First Administration of the Fc-Attenuated Anti-β Amyloid Antibody GSK933776 to Patients with Mild Alzheimer’s Disease: A Randomized,Placebo-Controlled Study

Objective

To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fc-inactivated anti-β amyloid (Aβ) monoclonal antibody (mAb) GSK933776 in patients with mild Alzheimer’s disease (AD) or mild cognitive impairment (MCI).

Methods

This was a two-part, single blind, placebo-controlled, first-time-in-human (FTIH) study of single (n = 18) and repeat dose (n = 32) intravenous GSK933776 0.001–6 mg/kg (ClinicalTrials.gov: NCT00459550). Additional safety data from an open-label, uncontrolled, single dose study of intravenous GSK933776 1–6 mg/kg (n = 18) are included (ClinicalTrials.gov: NCT01424436).

Results

There were no cases of amyloid-related imaging abnormalities-edema (ARIA-E) or –hemorrhage (ARIA-H) after GSK933776 administration in both studies. Three patients across the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t_1/2) was 10–15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased dose dependently; no changes were observed for placebo. For total Aβ42 the peak:trough ratio was ≤2 at doses ≥3 mg/kg; for total Aβ the ratio was ≤2 at 6 mg/kg. CSF concentrations of Aβ showed increases from baseline to week 12 for Aβ X–38 (week 12:baseline ratio: 1.65; 95%CI: 1.38, 1.93) and Aβ X–42 (week 12:baseline ratio: 1.18; 95%CI: 1.06, 1.30) for values pooled across doses.

Conclusion

In this FTIH study the Fc-inactivated anti-Aβ mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI.

Trial Registration

ClinicalTrials.gov NCT00459550     

The Mini-BESTest - a clinically reproducible tool for balance evaluations in mild to moderate Parkinson’s disease?

Background

The Mini-BESTest is a clinical balance test that has shown a high sensitivity in detecting balance impairments in elderly with Parkinson's disease (PD). However, its reproducibility between different raters and between test occasions has yet to be investigated in a clinical context. Moreover, no one has investigated the reproducibility of the Mini-BESTest's subcomponents (i.e. anticipatory postural adjustments; postural responses; sensory orientation and dynamic gait).We aimed to investigate the inter-rater and test-retest reproducibility (reliability as well as agreement) of the Mini-BESTest, as well as its subcomponents, in elderly with mild to moderate PD, performed under conditions assimilating clinical practice.

Method

This was an observational measurement study with a test-retest design.Twenty-seven individuals with idiopathic PD (66 - 80 years, mean age: 73; Hoehn & Yahr: 2-3; 1-15 years since diagnosis) were included. Two test administrators, having different experiences with the Mini-BESTest, administered the test individually, in separate rooms in a hospital setting. For the test-retest assessment, all participants returned 7 days after the first test session to perform the Mini-BESTest under similar conditions. Intra-class correlation coefficients (ICC_2.1), standard error of measurement (SEM_agreement), and smallest real difference (SRD) were analyzed.

Results

The Mini-BESTest showed good reliability for both inter-rater and test-retest reproducibility (ICC = 0.72 and 0.80). Regarding agreement, the measurement error (SRD) was found to be 4.1 points (accounting for 15% of the maximal total score) for inter-rater reproducibility and 3.4 points (12% of the maximal total score) for test-retest reproducibility. The investigation of the Mini-BESTest's subcomponents showed a similar pattern for both inter-rater and test-retest reproducibility, where postural responses had the largest proportional measurement error, and sensory orientation showed the highest agreement.

Conclusions

Our findings indicate that the Mini-BESTest is able to distinguish between individuals with mild to moderate PD; however, when used in clinical balance assessments, the large measurement error needs to be accounted for.

