Efficacy and safety of Privigen® in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective, single-arm, open-label Phase III study (the PRIMA study)

This prospective, multicenter, single-arm, open-label Phase III study aimed to evaluate the efficacy and safety of Privigen (R) (10% liquid human intravenous immunoglobulin [IVIG], stabilized with l-proline) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients received one induction dose of Privigen (2g/kg body weight [bw]) and up to seven maintenance doses (1g/kg bw) at 3-week intervals. The primary efficacy endpoint was the responder rate at completion, defined as improvement of 1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The preset success criterion was the responder rate being 35%. Of the 31 screened patients, 28 patients were enrolled including 13 (46.4%) IVIG-pretreated patients. The overall responder rate at completion was 60.7% (95% confidence interval [CI]: 42.41%-76.43%). IVIG-pretreated patients demonstrated a higher responder rate than IVIG-naive patients (76.9% vs. 46.7%). The median (25%-75% quantile) INCAT score improved from 3.5 (3.0-4.5) points at baseline to 2.5 (1.0-3.0) points at completion, as did the mean (standard deviation [SD]) maximum grip strength (66.7 [37.24] kPa vs. 80.9 [31.06] kPa) and the median Medical Research Council sum score (67.0 [61.5-72.0] points vs. 75.5 [71.5-79.5] points). Of 108 adverse events (AEs; 0.417 AEs per infusion), 95 AEs (88.0%) were mild or moderate in intensity and resolved by the end of study. Two serious AEs of hemolysis were reported that resolved after discontinuation of treatment. Thus, Privigen provided efficacious and well-tolerated induction and maintenance treatment in patients with CIDP

Identification and characterization of nanobodies targeting the EphA4 receptor

The ephrin receptor A4 (EphA4) is one of the receptors in the ephrin system that plays a pivotal role in a variety of cell-cell interactions, mostly studied during development. In addition, EphA4 has been found to play a role in cancer biology as well as in the pathogenesis of several neurological disorders such as stroke, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease. Pharmacological blocking of EphA4 has been suggested to be a therapeutic strategy for these disorders. Therefore, the aim of our study was to generate potent and selective Nanobodies against the ligand-binding domain of the human EphA4 receptor. Weidentified two Nanobodies, Nb 39 and Nb 53, that bind EphA4 with affinities in the nanomolar range. These Nanobodies were most selective for EphA4, with residual binding to EphA7 only. Using Alphascreen technology, we found that both Nanobodies displaced all known EphA4-binding ephrins from the receptor. Furthermore, Nb39 andNb53 inhibited ephrin-induced phosphorylationoftheEphA4proteininacell-basedassay. Finally, in a cortical neuron primary culture, both Nanobodies were able to inhibit endogenous EphA4-mediated growth-cone collapse induced by ephrin-B3. Our results demonstrate the potential of Nanobodies to target the ligand-binding domain of EphA4. These Nanobodiesmaydeservefurtherevaluationaspotentialtherapeutics in disorders in which EphA4-mediated signaling plays a role

Higher Plant Acclimation to Solar Ultraviolet-B Radiation

Plant acclimation to natural and intensified solar UV-B irradiance was investigated in three species, Oenothera stricta Ledeb., Rumex obtusifolius L., and R . patientia L. The objectives of this study were to determine: (1) the relationship between plant sensitivity and epidermal UV attenuation, (2) the effect of phenotypic changes in the leaf epidermis, resulting from UV-B exposure, on plant sensitivity to UV radiation, and (3) the plasticity of these changes in the epidermis leading to plant acclimation to UVB radiation. Epidermal UV transmittance was found to differ in magnitude and spectral distribution among the three species examined in this study. Epidermal tissue from the leaves of Oenothera stricta, Rumex obtusifolius, and R. patientiaattenuated up to 951, 90%, and 851 of the UV-B radiation incident on the leaf, respectively. The spectral distribution of transmittance appeared to be characteristic of each species. The capacity of the epidermis to attenuate UV-B radiation was found to have some degree of plasticity in Oenothera stricta and Rumex obtusifolius. After exposure to UV-B radiation for periods of 11 to 15 days, at a mean dose rate of approximately 2050 biologically effective J·m·-2d-1 , epidermal UV-B transmittance was significantly reduced by up to 36% in mature leaves of O. stricta. Increased capacity of the epidermis to attenuate UV-B radiation was not observed in young leaves of this species. These leaves only transmitted about 4% of the UV-8 radiation incident on the leaf, The transmittance of shorter wavelengths of visible radiation was reduced by 6 to 14% in young and mature leaves after UV-B irradiation. A similar reduction in epidermal UV-8 transmittance in the leaves of R. obtusifolius was also observed. Ultraviolet absorbance in leaf epidermal and mesophyll tissue of Oenothera stricta generally increased in response to UV-B irradiation. Absorbance increased more in young leaves than mature leaves after UV-B irradiation. This increase in UV absorbance was also found in mature leaves of Rumex obtusifolius and R. patientia after UV-B irradiation. The increase in absorbance was most likely caused by an increase in flavonoid and related phenolic compounds in leaf tissues. The rate of photosynthesis was used as an indicator of the degree of plant sensitivity to UV-B radiation. In general, photosynthesis was not significantly depressed in the leaves of any of the three species. A trend toward photosynthetic depression in response to UV-B irradiation was found, however, and thus some degree of UV-B sensitivity is suggested in these species. A limited degree of plant acclimation was suggested in plants that were exposed to a low UV-B dose rate prior to a higher dose rate. A mechanism of UV-B attenuation, possibly involving the biosynthesis of UV-ab sorbing flavonoid compounds in the epidermis and mesophyll under the stress of UV-B radiation, and a subsequent increase in the UV-B attenuation capacity of the epidermis, is suggested. The degree of plant sensitivity and acclimation to natural and intensified solar UV-B radiation may involve a dynamic balance between the capacity for UV-B attenuation and UV-radiation-repair mechanisms in the leaf

Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS

Defects in axonal transport are thought to contribute to the pathogenesis of neurodegenerative disease. Because α-tubulin acetylation facilitates axonal transport, inhibition of the α-tubulin deacetylating enzymes, histone deacetylase 6 (Hdac6) and silent information regulator 2 (Sirt2), is thought to be an interesting therapeutic strategy for these conditions. Amyotrophic lateral sclerosis (ALS) is a one such rapidly progressive and fatal neurodegenerative disorder, in which axonal transport defects have been found in vitro and in vivo. To establish whether the inhibition of Hdac6 or Sirt2 may be of interest for ALS treatment, we investigated whether deleting Hdac6 or Sirt2 from the superoxide dismutase 1, SOD1G93A mouse affects the motor neuron degeneration in this ALS model. Deletion of Hdac6 significantly extended the survival of SOD1G93A mice without affecting disease onset, and maintained motor axon integrity. This protective effect was associated with increased α-tubulin acetylation. Deletion of Sirt2 failed to affect the disease course, but also did not modify α-tubulin acetylation. These findings show that Hdac6, rather than Sirt2, is a therapeutic target for the treatment of ALS. Moreover, Sirt2 appears not to be a major α-tubulin deacetylase in the nervous syste

Leaf Epidermal Transmittance of Ultraviolet Radiation and Its Implication for Plant Sensitivity to Ultraviolet-Radiation Injury

Leaf epidermal transmittance of ultraviolet radiation (280-400 nm) was examined in several plant species to determine the capability of the epidermis to attenuate solar ultraviolet radiation. Epidermal samples were mechanically isolated and examined with a spectroradiometer/integrating sphere for transmittance. A survey of 25 species exposed to natural insolation was conducted. Although the species differed in life form, habitat type, and epidermal characteristics, epidermal transmittance was generally less than 10%. Ultraviolet radiation was attenuated 95 to 99% in more than half of the species. In 16 species, flavonoid and related pigments in the epidermis accounted for 20 to 57% of the attenuation. Several species exposed to supplemental ultraviolet irradiation (288-315 run) in a greenhouse exhibited significant (p≤0.05) depressions in epidermal transmittance of 31 to 47%, apparently resulting from an increase in ultraviolet-absorbing pigments

Pinus Ponderosa Seedling Establishment and the Influence of Competition with the Bunchgrass Agropyron Spicatum

Interspecific competition between Agropyron spicatum (Pursh.) Scrib. & Smith bunchgrasses and naturally established seedlings of Pinus ponderosa was examined within a pine/bunchgrass community. A wire mesh was used to separate bunchgrass culms from pine seedling shoots to determine if the bunchgrass canopy influenced the survival of pine seedlings. In addition, two lengths of root exclusion tubes were used to determine the effects of bunchgrass root overlap on pine seedlings. The bunchgrass canopy did not significantly affect pine seedling survival. However, root competition, presumably for water, significantly decreased pine seedling survival. Exclusion of bunchgrass roots from a 0.15-m- and 0.30-m-deep root zone of pine seedlings resulted in 40% and 80% reductions in mortality, respectively. Root exclusion also significantly delayed mortality 2-3 wk. Pine seedlings developed taproots that reached below the zone of maximum bunchgrass root density within 4 wk of germination. The pine/bunchgrass community is dominated by two species that utilize similar resource zones in the soil during the establishment of pine germinants in the bunchgrass understory. Interspecific competition tends to be greatest during this establishment stage and becomes reduced as pine seedlings grow and explore the deeper regions of the soil profile. In areas with shallow soils and an established bunchgrass understory, establishment of pine seedlings may occur successfully only if soil moisture is available in deeper soil horizons during the summer

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency < 0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency < 0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology