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BACKGROUND AND PURPOSE Mutations in the early growth response 2 gene (EGR2) cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc finger (ZNF) DNA-binding domain. The aim of this study was to provide a clinical and molecular analysis of a novel recessive mutation in EGR2. METHODS Clinical and electrophysiological assessments of three affected patients, from a consanguineous family, were performed. Genetic analyses of EGR2 were carried out by Sanger sequencing. Functional effects of clinical recessive mutations were assessed using a mammalian two-hybrid assay. RESULTS A novel missense mutation (c.791C>T; p.P264L) in the homozygous state was detected outside the ZNF domains of the EGR2 gene. Three affected siblings presented with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. Respiratory compromise and cranial nerve dysfunction were also found. Our data indicate that the p.P264L mutation prevents interaction of EGR2 transcription factor with NAB corepressors, suggesting that a disruption of the NAB-EGR2 protein interactions can result in dramatic neuropathy. CONCLUSION Mutations in, or next to, the R1 domain of EGR2 should be considered with extreme caution for genetic counseling, since these could cause a severe neuropathy with an autosomal recessive manner of transmission.

Objective To clarify whether high frequency oscillations (HFOs, >150 Hz) exist in the thalamus. So far, HFOs have only been observed in the basal ganglia. Methods Local field potentials from the ventral intermediate nucleus of the thalamus were recorded during implantation of electrodes for deep brain stimulation in 22 patients with different tremor syndromes: Essential Tremor (N = 16), Parkinsonian Tremor (N = 3), Holmes Tremor (N = 2), and Dystonic Tremor (N = 1). Recordings were performed with up to five electrodes featuring both micro- and macroelectrode contacts. These combined micro/macro-electrodes were simultaneously advanced to the predetermined stereotactic target. 11 patients were implanted under local anaesthesia and 11 under general anaesthesia. Results HFOs were found in all investigated tremor syndromes. An in-depth analysis of the Essential Tremor sub-group revealed that medial channels recorded HFOs more frequently than other channels, and that the highest HFO peaks were observed 4 mm above target. Furthermore, macro- and microelectrode channels differed in their sensitivity to HFOs: both detected peaks in the fast HFO range (>300 Hz) but only macroelectrodes additionally detected slow HFO peaks (150–300 Hz), which were stable across several depths and channels. We did not observe significant beta-HFO phase-amplitude coupling or a modulation of HFOs by anaesthesia. Conclusion HFOs exist in the human thalamus and are not specific to any of the tremor syndromes investigated here. Their spatial distribution is focal, and they have a different appearance on micro- and macroelectrodes. Significance Our results tally with converging evidence from other studies demonstrating that HFOs occur in various disorders and subcortical areas. While data from healthy controls are not available, such an unspecific occurrence suggests that HFOs might play a role in normal brain physiology.

Recent evidence suggests that there is a link between the gut microbial community and immune-mediated disorders. Systemic sclerosis (SSc) is an autoimmune disease characterized by immunonological abnormalities, vascular lesions, and extensive fibrosis. Since the gastrointestinal tract is one of the organs most involved, the goal of this study was to explore the composition of the intestinal microbiota in SSc patients with (SSc/GI+) and without gastrointestinal involvement (SSc/GI-) in comparison to healthy controls (HC). The fecal bacterial composition was investigated by Illumina sequencing of 16 S rRNA gene amplicons. The fecal microbiota of SSc/GI+ subjects was characterized by higher levels of Lactobacillus, Eubacterium and Acinetobacter compared with healthy controls, and lower proportions of Roseburia, Clostridium, and Ruminococcus. The gut microbiota of SSc/GI- subjects was more similar to the microbiota of HC than to that of SSc/GI+ subjects albeit Streptococcus salivarius was over-represented in SSc/GI- fecal samples compared with both SSc/GI+ subjects and controls. Our study reveals microbial signatures of dysbiosis in the gut microbiota of SSc patients that are associated with clinical evidence of gastrointestinal disease. Further studies are needed to elucidate the potential role of these perturbations in the onset and progression of systemic sclerosis, and gastrointestinal involvement in particular.

