients and healthyindividuals using magnetic resonance spectroscopy. We used a 2.0-Tesla magneticfield, repetition time of 1500 ms, and echo time of 135 ms. Spectra from 40 adult HDpatients and 26 control subjects were compared. Quantitative analysis was performedusing the LCModel method. There were statistically significant differences between HDpatients and controls in the concentrations ofN-acetylaspartate+N-acetylaspartylglutamate(NAA+NAAG; t-test, P<0.001), andglycerophosphocholine+phosphocholine (GPC+PCh; t-test, P=0.001)relative to creatine+phosphocreatine (Cr+PCr). The NAA+NAAG/Cr+PCr ratio wasdecreased by 9% and GPC+PCh/Cr+PCr increased by 17% in patients compared withcontrols. There were no correlations between the concentration ratios and clinicalfeatures. Although these results could be caused by T1 and T2 changes, rather thanvariations in metabolite concentrations given the short repetition time and long echotime values used, our findings point to thalamic dysfunction, corroborating priorevidence.