A severe form of amyloidotic polyneuropathy in a Costa Rican family with a rare transthyretin mutation (Glu54Lys)

Four affected siblings in a Costa Rican family presented an aggressive polyneuropathy with widespread involvement of many visceral organs and onset during the third decade of life with rapid loss of muscle mass in the lower limbs and severe dysautonomy. The medical histories include vitreous opacity, cardiac enlargement, dermal and gastrointestinal infiltration, and autonomic dysfunction including circulatory compromise and gastrointestinal disturbances. Histological studies using Congo red stain and immunohistochemical assays with antibodies against the transthyretin (TTR) protein showed widespread deposition of amyloid in extracellular areas, including dermis and gastrointestinal lamina propia, endo- and perineural spaces, and vascular walls. A mutation search in the transthyretin (ttr) gene was performed seeking the cause of this severe form of familial amyloidotic polyneuropathy (FAP). We applied single-stranded conformational polymorphism (SSCP)-analyses followed by sequencing of the four exons of the ttr gene, revealing a point mutation in exon 3, a G to A transition that causes a Glu54Lys codon change. Western blots of plasma proteins incubated with anti-transthyretin antibodies after gel electrophoresis provided separation of wild-type and mutant TTR protein in affected family members.     

MKK4 and metastasis suppression: a marriage of signal transduction and metastasis research

MAP kinase kinase 4 (MKK4) is a member of the stress-activated protein kinase (SAPK) signaling cascade and is involved in the regulation of many cellular processes. We have recently demonstrated a functional role for MKK4 in the suppression of metastases. In this review, we discuss the established cellular and biochemical functions of MKK4, as well as a new function for MKK4 as a metastasis suppressor gene. Because of the importance of signaling studies to this translational work, a detailed example of the strategy and tools that can be employed to define the biochemical mechanism of MKK4-mediated metastasis suppression is presented. Finally, the potential therapeutic utility of these findings is discussed.     

Influence of environment on speech-sound discrimination: findings from a longitudinal study

Event-related potentials (ERPs) from 134 children were obtained at 3 and 8 years of age and recorded to a series of consonant-vowel speech syllables and their nonspeech analogues. The HOME inventory was administered to these same children at 3 and 8 years of age and the sample was divided into 2 groups (low vs. high) based on their HOME scores. Discriminant functions analyses using ERP responses to speech and non-speech analogues successfully classified HOME scores obtained at 3 and 8 years of age and discriminated between children who received low vs. high levels of stimulation for language and reading.     

The roles of individual eukaryotic translation initiation factors in ribosomal scanning and initiation codon selection

To elucidate an outline of the mechanism of eukaryotic translation initiation, 48S complex formation was analyzed on defined mRNAs in reactions reconstituted in vitro from fully purified translation components. We found that a ribosomal 40S subunit, eukaryotic initiation factor (eIF) 3, and the eIF2 ternary complex form a 43S complex that can bind to the 5'-end of an unstructured 5'-untranslated region (5'-UTR) and in the presence of eIF1 scan along it and locate the initiation codon without a requirement for adenosine triphosphate (ATP) or factors (eIF4A, eIF4B, eIF4F) associated with ATP hydrolysis. Scanning on unstructured 5'-UTRs was enhanced by ATP, eIFs 4A and 4B, and the central domain of the eIF4G subunit of eIF4F. Their omission increased the dependence of scanning on eIFs 1 and 1A. Ribosomal movement on 5'-UTRs containing even weak secondary structures required ATP and RNA helicases. eIF4F was essential for scanning, and eIFs 4A and 4B were insufficient to promote this process in the absence of eIF4F. We report that in addition to its function in scanning, eIF1 also plays a principal role in initiation codon selection. In the absence of eIF1, 43S complexes could no longer discriminate between cognate and noncognate initiation codons or sense the nucleotide context of initiation codons and were able to assemble 48S complexes on 5'-proximal AUG triplets located only 1, 2, and 4 nt from the 5'-end of mRNA.     

BRCA1 and BRCA2 mutations in Russian familial breast cancer

We have screened index cases from 25 Russian breast/ovarian cancer families for germ‐line mutations in all coding exons of the BRCA1 and BRCA2 genes, using multiplex heteroduplex analysis. In addition we tested 22 patients with breast cancer diagnosed before age 40 without family history and 6 patients with bilateral breast cancer. The frequency of families with germline mutations in BRCA was 16% (4/25). One BRCA1 mutation, 5382insC, was found in three families. The results of present study, and those of a separate study of 19 breast‐ovarian cancer families, suggest that BRCA1 5382insC is a founder mutation in the Russian population. Three BRCA2 mutations were found in patients with breast cancer without family history: two in young patients and one in patients with bilateral breast cancer. Four novel BRCA2 mutations were identified: three frameshift (695insT, 1528del4, 9318del4) and one nonsense (S1099X). © 2002 Wiley‐Liss, Inc.     

Oxygen uptake-heart rate relationship in élite wheelchair racers

The American College of Sports Medicine (ACSM) recommends that, as a general rule for health purposes, individuals should exercise at 40%–85% of their maximal oxygen uptakes. Moreover, it has been suggested that 55%–90% of the maximal heart rate may be used as an alternative estimate of these percentage maximal oxygen uptake values. The present study examined the relationship between percentage peak heart rate (% HR_peak) and percentage peak oxygen uptake (% ) during steady-state incremental intensity wheelchair propulsion of 16 élite, male wheelchair racers (WR). Oxygen uptake was determined during each submaximal exercise stage and heart rate (HR) was continuously monitored. The was subsequently determined using a separate protocol. Linear regression equations of % HR_peak versus % for each participant included % HR_peak values corresponding to 40%, 60%, 80% and 85% . The linear regression equation, derived as the group mean of the slope and intercept terms determined for each individual, was: . The group mean of the individual correlation coefficients for the relationship was 0.99. The values of % HR_peak for each of the % values below 85% were significantly greater (P<0.01) than those suggested by the ACSM. This suggests that the ACSM guidelines below 85% , based on % HR_peak, may underestimate the relative exercise intensity (i.e. % ) in the WR population. However, in élite level WR, % HR_peak can be recommended as an alternative estimate of % at wheelchair propulsion intensities of 85% or more. Electronic Publication     

Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children

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The alpha-L-(1----2)-trirhamnopyranoside epitope on the group-specific polysaccharide of group B streptococci.

A number of epitope specificities associated with the group antigen (group B polysaccharide) of group B streptococci have been identified in a polyclonal antiserum induced in rabbits by a nonencapsulated variant strain of group B streptococci. This was achieved by using a series of oligosaccharide inhibitors, obtained by both synthetic and degradative procedures, to inhibit the binding of the group B polysaccharide to the polyclonal antiserum. While the dominant epitope expressed in the antiserum was alpha-L-Rhap(1----2)alpha-L-Rhap(1----2)alpha-L-Rhap, specificities associated with alpha-L-Rhap and alpha-L-Rhap(1----3)alpha-D-Galp(1----3)beta-D-Glcp-NAc(1----4)alp ha-L-Rhap were also identified. The dominant expression of the former epitope is consistent with its terminal location on the group antigen and also with highly branched multiantennary structure of this antigen. Antibodies specific for the alpha-L-trirhamnopyranoside epitope were purified by affinity chromatography, using the synthetic trisaccharide glucitol as the hapten. Oligosaccharide inhibition studies indicate that the specificity of these antibodies is identical to that of a murine monoclonal antibody induced by the same nonencapsulated strain of group B streptococci.