Background: Myokymia of the obliquus superior muscle is a rare episodic microtremor caused by uncontrolled activities of the trochlearis nerve fibres. Epilepsy is also caused by spontaneous discharges of neurons. In our report we present an associated epilepsy which to the best of our knowledge is described for the first time. Patient: An 61-year old man with twitches of the right eye for 6 weeks and a subjective feeling of eye movement was investigated at our hospital. His history was void of any ophthalmologic diseases. However, he suffered from cryptogenetic epilepsy known since childhood. The morphological and orthoptical findings of his eyes were normal. During the slit-lamp investigation a unilateral rotating microtremor of the right eye induced by looking downward was seen. The neurologic investigation, magnetic resonance imaging and assessment of the thyreoid function did not show further pathological results. The patient underwent treatment with carbamazepine. Under this therapy he did not show any symptoms of myokymia during follow-up. Summary: To the best of our knowledge this is the first case of myokymia of the obliquus superior muscle associated to epilepsy. To our opinion, any case of this syndrome should be investigated for epilepsy. A causal relation is unlikely since the most probable etiologies are either spontaneous discharges of trochlear nucleus neurons or a close contact between vessel and nerve analogously to trigeminal neuralgia.

Background: Medicare has proposed quality-of-care indicators for chronic hepatitis C virus (HCV) infection. The extent to which these standards are met in practice is largely unknown. Objective: To evaluate the quality of health care that patients with HCV receive and the factors associated with receipt of quality care. Design: Retrospective cohort study. Setting: Nationwide U.S. health insurance company research database. Participants: 10 385 patients with HCV enrolled in the database between 2003 and 2006. Patients were included if they were eligible for at least 1 quality indicator. Measurements: Quality of HCV care received by patients, as measured by 7 explicit quality indicators included in Medicare's 2009 Physician Quality Reporting Initiative. Results: Proportions of patients meeting quality indicators varied, ranging from 21.5% for vaccination to 79% for the HCV genotype testing indicator. Overall, 18.5% of patients (95% CI, 18% to 19%) received all recommended care. Older age and presence of comorbid conditions were associated with lower quality, whereas elevated liver enzyme levels, cirrhosis, and HIV infection were associated with higher quality. Patients who saw both generalists and specialists received the best care (odds ratio of receiving care for which a patient is eligible: specialists alone, 0.79 [CI, 0.66 to 0.95]; primary care physician alone, 0.44 [CI, 0.40 to 0.48]). Limitations: The study had an observational retrospective design, used a convenience sample, and had no information on patient ethnicity. It may be that the indicators or the reporting of the indicators of HCV care—and not the care itself—is suboptimum. Conclusion: Health care quality, based on Medicare criteria, is suboptimum for HCV. Care that included both specialists and generalists is associated with the best quality. Our results support the development of specialist and primary care collaboration to improve the quality of HCV care. Primary Funding Source: Saint Louis University Liver Center.

A variety of infectious and autoimmune diseases are described in association with pupillotonia. To our knowledge there is only one report on pupillotonia associated with hemiatrophia faciei. We describe another patient with this rare association. The aim is to investigate possible associations between both diseases.A twenty five-year-old male patient with hemiatrophia faciei, epilepsy and pupillotonia of the right eye since his twelfth birthday was presented for the first time at the age of fourteen at our institution. The patient underwent a complete neurological and paediatric as well as otolaryngological investigation; there was also an investigation by the internist. The patient also underwent a complete serological investigation for infectious and autoimmune disorders as well as an investigation of the local and systemic vascular reactivity by the "Ocular cold pressor test". The follow-up time is 11 years.The clinical picture of our patient was an association of hemiatrophia faciei, epilepsy and pupillotonia. There was no evidence of a local hyperactivity of the sympathetic nervous system. The serological investigation showed an elevated value of antinuclear antibodies.We assume that in our case the pupillotonia as well as the hemiatrophia faciei and the epilepsy is caused by a common autoimmune factor. All other aetiologies for these three diseases were excluded. Furthermore, the occurrence of pupillotonia, hemiatrophia faciei and epilepsy was simultaneous.

