Background

In this post-hoc analysis of a randomized, double blind, placebo controlled trial, we measured the sensitivity and specificity of Helicobacter pylori IgG-antibody titer changes, hematoxylin and eosin (H&E) stains, immunohistochemical (IHC) stains and culture results in NSAID using patients, following H. pylori eradication therapy or placebo.

Methods

347 NSAID using patients who were H. pylori positive on serological testing for H. pylori IgG-antibodies were randomized for H. pylori eradication therapy or placebo. Three months after randomization, gastric mucosal biopsies were taken for H. pylori culture and histological examination. At 3 and 12 months, blood samples were taken for repeated serological testing. The gold standard for H. pylori infection was based on a positive culture or both a positive histological examination and a positive serological test. Sensitivity, specificity and receiver operating curves (ROC) were calculated.

Results

H. pylori eradication therapy was successful in 91% of patients. Culture provided an overall sensitivity of 82%, and 73% after eradication, with a specificity of 100%. Histological examination with either H&E or IHC stains provided sensitivities and specificities between 93% and 100%. Adding IHC to H&E stains did not improve these results. The ROC curve for percent change in H. pylori IgG-antibody titers had good diagnostic power in identifying H. pylori negative patients, with an area under the ROC curve of 0.70 (95 % CI 0.59 to 0.79, P = 0.085) at 3 months and 0.83 (95% CI 0.76 to 0.89, P < 0.0001) at 12 months. A cut-off point of at least 21% decrease in H. pylori IgG-antibody titers at 3 months and 58% at 12 months provided a sensitivity of 64% and 87% and a specificity of 81% and 74% respectively, for successful eradication of H. pylori.

Conclusions

In NSAID using patients, following H. pylori eradication therapy or placebo, histological examination of gastric mucosal tissue biopsies provided good sensitivity and specificity ratios for evaluating success of H. pylori eradication therapy. A percentual H. pylori IgG-antibody titer change has better sensitivity and specificity than an absolute titer change or a predefined H. pylori IgG-antibody titer cut-off point for evaluating success of H. pylori eradication therapy.

To analyze risk factors for ischemic stroke and transient ischemic attack (TIA) in young adults under the age of 50. To make recommendations for additional research and practical consequences. From 97 patients with ischemic stroke or TIA under the age of 50, classical cardiovascular risk factors, coagulation disorders, history of migraine, use of oral contraceptives, cardiac abnormalities on ECG and echocardiography, and the results of duplex ultrasound were retrospectively analyzed. Literature was reviewed and compared to the results. 56.4% of the patients had hypertension, 12.1% increased total cholesterol, 20% hypertriglyceridemia, 31.5% an increased LDL-level, 32.6% a decreased HDL-level and 7.2% a disturbed glucose tolerance. Thrombophilia investigation was abnormal in 21 patients and auto-immune serology was abnormal in 15 patients. Ten of these patients were already known with a systemic disease associated with an increased risk for ischemic stroke (i.e. systemic lupus erythematosus). The ECG was abnormal in 16.7% of the cases, the echocardiography in 12.1% and duplex ultrasound of the carotid arteries was in 31.8% of the cases abnormal. Conventional cardiovascular risk factors are not only important in patients over the age of 50 with ischemic stroke or TIA, but also in this younger population under the age of 50. Thrombophilia investigation and/ or autoimmune serology should be restricted to patients without conventional cardiovascular risk factors and a history or other clinical symptoms associated with hypercoagulability and/ or autoimmune diseases.

Background

It is taken for granted that diuretics may induce gout, but there is a general lack of evidence on this topic.

Objectives

To determine the incidence of gout in patients who use diuretics, taking into account concurrent hypertension and cardiovascular diseases.

Methods

A case‐control study was designed. From a primary care population all patients with a first gout registration (59 men, 11 women; mean (SD) age 55.1 (13.5)) were identified as cases. To relate the occurrence of gout to diuretic use a matched reference series of three controls for each case was compiled. Conditional logistic regression analyses were applied to estimate incidence rate ratios (IRRs) of gout, and 95% confidence intervals (CIs), in subjects with and without diuretic treatment, hypertension, and cardiovasculardiseases. Additional stratification analyses were made, particularly in the subjects not using diuretics.

