Asfotase alfa mineralizes the HPP skeleton, including the ribs, and improves respiratory function and survival in life-threatening perinatal and infantile HPP.

The development of aprotic lithium-oxygen (Li-O2) batteries suffers from high charging overvoltages. Dissolved redox mediators, like nitroxides, providing increased energy efficiency and longer lifetime are promising tools to overcome this challenge. Since this auspicious concept is still in its infancy, the underlying chemical reactions as well as the impact of the different (electro)chemical parameters are poorly understood. Herein, we derive an electrochemical model for the charging reactions, which is validated by potentiostatic measurements. The model elucidates the impact of the major factors including basic cell parameters and the chemical properties of the redox mediator. The model is applied to the promising class of nitroxides, which is systematically investigated by using derivatives of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy), AZADO (2-azaadamantane-N-oxyl), and an azaphenalene based nitroxide. The nitroxides are electrochemically characterized by cyclic voltammetry and their performance as redox mediators is studied in Li-O2 batteries with an ether-based electrolyte. Based on the presented model, the charging profiles of the different nitroxide redox mediators are correlated with their molecular structures.

No abstract

No abstract

The granulocyte antigens HNA-1a, -1b, and -1c (formerly named NA1, NA2 and SH) which reside on the neutrophil FcgammaReceptor IIIb (FcgammaRIIIb) play a major role in immune neutropenias and pulmonary transfusion reactions. In an attempt to shed some light on the origin and history of these antigens we typed the DNA of Blacks from South Africa (n=99), and Ghana (n=27), of 56 African Americans, and of 138 Chinese from Taiwan for HNA-1a,-1b, and -1c antigens using polymerase chain reaction with sequence-specific primers (PCR-SSP). In African and American Blacks, the HNA-1b antigen was more frequent than HNA-1a (77 vs. 67% and 77 vs. 59%, respectively). In contrast, in Chinese HNA-1a was more frequent than HNA-1b (91 vs. 54%). We observed 3 individuals with FcgammaRIIIB deficiency among the 126 tested African Blacks indicating a higher frequency of FcgammaRIIIB deficiency in Blacks than the reported 0.1% in Europeans. In addition, the frequency of HNA-1c in African and American Blacks (38 and 23%, respectively) was higher than the reported 5% in Europeans. Among the 57 HNA-1c (+) Blacks, all were HNA-1b (+) but only 26 were HNA-1a (+) supporting the idea that the HNA-1c antigen is the result of an additional point mutation in the allele coding for HNA-1b. Recently, HNA-1a, -1b, and -1c (+) Europeans have been reported to have three distinct FcgammaRIIIB genes. Among 26 Blacks who had been typed HNA-1a,b,c (+) by PCR-SSP we identified only 7 having three FcgammaRIIIB genes by DNA sequencing. When we sequenced the DNA of 6 HNA-1a,b,c (+) Europeans we found 4 of the individuals had three FcyRIIIB genes. Therefore, we assume that in Africa the point mutation occurred first in the HNA-1b allele resulting in the HNA-1c allele and the FcgammaRIIIB gene duplication took place later.

No abstract

Context Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited. Objective To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years. Design Phase 2 open-label study (July 2010 to September 2016). Setting Twenty-two sites; 12 countries. Participants Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months. Intervention Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously. Main Outcome Measures Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [−3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2). Results During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (−1.7, +3.0)], Year 1 [+2.0 (−2.3, +3.0)], and Last Assessment [+2.3 (−2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment. Conclusions Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.

Hypophosphatasia (HPP) is a clinically heterogeneous rare, inherited disorder of bone and mineral metabolism with extensive allelic heterogeneity in the ALPL gene. In this report, we present a family with heterozygous parents (maternal p.(Glu191Lys), paternal p.(Gly334Asp) mutations in the ALPL gene) and four children (one genotypically normal, one heterozygous carrier and two compound heterozygous) showing an unexpected high phenotypic variability. One of the compound heterozygous showed clinical symptoms of the mild childhood form mainly affecting the teeth. The other one was more seriously affected with severe failure to thrive, delayed motor development, need for oxygen supply and profound mineralization deficit compatible with an infantile form of HPP. Functional in vitro studies identified p.(Glu191Lys) as mild (68%, no dominant-negative effect) and p.(Gly334Asp) as severely affected allele (1.2%, dominant-negative effect). In vitro simulation of the children's genetic status showed a residual AP activity of 29%, while the biochemical AP activity in the serum was comparably reduced in both children (22 and 36 U/l). This family report indicates that mapping ALPL mutations within the gene does not necessarily help to predict the clinical severity of the phenotype. Therefore, results of prenatal diagnostics have to be interpreted with caution and prenatal genetic diagnosis and counseling for HPP should be provided within an experienced multidisciplinary team. Research about other confounding factors is urgently needed.