A strong association between the antinuclear antibody anti-La (SS-B) and the kappa chain allotype Km(1)

The distribution of immunoglobulin allotypes of the Gm and Km systems was examined in 51 patients with antinuclear antibodies (ANA), which reacted with two saline-extractable non-DNA nuclear antigens, anti-La (SS-B) and anti-RNP, which characterize certain multisystem autoimmune diseases. Forty-six percent of the 26 patients with anti-La were positive for the Km(1) allotype compared with 14% of the 35 with anti-RNP and 16% of 1204 of healthy subjects (corrected P value < 0.005). The high frequencies of the Km(1) allotype (46%), female sex (100%), and the HLA-B8, DR3 phenotype (> 90%) in patients with anti-La are indicative of a substantial inherited predisposition to the development or expression of this autoantibody. The strong association between the Km(1) allotype and the anti-La response may be due to linkage disequilibrium between genes coding for the constant region of immunoglobulin kappa light chains and genes coding for the variable regions of kappa light chains which confer antibody specificity for the special configuration of the ribonucleoprotein known as La.     

Pseudocholinesterase activity and E1 phenotypes in Down's syndrome and mental retardation.

Pseudocholinesterase activity and the phenotypes controlled by the E1 locus have been determined in a sample of 307 Down's syndrome patients and 206 patients suffering from nonspecific mental retardation and compared to those in the healthy population. Both groups of patients have an elevated frequency of phenotypes possessing the rate E1f allele. The mentally retarded patients have a higher mean pseudocholinesterase activity than those with Down's syndrome who, in turn, have activity than the healthy controls.     

Role of ultrasonography in diagnosing early rheumatoid arthritis and remission of rheumatoid arthritis - a systematic review of the literature

Introduction

Ultrasonography (US) might have an added value to clinical examination in diagnosing early rheumatoid arthritis (RA) and assessing remission of RA. We aimed to clarify the added value of US in RA in these situations performing a systematic review.

Methods

A systematic literature search was performed for RA, US, diagnosis and remission. Methodological quality was assessed; the wide variability in the design of studies prohibited pooling of results.

Results

Six papers on the added value of US diagnosing early RA were found, in which at least bilateral metacarpophalangeal (MCP), wrists and metatarsophalangeal (MTP) joints were scanned. Compared to clinical examination, US was superior with regard to detecting synovitis and predicting progression to persistent arthritis or RA. Eleven papers on assessing remission were identified, in which at least the wrist and the MCP joints of the dominant hand were scanned. Often US detected inflammation in patients clinically in remission, irrespective of the remission criteria used. Power Doppler signs of synovitis predicted X-ray progression and future flare in patients clinically in remission.

Conclusions

US appears to have added value to clinical examination for diagnosing of RA when scanning at least MCP, wrist and MTP joints, and, when evaluating remission of RA, scanning at least wrist and MCP joints of the dominant hand. For both purposes primarily power Doppler US might be used since its results are less equivocal than those of greyscale US.     

GM and KM allotypes and GM RFLP allogenotypes in Micronesians from Nauru.

Immunoglobulin allotypes of the GM and KM systems were determined in a sample of Micronesian subjects from Nauru. Four GM haplotypes were identified in the sample: GM*1,3 23 5, 10,11,13,14, GM*1,17 23' 21, GM*1,3 23' 5,10,11,13,14, and GM*1,2,17 23' 21, although the last of these may have been introduced by non-Micronesian admixture. The frequency of the KM*1 allele is 0.115 +/- 0.033, which is slightly lower than reported in Micronesians from the Caroline Islands. RFLPs generated by the enzymes Taq I and Pvu II and detected by a Hu gamma 4 probe were related to GM phenotypes. The haplotypes GM*1,3 +/- 23 5,10,11,13,14 were strongly associated with a Taq I 5.0-kb band. The presence and absence of the allotype G2M 23 were marked by a Pvu II 7.0 + 2.0 kb pair and a Pvu II 9.0-kb fragment, respectively. GM*1,17 23' 21 was strongly associated with a Pvu II 5.0 + 2.7 kb pair. The different relationships between GM haplotypes and Hu gamma 4 RFLPs in Micronesians and Caucasians indicate that a universal GM allogenotyping procedure cannot yet be developed; instead, population-specific procedures are necessitated by differences in GM allotype arrangements between populations.     

The relation of sex,age, smoking status,birth rank and parental ages to pseudocholinesterase activity and phenotypes in a sample of Australian Caucasian adults

Summary The frequencies of the pseudocholinesterase alleles E₁ ^u, E₁ ^a and E₁ ^f have been determined in a random sample of Australian residents. The frequency of E₁ ^a is the highest yet reported in a large caucasian sample. The considerable variation in E₁ ^f frequencies in previously reported samples is discussed in terms of possible sources of error in fluoride number determinations.Enzyme activity was found to increase with age in adulthood and was higher in males than in females. It was also positively correlated with dibucaine number in type U subjects. These observations are in conflict with those reported in previous investigations.This work was supported by grants from the National Health and Medical Research Council of Australia and the Australian Tobacco Research Foundation.     