Results

The IRRs of gout in subjects with v those without diuretic treatment, hypertension, heart failure, and myocardial infarction were 2.8 (95% CI 1.2 to 6.6), 2.6 (95% CI 1.2 to 5.6), 20.9 (95% CI 2.5 to 173.8), and 1.9 (95% CI 0.7 to 4.7), respectively. After adjustment, the IRR of gout for diuretic use dropped to 0.6 (95% CI 0.2 to 2.0), while the IRRs of gout for hypertension, heart failure, and myocardial infarction were still >1. This was also the case for subjects with hypertension or myocardial infarction, who had not used diuretics.

Conclusion

The results suggest that diuretics do not actually increase the risk of gout. Cardiovascular indications for treatment may have confounded previous inferences.

Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified.

Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity.

Methods: A candidate gene approach combined with homozygosity mapping.

Results: Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway.

Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.

Background: Leflunomide is the prodrug of the disease modifying antirheumatic metabolite A77 1726. More than 50% of patients withdraw from leflunomide treatment within one year, mainly because of adverse drug reactions. Therapeutic drug monitoring of A77 1726 may be useful in predicting the efficacy of leflunomide treatment.

Objective: To study the relation between A77 1726 steady state serum concentrations and disease activity using the 28 joint (DAS28) response.

Methods: Outpatients with rheumatoid arthritis on a stable leflunomide dose for >4 months were included. DAS28 score and adverse drug reactions were recorded. Blood samples were taken for determination of A77 1726 concentrations. The primary end point was the relation of serum A77 1726 concentrations with DAS28 response category

Results: Serum A77 1726 concentrations were determined in 52 patients. A receiver operating characteristic (ROC) curve showed an area under the curve (AUC) of 0.73 (95% confidence interval, 0.54 to 0.93) (p<0.05). The sensitivity exceeded 99% at concentrations below 16 mg/l. DAS28 values at the point of sampling showed no relation with A77 1726 concentrations (AUC of the ROC curve = 0.50 (0.33 to 0.67) (NS)).

Conclusions: A77 1726 steady state serum concentrations show a relation with DAS28 response. Determination of serum A77 1726 concentrations in patients with insufficient response to treatment may help when decisions have to be made about continuation of treatment or dose adjustment.

Objectives

Our aim was to compare the quantitative position of the level descriptors of the standard EQ-5D three-level system (3L) and a newly developed, experimental five-level version (5L) using a direct and a vignette-based indirect method.

Methods

Eighty-two respondents took part in the study. The direct method represented a visual analog scale (VAS) rating of the nonextreme level descriptors for each dimension and each instrument separately. The indirect method required respondents to score 15 health scenarios with 3L, 5L and a VAS scale. Investigated were: (1) equidistance (Are 3L and 5L level descriptors distributed evenly over the VAS continuum?); (2) isoformity (Do the identical level descriptors on 3L and 5L yield similar results?); and (3) consistency between dimensions (Do the positions of similar level descriptors differ across dimensions within instruments?).

Results

Equidistance without transformation was rejected for all dimensions for both 3L and 5L but satisfied for 5L after transformation. Isoformity gave mixed results. Consistency between dimensions was satisfied for both instruments and both methods.

Discussion

The level descriptors have similar distributions across comparable dimensions within each system, but the pattern differs between 3L and 5L. This methodological study provides evidence of increased descriptive power and a broadened measurement continuum that encourages the further development of an official five-level EQ-5D.

In food technology, organic acids (e.g., lactic acid, acetic acid, and citric acid) are popular preservatives. The purpose of this study was to separate the individual effects of the influencing factors pH and undissociated lactic acid on Listeria innocua inactivation. Therefore, the inactivation process was investigated under controlled, initial conditions of pH (pH0) and undissociated lactic acid ([LaH]0). The resulting inactivation curves consisted of a (sometimes negligible) shoulder period followed by a descent phase. In a few cases, a tailing phase was observed. Depending on the conditions, the descent phase contained one or two log-linear parts or had a convex or concave shape. In addition, the inactivation process was characterized by a certain variability, dependent on the severity of the conditions. Furthermore, in the neighborhood of the growth/no growth interface sometimes contradictory observations occurred. Overall, the individual effects of the influencing factors pH and undissociated lactic acid could clearly be distinguished and were also apparent based on fluorescence microscopy. Appropriate model types were developed and enabled prediction of which conditions of pH0 and [LaH]0 are necessary to obtain a predetermined inactivation (number of decimal reductions) within a predetermined time range.

