Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis

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Zosterops intermedia mentoris nom. nov

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Ciclosporin A proof of concept study in patients with active, progressive HTLV-1 associated myelopathy/tropical spastic paraparesis

Introduction

Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-α, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP.

Materials and Methods

Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA), in seven patients with ‘early’ (50% deterioration in timed walk during the preceding three months) HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure.

Results

All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas) disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse.

Conclusions

These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agent''s safety and effectiveness in larger, randomised controlled studies in carefully selected patients with disease progression.     

The Galls on Forsythia intermedia Zab.

The galls on Forsythia intermedia Zab. consist of much-branched,root-like structures embedded in corky material which appearsto be sloughed-off from them. These gall ‘roots’have 7 to 14 vascular bundles compared with the 5 of normalroots and contain much more IAA. When galls were incubated in damp chambers the gall ‘roots’extended their growth. These extensions had a root-cap and root-hairsbut also had more vascular bundles than normal and they didnot respond geotropically like normal roots. Two fungi, Gibberella baccata (Wallr.) Sacc. (conid, stat. Fusarlumlateritium Nees.) and Phomopsis dominici Trav. were associatedwith die-back of gall ‘roots’ and two bacteria resemblingCorynebacterium fascians (Til.) Dowson and Agrobacterium tumefaciens(Sm. and Towns.) Conn respectively were isolated from galls.All produced IAA in culture media but their role in the etiologyof the gall, if any, remains in doubt.     

Preferences for Call Spectral Properties in Hyla intermedia

We studied the pattern of variation in the spectral properties of male advertisement calls and female preference functions for these same properties in the Italian treefrog (Hyla intermedia). The call spectral properties (fundamental and dominant frequencies) were highly negatively correlated with body size, they showed low within‐individual variation, and, at the population level, they were found to be under weak stabilizing selection. In two‐choice discrimination tests, females did not show preferences between calls with fundamental and dominant frequencies within two standard deviations from the population mean, whereas females significantly discriminated against calls when their frequencies were three (or more) standard deviations above or below the population mean. Consistent with the observed permissiveness in female preference over the call spectral structure, in the natural population, we found no evidence either of directional selection on male body size or of a size‐assortative mating pattern. The pattern of preferences observed at the population level did not mirror the preferences of individual females. In fact, in a multi‐trial discrimination experiment, females showed significant differences in their choice between the average frequency call and a two standard deviation lower than average frequency alternative, for which no significant preferences were observed at the population level. Variations in preference were not found to correlate with female body size.     

Diurnal rhythm of hypophyseal cells in mich. II. Pars intermedia.

By the use of Mac Conaill's lead hematoxylin, periodic acid and Schiff's reagent (PAS, PbH-positive and PAS-positive cells were distinguished in the pars intermedia of the hypophysis in mice. Nuclear volume in PbH-positive and PAS-positive cells in the pars intermedia of the hypophysis in male and female mice under conditions of 12 h light and 12 h darkness shows distinct diurnal rhythmicity. Maximum nuclear volume in PbH-positive cells of the pars intermedia in both sexes was observed at 1800 h, and minimum at 2400 h. In the Pas-positive cells in females maximum nuclear volume was observed at 600 h, and minimum at 2400 h. In males maximal nuclear volume in these cells appears at 2400 h, and minimum at 1800 h. Maximum number of vacuoles in the nuclei of PbH-positive cells in the pars intermedia in both sexes appeared at 1800 h, and minimum at 2400 h. Maximum numbers of vacuoles in the nuclei of PAS-positive cells in females was noted at 1200 h, and minimum at 2400 h. In males the maximum number of vacuoles appeared at 600 h, and minimum at 1200 h. Differences in the number of vacuoles in the nuclei of PAS-positive cells between males and females were also noted.     

Coaggregation of Porphyromonas gingivalis and Prevotella intermedia.

Porphyromonas gingivalis cells coaggregated with Prevotella intermedia cells. The coaggregation was inhibited with L-arginine, L-lysine, Nalpha-p-tosyl-L-lysine chloromethyl ketone, trypsin inhibitor, and leupeptin. Heat- and proteinase K-treated P. gingivalis cells showed no coaggregation with P. intermedia cells, whereas heat and proteinase K treatments of P. intermedia cells did not affect the coaggregation. The vesicles from P. gingivalis culture supernatant aggregated with P. intermedia cells, and this aggregation was also inhibited by addition of L-arginine or L-lysine and by heat treatment of the vesicles. The rgpA rgpB, rgpA kgp, rgpA rgpB kgp, and rgpA kgp hagA mutants of P. gingivalis did not coaggregate with P. intermedia. On the other hand, the fimA mutant lacking the FimA fimbriae showed coaggregation with P. intermedia as well as the wild type parent. These results strongly imply that a heat-labile and proteinous factor on the cell surface of P gingivalis, most likely the gingipain-adhesin complex, is involved in coaggregation of P. gingivalis and P. intermedia.     

Mitochondrial abnormalities in progressive ophthalmoplegia.

A clinically diagnosed case of progressive external ophthalmoplegia was biopsied and ultrastructurally evaluated. The disease was found to be characterized by numerous giant mitochondria. The intramitochondrial changes consisted of either swirls of cristae or of paracrystalline structures which were in apposition with the membranes of the cristae. The internal structure of the paracrystalline units consisted of parallel bands of material which were aligned in the same plane as the membranes of the related cristae.     

Postural stability during gait for adults with hereditary spastic paraparesis

Individuals with hereditary spastic paraparesis (HSP) are often impaired in their ability to control posture as a result of the neurological and musculoskeletal implications of their condition. This research aimed to assess postural stability during gait in a group of adults with HSP. Ten individuals with HSP and 10 healthy controls underwent computerized gait analysis while walking barefoot along a 10-m track. Two biomechanics methods were used to assess stability: the center of pressure and center of mass separation (COP-COM) method, and the extrapolated center of mass (XCOM) method. Spatiotemporal and kinematic variables were also investigated. The XCOM method identified deficits in mediolateral stability for the HSP group at both heel strike and mid-stance. The group with HSP also had slower walking velocity, lower cadence, more time spent in double stance, larger step widths, and greater lateral trunk flexion than the control group. These results suggest that individuals with HSP adjust characteristics of their gait to minimize the instability arising from their impairments but have residual deficits in mediolateral stability. This may result in an increased risk of falls, particularly in the sideways direction.