Systemic juvenile idiopathic arthritis: The Great Ormond Street Hospital experience (2005-2021).

Systemic juvenile idiopathic arthritis (sJIA) is a complex, systemic inflammatory disorder driven by both innate and adaptive immunity. Improved understanding of sJIA pathophysiology has led to recent therapeutic advances including a growing evidence base for the earlier use of IL-1 or IL-6 blockade as first-line treatment. We conducted a retrospective case notes review of patients diagnosed with sJIA over a 16-year period (October 2005-October 2021) at Great Ormond Street Hospital for Children. We describe the clinical presentation, therapeutic interventions, complications, and remission rates at different timepoints over the disease course. We examined our data, which spanned a period of changing therapeutic landscape, to try and identify potential therapeutic signals in patients who received biologic treatment early in the disease course compared to those who did not. A total of 76-children (female n = 40, 53%) were diagnosed with sJIA, median age 4.5 years (range 0.6-14.1); 36% (27/76) presented with suspected or confirmed macrophage activation syndrome. A biologic disease-modifying anti-rheumatic drug (bDMARD) alone was commenced as first-line treatment in 28% (n = 21/76) of the cohort; however, at last review, 84% (n = 64/76) had received treatment with a bDMARD. Clinically inactive disease (CID) was achieved by 88% (n = 67/76) of the cohort at last review; however, only 32% (24/76) achieved treatment-free CID. At 1-year follow-up, CID was achieved in a significantly greater proportion of children who received treatment with a bDMARD within 3 months of diagnosis compared to those who did not (90% vs. 53%, p = 0.002). Based on an ever-increasing evidence base for the earlier use of bDMARD in sJIA and our experience of the largest UK single-centre case series described to date, we now propose a new therapeutic pathway for children diagnosed with sJIA in the UK based on early use of bDMARDs. Reappraisal of the current National Health Service commissioning pathway for sJIA is now urgently required.

Sagital abdominal diameter, but not waist circumference is strongly associated with glycemia, triacilglycerols and HDL-C levels in overweight adults.

AIM: To correlate the sagittal abdominal diameter (SAD) and waist circumference (WC) with metabolic syndrome-associated abnormalities in adults. METHODS: This cross-sectional study included onehundred twelve adults (M=27, F=85) aging 54.0±11.2 yrs and average body mass index (BMI) of 30.5±9.0 kg/m². The assessment included blood pressure, plasma and anthropometric measurements. RESULTS: In both men and female, SAD and WC were associated positively with body fat% (r=0.53 vs r=0.55), uric acid (r=0.45 vs r=0.45), us-PCR (r=0.50 vs r=0.44), insulin (r=0.89 vs r=0.75), insulin resistance HOMA-IR (r=0.86 vs r=0.65), LDL-ox (r=0.51 vs r=0.28), GGT (r=0.70 vs r=0.61), and diastolic blood pressure (r=0.35 vs r=0.33), and negatively with insulin sensibility QUICKI (r=-0.89 vs r=-0.82) and total cholesterol/TG ratio (r=-0.40 vs r=-0.22). Glycemia, TG, and HDL-c were associated significantly only with SAD (r=0.31; r = 39, r=-0.43, respectively). CONCLUSION: Though the SAD and WC were associated with numerous metabolic abnormalities, only SAD correlated with dyslipidemia (TG and HDL-c) and hyperglycemia (glycemia).

Accuracy of sagittal abdominal diameter as predictor of abdominal fat among Brazilian adults: a comparation with waist circumference.

AIM: We aim was to compare the sagittal abdominal diameter (SAD) with waist circumference (WC) as a predictor of central obesity among adults and to identify the sensitivity and specificity of the best cut-off point for SAD. METHODS: A cross-sectional study of 266 Brazilians adults (euthrophic and overweight), aged 31-84 years old, of which 89 men and 177 women, was carried out. Anthropometric measurements such as SAD, weight, height, waist and hip circumferences, waist and hip ratio, body mass index, body fat percentage were performed. Receiver Operating Characteristics (ROC) curve was used to identify the sensitivity and specificity of the best cut off point for SAD as a predictor of central obesity. Statistical analysis were considered significant with a value of p < 0.05. RESULTS: The SAD measurement was positively correlated with WC for both genders, although stronger among overweight and obesity women (r = 0.71; p < 0.001 and r = 0.79; p < 0.001, respectively) than men. ROC curves identified the best cut-off points for SAD of 23.1 cm and 20.1 cm for men and women (96% and 85% sensitivity, 86% and 84% specificity, respectively). CONCLUSION: SAD measurement may be used as an anthropometric tool to identify central obesity among women for presenting adequate sensitivity and specificity.

The use of calf circumference measurement as an anthropometric tool to monitor nutritional status in elderly inpatients.

OBJECTIVE: The objective of this study was to identify the nutritional status of hospitalized elderly and verify if calf circumference can be a tool to monitor nutritional status in this population. METHODS: A total of 170 inpatients (79 men and 91 women) aged more than 60 years were assessed. Anthropometric and dietary assessments were done according to standard procedures. The software STATISTICA 6.0 was used for the statistical analysis. The confidence interval was set at 95% and significance level at 5% (p < 0.05). RESULTS: Body mass index assessment revealed a high rate of underweight patients (45.3%), and arm circumference and triceps skinfold revealed a high prevalence of depletion. Males had more lean mass according to the mid-arm muscle circumference (p=0.017) and mid-arm muscle area (p=0.01), and females presented higher triceps skinfold values (p < 0.001). There was a positive correlation between calf circumference and Body Mass Index (p < 0.001), arm circumference (p=0.001), triceps skinfold (p=0.001), mid-arm muscle circumference (p=0.001), and mid-arm muscle area (p=0.001). CONCLUSION: This study found a positive correlation between calf circumference and nutritional status of assessed patients indicating that this measurement can be used as a complementary tool for monitoring the nutritional status of elderly inpatients.