Rationale

We validated heart rate (HR) and six time and six frequency domain measures of heart rate variability (HRV) as estimators of autonomic outflow in 44 young healthy male subjects. Gold standards for autonomic outflow were the Rosenblueth-Simeone factors m (sympathetic tone) and n (vagal tone), and the sympathovagal balance m·n, determined by two-stage complete autonomic blockade.

Methods

Rank correlations were computed between HR and the HRV measures obtained before autonomic blockade, and m, n and m·n. Also, the maximal mean performances (averaged sensitivity and specificity) for HR and HRV as discriminators between low and high values of m, n or m·n were computed.

Results

The spectral HRV measures showed less good correlations and performances than the time domain HRV measures. Correlations with sympathetic tone were all below 0.31. Respiratory sinus arrhythmia during 15 cycles/min metronome breathing was superior in estimating vagal tone and sympathovagal balance (correlations -0.71/-0.73; both performances 0.82), heart rate scored similarly for assessing the sympathovagal balance (correlation 0.71; performance 0.82).

Conclusions

It does not appear justified to evaluate HR or HRV in terms of sympathetic tone, vagal tone, or sympathovagal balance. HR and HRV are specifically weak in assessing sympathetic tone. Respiratory sinus arrhythmia during 15 cycles/min metronome breathing is superior in assessing vagal tone. Current HRV analysis techniques offer no advantages compared with HR in assessing the sympathovagal balance.

OBJECTIVE—To identify clinical and serological differences of patients with reactive arthritis after infection with Lancefield group A β-haemolytic streptococci (GAS), compared with non-group A—that is, group C or G streptococci (NGAS:GCS/GGS), and a group of culture negative or unidentified streptococci (GUS).
METHODS—A prospective study of consecutive patients with reactive arthritis after serologically or culture confirmed infection with β-haemolytic streptococci, presenting to the outpatient department of rheumatology from January 1992 until January 1998. Alternative causes for reactive arthritis were excluded. Main outcome measures were clinical and serological characteristics including antistreptolysine-O (ASO) and antideoxyribonuclease-B (antiDNase-B) antibody titres.
RESULTS—41 patients (female/male ratio 22/19; mean (SD) age 38 (13) years) with reactive arthritis were included. Culture of throat swab was positive in 13 cases (32%): 6 (15%) GAS, 7 NGAS (17%), that is, 5 (12%) GCS, 2 (5%) GGS. In 28 cases throat culture remained negative resulting in a group of unidentified streptococci; antibiotic pre-treatment had been given by the general practitioner in 18 cases (64%). Arthritis was non-migratory, the number of arthritic joints in GAS and NGAS was similar, whereas in NGAS patients fewer joints were involved than in GUS: mean (SEM) 36 swollen joint index: 3.3 (1.0) in NGAS v 5.6 (1.0) in GUS (p<0.005); 28 swollen joint index: 2.9 (1.0) in NGAS v 4.3 (0.8) in GUS (p<0.05). Extra-articular manifestations—that is, erythema nodosum/ multiforme, AV conduction block or hepatitis—were observed after GAS or GUS infection, but not after NGAS infection. ASO and/or antiDNase-B rose significantly in all patients. The maximal titres for ASO and antiDNase-B in 41 PSRA patients were: mean (SEM) 1242 (232) U/l and 890 (100) U/l respectively; the maximal ASO titres were similar in the three groups: mean (SEM) 1125 (185) in GAS, 625 (160) in NGAS (GAS v NGAS: p=0.17), and 1430 (320) U/l in GUS (NGAS v GUS: p=0.10). AntiDNase-B titres were: mean (SEM) 1075 (180) in GAS, 375 (105) in NGAS (GAS v NGAS: p<0.01), and 995 (125) U/l in GUS (NGAS v GUS: p<0.005). ASO: antiDNase-B ratios were: mean (SEM) 0.89 (0.21) in GAS, 2.60 (0.76) in NGAS (GAS v NGAS: p<0.05), and 1.43 (0.28) in GUS (NGAS v GUS: p=0.12).
CONCLUSION—Post-streptococcal reactive arthritis occurs not infrequently. Differentiation of PSRA based on the causative streptococcal strain is frequently thwarted by negative throat cultures. Sometimes extra-articular manifestations are present that exclude NGAS as the causative organism. Serologically, lower antiDNase-B titres may be indicative for primary NGAS infection; the ASO/antiDNase-B ratio may be of additive value for differentiation in cases of a negative throat culture: the higher ASO/antiDNase-B ratios suggesting primary NGAS infection. In reactive arthritis, serological monitoring consisting of a simultaneous titration of antiDNase-B and ASO, seems to be of clinical importance to trace GAS induced cases, especially when throat cultures remain negative.