Starch as a sugar reservoir for nematode-induced syncytia

The plant parasitic nematode Heterodera schachtii invades the roots of Arabidopsis thaliana to induce nematode feeding structures in the central cylinder. During nematode development, the parasites feed exclusively from these structures. Thus, high sugar import and specific sugar processing of the affected plant cells is crucial for nematode development. In the present work, we found starch accumulation in nematode feeding structures and therefore studied the expression genes involved in the starch metabolic pathway. The importance of starch synthesis was further shown using the Atss1 mutant line. As it is rather surprising to find starch accumulation in cells characterised by a high nutrient loss, we speculate that starch serves as long- and short-term carbohydrate storage to compensate the staggering feeding behaviour of the parasites.Key words: Heterodera schachtii, Arabidopsis, nematode, starch metabolism, syncytiaThe obligate plant parasitic nematode Heterodera schachtii is entirely dependent on a system of nutrient supply provided by the plant. Host plants—among those the model plant Arabidopsis thaliana—have to endure invasion of second stage juveniles and the establishment of nematode feeding structures in the plant''s vascular cylinder. For induction of the specific feeding structures, the juveniles pierce one single plant cell with their stylet and inject secretions, thus triggering the formation of a syncytium by local cell walls dissolutions.¹ Further, the central vacuole of the syncytial cells disintegrates, nuclei enlarge and many organelles proliferate.¹ About 24 hours after feeding site induction, the nematode juveniles start feeding in repetitive cycles.² Syncytia have previously been described as strong sinks in the plant''s transport system.³ Thus, in the recent years several studies were carried out to discover solute supply to syncytial cells.^4–7 To our present knowledge, syncytia are symplasmically isolated in the first days of nematode development. During that period, the nematodes depend on transport protein activity in the syncytia plasmamembranes. At later stages plasmodesmata appear to open to the phloem elements, facilitating symplasmic transport.Incoming solutes may either be taken up by the feeding nematode or are synthesised and catalysed by the syncytium''s metabolism. Due to the microscopically observable high density of the cytosol¹ and the increased osmotic pressure,⁸ syncytia appear to accumulate high solute concentrations. In fact, significantly increased sucrose levels have been found in syncytia in comparison to non-infected control roots.⁷ In case of high sugar levels, plant cells generally synthesize starch in order to reduce emerging osmotic stress.⁹ The aim of the work of Hofmann et al.,¹⁰ was to elucidate if starch is utilised as carbohydrate storage in nematode-induced syncytia and to study expression of genes involved in starch metabolism with an emphasis on nematode development.Starch levels of nematode induced syncytia and roots of non-infected plants grown on sand/soil culture were measured by high performance liquid chromatography (HPLC). The results showed a high accumulation of starch in syncytia that was steadily decreasing during nematode development. The accumulation of starch could further be localised within syncytial cells by electron microscopy. Based on these results, we studied the gene expression of the starch metabolic pathway by Affymetrix gene chip analysis. About half of the 56 involved genes were significantly upregulated in syncytia compared to the control and only two genes were significantly downregulated. Thus, the high induction of the gene expression is consistent with the high starch accumulation. Finally, we applied an Arabidopsis mutant line lacking starch synthase I expression that has been described previously.¹¹ Starch synthase I was the second highest upregulated gene in syncytia. It catalyses the linkage of ADP-glucose to the non-reducing end of an a-glucan, forming the linear glucose chains of amylopectin. In a nematode infection assay we were able to prove the significant importance of the gene for nematode development.With the presented results, we can unambiguously prove the accumulation of starch and the induction of the gene expression of the starch metabolic pathway in nematode-induced syncytia. The primary question however is: why do syncytia accumulate soluble sugars and starch although their metabolism is highly induced and nematodes withdraw solutes during continuously repeating feeding cycles?One explanation may be found where least expected—in nematode feeding. It is the feeding activity that induced solute import mechanisms into syncytia resulting in a newly formed sink tissue. However, during moulting events to the third, the fourth juvenile stage and to the adult stage nematodes interrupt feeding for about 20 hours.² During this period sugar supply mechanisms will most probably not be altered thus leading to increasing levels of sugars in the syncytium. Starch may serve as short-term carbohydrate buffering sugar excess. Further, starch may serve as long-term carbohydrate storage during nematode development. In the early stages of juvenile development nematodes withdraw considerably small quantities (about 0,8-times the syncytium volume a day).¹² At later stages, nutrient demand increases so that adult fertilised females require 4-times the syncytium volume per day in order to accomplish egg production.¹² Thus, excessive sugar supply in the first days may be accumulated as starch that gets degraded at later stages when more energy is required from the parasites. Consequently, starch reserve serves as both short-term and long-term carbohydrate storage in nematode-induced syncytia in order to buffer changing feeding pattern of the parasites.? Open in a separate windowFigure 1Arabidopsis wild-type Columbia-0 plants were grown in sand/soil culture. Nematode-induced syncytia and non-infected control roots were harvested at 10, 15 and 20 days after inoculation (dai) and starch content was measured as glucose (Glc) equivalents. Values are means ± SE, n = 3. Different letters indicate significant variations (p < 0.05). © ASPBOpen in a separate windowFigure 2Transmission electron microscope picture of a cross-section of a syncytium associated with female fourth stage juvenile (H. schachtii) induced in roots of Arabidopsis. Bar = 2 µm. S, syncytium; Se, sieve tube; arrow, plastid; asterisk, starch granule. © ASPB     

Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study

Introduction  

Improvement of rheumatoid arthritis (RA) during pregnancy has been causatively associated with increased galactosylation of immunoglobulin G (IgG) N-glycans. Since previous studies were small, did not include the postpartum flare and did not study sialylation, these issues were addressed in the present study.     

A Phase I Clinical Trial of Systemically Delivered NEMO Binding Domain Peptide in Dogs with Spontaneous Activated B-Cell like Diffuse Large B-Cell Lymphoma

Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.