Serious infections in patients with myasthenia gravis: population-based cohort study.

BACKGROUND AND PURPOSE: To characterize the frequency and risk of serious infections in patients with myasthenia gravis (MG) relative to age/sex/area-matched comparators. METHODS: This was a population-based cohort study in Ontario, Canada of patients with newly-diagnosed MG and 1:4 age/sex/area-matched general population comparators accrued from 1 April 2002 to 31 December 2015. The main outcome was a serious infection, defined by a primary diagnosis code on a hospitalization or emergency department record. We computed crude overall and sex-specific rates of infection among patients with MG and comparators, and the frequency of specific types of infection. Adjusted hazard ratios and 95% confidence intervals were estimated using Cox regression. RESULTS: Among 3823 patients with MG, 1275 (33.4%) experienced a serious infection compared with 2973/15 292 (19.4%) of comparators over a mean follow-up of over 5 years. Crude infection rates among patients with MG were twice those in comparators (72.5 vs. 35.0 per 1000 person-years, respectively). The most common infection types were respiratory infections, particularly bacterial pneumonia. After adjustment for potential confounders, MG was associated with a 39% increased infection risk (adjusted hazard ratio, 1.39; 95% confidence intervals, 1.28-1.51). CONCLUSIONS: Patients with MG are at a significantly higher absolute and relative risk of serious infections compared with age/sex/area-matched comparators. This needs to be considered when selecting MG treatments and when planning vaccination/prophylaxis. Determining whether this risk is due to the use of immunosuppressive medications (vs. MG itself) is an important area for future research.

Cerebrospinal fluid total protein in Guillain-Barré syndrome variants: correlations with clinical category, severity, and electrophysiology.

The discriminative value of CSF total protein (CSF-TP) in subtypes of Guillain-Barré syndrome has not been well documented in North-American patients. We reviewed 173 cases from a single institution, comprising the following clinical categories of neuropathy: 134 Sensorimotor (SM) GBS, 13 Motor (M) GBS, 8 Localized (L) GBS, and 18 Miller Fisher syndrome (MFS). We grouped the electrophysiological interpretation in primarily demyelinating, primarily axonal and normal / equivocal categories. Mean CSF-TP were substantially higher for SM and L-GBS, as well as cases classified as Acute-onset chronic inflammatory demyelinating polyneuropathy. They were lower for M-GBS and L-GBS. The most statistically significant correlation was found for elevated CSF-TP in GBS cases showing an electrophysiologic pattern classified as demyelinating (1.56 g/L) compared with axonal (0.68 g/L) or normal/ equivocal patterns (0.65 g/L). There was a correlation between CSF-TP and time interval between symptom onset and lumbar puncture. There was a weak correlation between CSF-TP and maximal overall-clinical severity grade, which was likely mostly determined by the electorphysiological pattern. Though CSF-TP is a sensitive test for GBS in the second week after onset, it may not be a reliable predictor of clinical severity. There is a robust association of CSF-TP elevation and a demyelinative electrophysiologic pattern and a suggestion that lower mean CSF-TP values can be expected in GBS-spectrum disorders thought to represent nodo-paranodopathies.

Recent duplication and germ-line diversification of rat immunoglobulin kappa chain gene joining segments.

Sequence determination of the joining segment gene (J) cluster in the kappa chain (J kappa) in the embryonic context demonstrates that rat genome contains seven J kappa gene segments that expanded from an ancestral cluster of five J kappa genes. The rat J segments are separated by about 300 base pairs (bp) and are flanked 5' by the presumed variable region (V)/J recombination signal sequence and 3' by the RNA splicing signal. Two of the J gene segments designated J2A and J2B and their 5'-flanking spacer DNA bear striking homology to J2 and its 5'-flanking spacer. Thus, the unit of duplication was the entire J kappa coding region and 5' noncoding spacer (345 bp). The duplication probably occurred as two separate unequal crossing-over (UXO) events. The first UXO event can be confined to recombination within an identical stretch (14 bp long) located at the 3' ends of the coding regions of J1 and J2. The second event could involve a longer segment (372 bp) of tight homology generated by the first UXO event, thus increasing the probability of repeated expansion of the same DNA segment. The sequence homology among the rat duplicated segments (98-99%) is larger than the homology between the corresponding rat and mouse segments (89%), showing that the rat J kappa gene expansion must have occurred after rat and mouse divergence 10 X 10(6) yr ago. We estimate that the first and second UXO events occurred 2 X 10(6) and 1 X 10(6) yr ago, respectively. J3 of rat and mouse share the same mutation (G leads to C) in the RNA splicing signal that presumably inactivates J3. This mutation preceded divergence of the two species. A mutation in the first nucleotide of codon 96 has occurred in both duplicated segments, the only position along 345 bp where J2, J2A, and J2B differ from each other. This results in three different amino acids at position 96 not present in any other J kappa. These mutations are physiologically significant because they diversify the third complementarity-determining region (CDR3) and, thus, may reflect selective pressure to increase antibody diversity. The germ-line diversification of CDR3 was exercised within the last 1-2 X 10(6) yr.