Reactive oxygen metabolites are implicated in the initiation and promotion of cancer. In addition, oxidant scavengers, such as manganese--(Mn-SOD) and copper/zinc--superoxide dismutase (Cu/Zn-SOD), are thought to contribute to colorectal cancer treatment response. In the present study, the prognostic significance of the Mn- and Cu/Zn-SOD antigen content of normal mucosa and carcinomas of 163 patients with colorectal cancer was evaluated in comparison with major clinicopathological parameters, with respect to the 5-year overall survival. The Mn-SOD content of carcinomas was found to be significantly higher than that of normal mucosa, whereas there was no difference in the Cu/Zn-SOD content between the normal mucosa and carcinomas. No association was demonstrable between the Mn-SOD and Cu/Zn-SOD content of the tissues and the assessed clinicopathological parameters (gender, age, localization, differentiation grade, diameter and Dukes' stage), with the exception of the Cu/Zn-SOD and the differentiation grade of the carcinomas. Univariate analysis showed that a high Mn-SOD content of carcinomas was associated with a poor 5-year overall survival of the patients with colorectal cancer. Multivariate analysis including all clinicopathological parameters revealed that this Mn-SOD parameter was prognostically independent. The Mn- and Cu/Zn-SOD content of normal mucosa and the Cu/Zn-SOD content of carcinomas were not associated with the overall survival of the patients. In conclusion, this study demonstrates that for patients with colorectal cancer the Mn-SOD content of colorectal carcinomas has a significant prognostic value that is independent from major clinicopathological parameters, including Dukes' stage.

OBJECTIVES--To assess prospectively the influence of intramuscular gold therapy on Helicobacter pylori serology in patients with rheumatoid arthritis (RA). METHODS--Fifty patients with RA were started on intramuscular gold or chloroquine, as the control group and were followed serologically for H pylori infection for 12 months. RESULTS--Twelve patients treated with gold and eight control patients treated with chloroquine, all with serological evidence for H pylori infection, showed no significant decline of IgA and IgG anti-H pylori antibody levels or serum pepsinogen A and C levels. Total serum IgA and IgG levels declined significantly during gold therapy, while they remained unchanged during chloroquine therapy. CONCLUSIONS--Intramuscular gold therapy in patients with RA does not influence the serological parameters of H pylori infection.

BACKGROUND: Sodium aurothiomalate has been reported to have in vitro activity against Helicobacter pylori. Intramuscular gold, as given to patients with rheumatoid arthritis (RA), may therefore influence the colonisation of the gastric mucosa with H pylori. METHODS: Two groups were compared. One group of 42 patients was treated with intramuscular gold; the other group of 58 patients was treated with antimalarial drugs. Antibodies to H pylori (IgA and IgG) were assessed by an enzyme linked immunosorbent assay (ELISA) and total IgA and IgG were measured by nephelometry. RESULTS: IgA and IgG antibody titres against H pylori and total IgA and IgG levels were lower in the patients treated with gold than in the group treated with antimalarial drugs. The ratio of IgA antibodies to H pylori to total IgA antibodies and the ratio of IgG antibodies to H pylori to total IgG antibodies were lower in the group treated with gold. The percentage of seropositivity to H pylori was significantly lower in the group treated with gold than in the group treated with antimalarial drugs for the two IgA antibodies (35 and 55% respectively) and IgG antibodies to H pylori (40 and 65% respectively). CONCLUSIONS: Although this study cannot completely exclude the possibility that a suppressive effect of intramuscular gold on total immunoglobulin production plays a part in the decrease in the titres of IgA antibodies to H pylori and IgG antibodies to H pylori, the lower ratios of antibodies to H pylori to total immunoglobulin antibodies and the lower percentages of seropositivity to H pylori in the group treated with gold suggests that treatment with intramuscular gold decreases H pylori colonisation.