     

Distribution Patterns of Isomorphic Cold-Water Dinoflagellates (Scrippsiella/Woloszynskia Complex) Causing ‘red tides’ in the Baltic Sea

During the latest years medium-sized (15–30 μm), single-celled dinoflagellates have been reported to form blooms in the northern Baltic Proper and the Gulf of Finland in winter and spring. Recent studies (Kremp et al., 2003. Proceedings of the 7th International conference of Modern and Fossil Dinoflagellates, September 21–25, Nagasaki, Japan, 66 pp.) indicate that those blooms are caused by two isomorphic species – Scrippsiella hangoei (Schiller) Larsen, and a new species, tentatively belonging to the genus Woloszynskia. Until now there has been no report on how widely distributed these phytoplankton species are in the Baltic Sea. In this study, the occurrence of Scrippsiella/Woloszynskia complex in the entire Baltic Sea was investigated, by using monitoring data from 1997 to 2003. The species occurred in a salinity range from 2 to 8 PSU. Highest concentrations were observed at salinity 4.5–6.5 PSU. Maximum cell densities of Scrippsiella/Woloszynskia complex in the water column were mainly obtained in April or in the beginning of May by the water temperature <3 °C prior to stratification was formed. In the central Gulf of Finland, the second maximum was found in 1999 and 2002 by the temperature >6 °C. Bloom formations in the Baltic Proper and in the Gulf of Finland may not only be explained by optimum temperature and salinity, but also with other factors e.g. high nutrient concentrations and good seeding conditions from the sediments.     

WT1 mutations in patients with Denys-Drash syndrome: a novel mutation in exon 8 and paternal allele origin

Denys-Drash syndrome (DDS) is characterized by early onset nephropathy, pseudohermaphroditism in males and a high risk for developing Wilms' tumour (WT). The exact cause of DDS is unknown but germline mutations in the Wilms' tumour suppressor gene (WT1) have recently been described in the majority of DDS patients studied. These mutations occur de novo and are clustered around the zinc finger (ZF) coding exons of the WT1 gene. Analysis of exons 2–10 of the WT1 gene in constitutional DNA from five patients with DDS was carried out using the polymerase chain reaction (PCR) and direct DNA sequencing. In four out of the five patients, heterozygous germline mutations were found: a novel point mutation in exon 8 (ZF₂) at codon 377 altering the wild-type histidine to arginine, and three previously described point mutations in exon 9 (ZF₃) in the codons corresponding to amino acids ³⁹⁴Arg and ³⁹⁶Asp. In one patient, no mutations could be demonstrated. In three patients where parental DNA was available, the mutations were shown to have occurred de novo. Furthermore, since tumour DNA in two of these cases had lost the wild-type allele, polymorphic markers from the short arm of chromosome 11 were used to determine the parental origin of the mutant chromosome. In both cases, the mutant chromosome was shown to be of paternal origin. Since the majority of published WT1 mutations in DDS patients alter a RsrII restriction site in exon 9, we were able to perform PCR-based diagnosis in a female patient with early renal insufficiency and normal external genitalia.     

Transductional mapping of nine linked chromosomal genes in Bacillus thuringiensis

Summary We have previously described a phage (63) for generalized transduction in Bacillus thuringiensis and used it for mapping of four chromosomal antibiotic resistance markers, namely nalA-rifA-strA-spcA (Landén et al. 1981). From 63 we have now isolated a host range mutant called 64 which contains 52–56 megadalton of DNA. Phage 64 was found to be a more efficient transducing vector than 63. The host range of 64 is wide, with good growth on subspecies gelechiae, kurstaki, galleriae, thuringiensis and thompsoni, restriction on some derivatives of finitimus and ostrinae and no growth on alesti, israelensis and aizawai.Using 64 and a series of new mutants of subspecies gelechiae we have no added five new genes to the antibiotic resistance group described before. The gene order found was guaB-purB-metA-novA-(purA-nalA)-rifA-strA-spcA. Linkage was also demonstrated between hisA and lysA.     

Deficiency of Bax and Bak protects photoreceptors from light damage in vivo

Photoreceptors of bax(-/-)bak(-/-) but neither bax(-/-) mice nor bak(-/-) mice are protected from developmental apoptosis, suggesting that bax(-/-)bak(-/-) photoreceptors may also be protected from pathologic apoptosis. To test this possibility, we exposed bax(-/-)bak(-/-) and bax(-/-) mice to bright light, which normally induces photoreceptor death. Photoreceptors in bax(-/-)bak(-/-) mice were protected from death compared to bax(-/-) mice as indicated by a reduction in the number of TUNEL-positive photoreceptor nuclei 24 h following light damage and almost complete preservation of photoreceptors 7 days following light damage. These results provide the first in vivo evidence that combined deficiency of Bax and Bak can rescue cells from a pathologic stimulus more effectively than Bax deficiency and suggest that combined deficiency of Bax and Bak may also protect cells from other insults.