Myokymia of the obliquus superior muscle is a rare episodic microtremor caused by uncontrolled activities of the trochlearis nerve fibres. Epilepsy is also caused by spontaneous discharges of neurons. In our report we present an associated epilepsy which to the best of our knowledge is described for the first time.An 61-year old man with twitches of the right eye for 6 weeks and a subjective feeling of eye movement was investigated at our hospital. His history was void of any ophthalmologic diseases. However, he suffered from cryptogenetic epilepsy known since childhood. The morphological and orthoptical findings of his eyes were normal. During the slit-lamp investigation a unilateral rotating microtremor of the right eye induced by looking downward was seen. The neurologic investigation, magnetic resonance imaging and assessment of the thyreoid function did not show further pathological results. The patient underwent treatment with carbamazepine. Under this therapy he did not show any symptoms of myokymia during follow-up.To the best of our knowledge this is the first case of myokymia of the obliquus superior muscle associated to epilepsy. To our opinion, any case of this syndrome should be investigated for epilepsy. A causal relation is unlikely since the most probable etiologies are either spontaneous discharges of trochlear nucleus neurons or a close contact between vessel and nerve analogously to trigeminal neuralgia.

Three substances known to act on N-acetylneuraminic acid (NANA), were tested for their activity on rat peritoneal mast cells. Both neuraminidase, which splits off NANA, and the lectin from Cepaea nemoralis directed against NANA are histamine releasers. Periodate itself did not trigger the cells but inhibited the releasing action of other substances. The results provide further evidence for the role of NANA in the triggering of mast cells. A cytotoxic substance, benzyl-polyethylene imine, triggers mast cells without affecting NANA. In addition, the role of histamine-BSA conjugates as histamine releasers is described.

The guinea pig alveolar surfactant reduces the contraction of the isolated guinea pig ileum, induced by Angiotensin II. It is tentatively proposed, that the surfactant system suppresses the reactivity of lung blood vessels towards contacting stimuli.

Protamine sulfate, known for a long time as a histamine releaser, was labeled with a fluorescent dye (FITC). This conjugate was shown to stain selectively the mast cell fraction of rat peritoneal cells. Within a few seconds, the protamine was found inside the cells. Although the cells had lost their histamine completely, no granules were found outside the cells. In the electron microscope, the protamine treated mast cells showed a loss of the electron density of their granules, a vacuolization, and other signs of histamine release. Evidence for a direct connection between the vacuoles and the extracellular fluid was gained by incubating mast cells in FITC-labeled human serum albumin followed by the addition of unlabeled protamine. After washing, the fluorescence was found to be located inside the cells, demonstrating an influx of the FITC-HSA under the influence of protamine. The protamine-induced release reaction is increased after addition of Ca2+, reduced by lowering the temperature, addition of 2-deoxyglucose, or cytochalasin B. Disodium cromoglycate also diminished the histamine release in a dose dependent manner. Protamine did not induce a loss of lactate dehydrogenase from the mast cells. The release reaction is mediated by the cell membrane, as shown by the releasing activity of insolubilized protamine. We conclude that the protamine-induced release is a non-cytotoxic reaction, fulfilling some criteria of the anaphylactic histamine release.

A rosetting of isolated rat mast cells with complement coated zymosan does not induce a histamine release. However, this procedure potentiated the release induced by ATP. Treatment of rats with prednisolone diminishes the number of the rosette forming mast cells.

Using fluoresceine isothiocyanate labeled protamine sulfate it is possible to stain rat mast cell fractions of isolated periotoneal cells in a selective way. The cells are not degranulated, though they have lost their histamine completely. The method shows the dissociation of the mediator release and the extrusion of the granules.

Using rat complement-treated zymosan particles a rosetting of purified rat peritoneal mast cells could be demonstrated. The question was investigated whether the binding of activated complement could be a trigger of histamine release. Varying the degree of complement label on the zymosan particles, the time and temperature of incubation and the dependence on Ca2+ ions, we could not induce a release of histamine in any case. The addition of labeled zymosan increased slightly the mediator release induced by ATP. The immunologic significance of the complement receptors on mast cells is still unclear.

The protamine sulfate-induced release of histamine from rat mast cells is a non-cytotoxic reaction, similar to the 48/80-induced secretion. Polyethylene imine was found to be a less potent releaser. It is a cytotoxic substance without specificity for mast cells and acts on membranes generally. Although the two agents are related concerning their molecular weight and polybasicity, their mode of action on mast cells is clearly different.

2-Cyanoethylurea (2; CEU or BA 1-4) obtainable from 1-carboxamido-2-cyanoaziridine (2; BA l) by ring fission possesses immunomodulating properties like its parent compound containing the intact aziridine ring, as well as other 2-cyanoaziridine (1) derivatives. As was shown in a mouse model, CEU accelerated the time of rejection of skin allografts (immunostimulation) and reduced the prolonged tolerance time of mice immunosuppressed with cyclophosphamide to values found in normal control animals (immunorestoration).

Literature review. Mast cells and basophils are included not only in anaphylactic but also in complement activating and cell-mediated immune reactions. A histamine release can be induced via the IgE mechanism, the anaphylatoxins, the histamine releasing activity, and by other reactions. Histamine and several other mediators induce a local inflammation reaction either by a direct action on their target cells or indirectly by the activation of other humoral and/or cellular effector systems. Histamine influences several immune reactions. Here, its influence on histamine receptor-bearing lymphocytes is discussed more in detail. Using in vitro test systems, it has been shown that histamine has a dual effect, it induces a suppression when applied in higher concentrations, while low concentrations are stimulating. In vivo, histamine receptor-bearing lymphocytes have suppressive functions, mediated by H2 receptors. Some preliminary evidence for the inclusion on histamine in the immunoreagulation of patients with several diseases is presented.

Antisera produced in rabbits against Triton X-100 solubilized human erythrocyte ghosts formed several several precipitation lines in immunoelectrophoresis and immunodiffusion tests against the solubilized ghosts. The antisera were used for detecting several membrane components during chromatographic separation. A membrane component was partially isolated using gel filtration on SEPHADEX G-200 (fraction F1/F2). Spectrin (Tektin A) was shown to be the main moiety of these fractions. Associated proteins (haemoglobin, GAPD) could not be detected by the antisera against whole ghost solubilisate.

The histamine binding capacity of cells in various lymphoid organs has been determined by flow cytofluorometric (FCF) analysis of histamine receptors. Using fluoresceinated bovine serum albumin conjugated to histamine (HIS-BSA-FITC) as a staining reagent two distinct lymphocyte subpopulations of differing fluorescence intensity have been identified in each organ investigated. The thymus has a low number of histamine-receptor bearing cells, while bone marrow, lymph nodes and spleen reveal increasing binding capacities to the histamine conjugate. It is suggested that there exists a different susceptibility of distinct lymphocyte subpopulations for histamine, thereby enabling its controlled immunoregulatory activity.

The supernatant of mitogen- or antigen-stimulated mononuclear cell cultures is known to contain a large number of biologically active molecules. In the present study, we have stimulated human mononuclear cells and rat spleen cells with Con A or antigen (PPD) respectively to produce lymphokines, such as histamine releasing factor (HRF), which is capable of causing histamine release from rat mast cells and human basophils. Histamine was measured fluorimetrically by Shore et al. This assay is sensitive and reproducible: replicates varied by less than 15% in triplicate samples.

In 43 recipients of allogenic cadaver kidneys before and three times a week after transplantation to the discharge from the hospital care the antibody titre against the Thomsen-Friedenreich-antigen (Anti-T) was determined and the score value was calculated from the agglutination intensity. A prognostic significance of the value got before operation could not be found. No changes of the titre appeared under the influence of the postoperatively performed immunosuppression as well as in connection with rejection crises. In 9 patients with clinically manifest systemic infections (8 cytomegalovirus infections, 1 bacterial infection) unequivocal (greater than or equal to 8 fold) increases of the anti-T-titre could be proved. These findings speak for an infection-induced formation of these cross-reacting anti-T-antibodies.

The carbohydrate binding glycoprotein Anti-AHP binds to the plasma membrane of the (transformed) L-cell both in agglutination reactions and by the immunofluorescence technique. On the surface of (normal) mouse embryo fibroblast cells Anti-AHP receptors were not detectable. Anti-AHP is suitable as another marker for L cells. The random distribution of the binding sites at 4 degrees C changes with elevated temperatures (clustering, capping of sites). Anti-AHP inhibits the growth of L cells much more than that of fibroblasts. It does not act as a mitogen for the investigated cells.

The combined application of psoralen and UVA radiation to skin grafts induced a prolongation of the survival time of the grafts in mice. This was observed using the H-Y barrier, an allogeneic barrier without H-2 disparities, and a strong H-2 incompatible barrier. The effect is probably due to a reduction of antigen-presenting cells, or to other, unknown mechanisms.