Rheumatoid nodules are a common extra-articular manifestation in rheumatoid arthritis. Intra-articular localisation of these nodules is rare and may produce clinical symptoms. Seven patients with walking problems due to an intra-articular rheumatoid nodule, which became entrapped on the ridge of the tibial plateau of the knee joint resulting in a phenomenon referred to as trigger knee, are described. After excision of the nodules all symptoms completely disappeared.

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Tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives were shown to specifically block human immunodeficiency virus type 1 (HIV-1) replication through a unique interaction with the HIV-1 reverse transcriptase (RT). Through further modification of the lead compounds and structure-activity relationship analysis several new TIBO derivatives that show high potency, selectivity, and specificity against HIV-1 have been obtained. A new TIBO derivative, R86183, inhibits the replication of HIV-1, but not HIV-2, in a variety of CD4+ T-cell lines and peripheral blood lymphocytes, at a concentration of 0.3 to 30 nM, which is at least 4 orders of magnitude lower than the 50% cytotoxic concentration. Whereas an HIV-1 strain containing the Leu-100-->Ile mutation in the RT gene is about 400-fold less susceptible, R86183 still inhibits the replication of an HIV-1 strain containing the Tyr-181-->Cys RT mutation by 50% at a concentration of 130 nM. R86183 inhibits the poly(C).oligo(dG)12-18-directed HIV-1 RT reaction by 50% at a concentration of 57 nM. The antiviral activity of 22 TIBO derivatives in cell culture correlated well with their activity against HIV-1 RT. No such correlation was found for their cytotoxicity. The combination of R86183 with either zidovudine or didanosine resulted in a synergistic inhibition of HIV-1 (strain IIIB) replication. Combination of R86183 with the protease inhibitor Ro31-8959 was found to be additive. Also described is a dilution protocol circumventing overestimation and underestimation of antiviral activity due to adherence to plastic surfaces.

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We used molecular cloning and functional analyses to extend the family of Neu differentiation factors (NDFs) and to explore the biochemical activity of different NDF isoforms. Exhaustive cloning revealed the existence of six distinct fibroblastic pro-NDFs, whose basic transmembrane structure includes an immunoglobulin-like motif and an epidermal growth factor (EGF)-like domain. Structural variation is confined to three domains: the C-terminal portion of the EGF-like domain (isoforms alpha and beta), the adjacent juxtamembrane stretch (isoforms 1 to 4), and the variable-length cytoplasmic domain (isoforms a, b, and c). Only certain combinations of the variable domains exist, and they display partial tissue specificity in their expression: pro-NDF-alpha 2 is the predominant form in mesenchymal cells, whereas pro-NDF-beta 1 is the major neuronal isoform. Only the transmembrane isoforms were glycosylated and secreted as biologically active 44-kDa glycoproteins, implying that the transmembrane domain functions as an internal signal peptide. Extensive glycosylation precedes proteolytic cleavage of pro-NDF but has no effect on receptor binding. By contrast, the EGF-like domain fully retains receptor binding activity when expressed separately, but its beta-type C terminus displays higher affinity than alpha-type NDFs. Likewise, structural heterogeneity of the cytoplasmic tails may determine isoform-specific rate of pro-NDF processing. Taken together, these results suggest that different NDF isoforms are generated by alternative splicing and perform distinct tissue-specific functions.

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A patient is described, who presented with pain in the calf due to a palpable nodule as the presenting symptom of sarcoidosis. The patient was treated with rest and diclofenac, followed by intralesional injections with triamcinolone hexacetonide and became free from pain.

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Total DNA from five Campylobacter species was digested with a mixture of XhoI and BglII restriction endonucleases and analyzed by Southern hybridization by using a probe complementary to the DNA coding for the 16S rRNA. Each of the Campylobacter species, including C. jejuni, C. coli, C. laridis, C. fetus, and C. upsaliensis, displayed a characteristic pattern. Although some bands may be common to different species, the simplicity of the hybridization pattern enabled us to discriminate among the different species of Campylobacter.

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