Somatic DNA rearrangement generates functional rat immunoglobulin kappa chain genes: the J kappa gene cluster is longer in rat than in mouse.

The kappa immunoglobulin (Ig) genes from rat kidney and from rat myeloma cells were cloned and analyzed. In kidney DNA one C kappa species is observed by Southern blotting and cloning in phage vectors; this gene most likely represents the embryonic configuration. In the IR52 myeloma DNA two C kappa species are observed: one in the same configuration seen in kidney and one which has undergone a rearrangement. This somatic rearrangement has brought the expressed V region to within 2.7 kb 5' of the C kappa coding region; the rearrangement site is within the J kappa cluster which we have mapped. The rat somatic Ig rearrangement, therefore, closely resembles that seen in mouse Ig genes. In the rat embryonic fragment two J kappa segments were mapped at 2 and 4.3 kb 5' from the C kappa coding region. Therefore, the rat J kappa cluster extends over about 2.3 kb, a region much longer than the 1.4 kb of the mouse and human J kappa clusters. In the region between C kappa and the expressed J kappa of IR52 myeloma DNA, and XbaI site present in the embryonic kappa gene has been lost. A somatic mutation has therefore occurred in the intervening sequence DNA approx. 0.7 kb 3' from the V/J recombination site. Southern blots of rat kidney DNA hybridized with different rat V kappa probes showed non-overlapping sets of bands which correspond to different subgroups, each composed of 8-10 closely related V kappa genes.

The organization of a nuclear DNA sequence from a higher plant: molecular cloning and characterization of soybean ribosomal DNA.

The recombinant DNA vector, lambda Charon 4A, was used to construct a library of DNA sequences from the genomic DNA of soybean (Glycine max). To define the organization of ribosomal DNA (rDNA) in the soybean genome, clones containing sequences complementary to both 17S and 25S rRNA have been isolated from this library and used in conjunction with Southern blot hybridization. The rRNA genes are tandemly reiterated with a relatively small unit repeat length of 7.8 kb. There is no heterogeneity in the length of the rDNA repeat units although they display limited differences in either base sequence or pattern of methylation. The cloned rDNA sequences are shown to comprise the entire repeat unit and have been used to obtain a detailed restriction map as well as an approximate transcription map of soybean rRNA genes. The cloning of rDNA from soybean suggests that recombinant DNA techniques can be successfully applied to the genomic DNA of higher plants despite the high degree of methylation exhibited by plant DNA.

Precise localization of human beta-globin gene complex on chromosome 11.

Cloned DNA probes were used in combination with a panel of five hybrid cell clones containing a series of different terminal deletions in human chromosome 11 to map precisely the human hemoglobin beta and delta chain structural genes contained on this chromosome. The region of deletion in each clone of the panel has been defined by biochemical, immunologic, and cytogenetic markers. DNA from clones containing successively larger terminal deletions was tested with appropriate DNA probes to determine the point on the chromosome at which DNA for these two closely linked hemoglobin genes is deleted. These genes, and by inference the closely linked G gamma and A gamma globin genes as well, have been assigned to the intraband region 11p1205 leads to 11p1208 on the short arm of chromosome 11, an interval containing approximately 4500 kilobases of DNA. The approach appears to have potential for even greater resolution and reasonably wide applicability for gene mapping.