In-feed administered sub-therapeutic chlortetracycline alters community composition and structure but not the abundance of community resistance determinants in the fecal flora of the rat.

The impact of continuous sub-therapeutic chlortetracycline on community structure, composition and abundance of tetracycline resistance genes in the rat fecal community was investigated. Rats were fed a standard diet containing chlortetracycline at 15 microg g(-1) diet for 28 days, followed by 30 microg g(-1) diet to completion of the study on day-56. These levels are similar to those administered to swine during the grow-out phase. Sub-therapeutic chlortetracycline affected the fecal community as determined through change in the cultivable anaerobic community and through molecular-based analyses including denaturing gradient gel electrophoresis profiles of the variable 2-3 region community 16S rRNA genes over time and through comparative sequence analysis of 16S rRNA gene community libraries. Significant decreases in fecal phylotype diversity occurred in response to sub-therapeutic chlortetracycline, although total bacterial output remained constant over the entire feeding trial. Chlortetracycline at 15 microg g(-1) diet resulted in significant change in community composition, but only modest change to the fecal community structure in terms of the distribution of individual phylotypes among the major fecal lineages. Chlortetracycline at 30 microg g(-1) diet significantly altered the distribution of phylotypes among the major fecal lineages shifting the overall community such that Gram-negative phylotypes aligning within the phylum Bacteroidetes became the dominant lineage (>60% of total community). While chlortetracycline impacted both fecal community structure and composition, there was no significant effect on the abundance of community tetracycline resistance genes [tet(Q), tet(W), tet(O)] or on the emergence of a new putative tetracycline resistance gene identified within the fecal community. While sub-therapeutic chlortetracycline provides sufficient selective pressure to significantly alter the fecal community, the primary outcome appears to be the development of a community which may have a higher inherent tolerance to sub-therapeutic levels of chlortetracycline rather than an overgrowth of the tetracycline resistant bacteria already present within the community.

Non-pertussis components of combination vaccines: problems with potency testing.

Vaccines comprising combinations of diphtheria, tetanus and pertussis (DTP) with Haemophilus influenzae type b polysaccharide-protein conjugate (Hib), inactivated poliomyelitis virus (IPV) and hepatitis B virus (HBV) are already available, and new combinations using acellular pertussis components in a triple vaccine (DTaP) are under development. Evidence to date has shown that control of the efficacy, safety and stability of combination vaccines cannot be based on information already available on the individual components or existing licensed formulations. Several examples of immunological interference between components of a combination vaccine have been observed both in clinical trials and in laboratory tests. Examples of these for D, T and Hib components in DTP and DTaP combinations have been investigated.

Age, testing at preferred or nonpreferred times (testing optimality), and false memory.

Two experiments investigated whether age and testing at preferred (optimal) times of day or nonpreferred (nonoptimal) times affected the ability to select relevant from irrelevant but thematically related alternatives in a verbal false memory paradigm. A 3rd experiment pursued the same issues with a visual false memory paradigm. In all 3 experiments, younger adults (n = 195) correctly recalled studied items more often than older adults (n = 121), whereas the 2 age groups correctly recognized about the same numbers of previously studied items. In all 3 experiments, nonoptimally tested older adults had more difficulty excluding nonstudied but thematically related items than the other groups; thus, they showed the greatest evidence of false memory, although all groups did so to a significant extent. The results suggest that optimality and its circadian determinants need to be considered with some tasks for the elderly. Various models and mechanisms are discussed.

Therapeutic botulinum type A toxin: factors affecting potency.

The type A neurotoxin produced by Clostridium botulinum is a potent neuromuscular blocking agent which causes paralysis by preventing the release of neurotransmitter from motor neurons. This property has resulted in the use of the toxin in the treatment of a number of neuromuscular diseases involving muscle spasms. At present, the only recognised assay to estimate accurately the potency of botulinum toxin in clinical preparations is bioassay, in which lethality is used as the endpoint. Such bioassay is inherently variable and large interlaboratory variability has been reported, highlighting problems for standardisation of activity in the absence of any commonly used reference preparation. In the present study, we have confirmed that many different assay conditions can affect potency estimates of clinical formulations of type A botulinum toxin. Further, our studies indicate that different preparations, because of their unique formulation and stability, are differentially affected by some of these assay conditions and that these differences might well contribute to the differences observed in their clinical use.

Refinement and validation of an alternative bioassay for potency testing of therapeutic botulinum type A toxin.

The type A neurotoxin produced by Clostridium botulinum is a potent neuromuscular blocking agent which causes paralysis by preventing the release of neurotransmitter from motor neurones. This property has led to the use of the toxin in the treatment of a number of neuromuscular diseases involving muscle spasms. At present, the only recognised assay with the specificity and sensitivity to estimate accurately the potency of botulinum toxin in clinical preparations is bioassay, in which lethality is used as the end point. Refinement of this assay, with respect to the end point, was explored on the basis of the development of flaccid paralysis of muscles following subcutaneous injection of the toxin at the inguinocrural region. Potency estimates, relative to in house reference preparations, for different therapeutic preparations obtained using flaccid paralysis as a scored response gave excellent agreement with estimates obtained in independent assay using the currently required control method. This study demonstrates that an alternative, more humane bioassay for potency testing of clostridia neurotoxins gives valid estimates equivalent to those currently in use.

Estimation of antigenic tetanus toxoid extracted from biodegradable microspheres.

Microspheres made from poly (lactic/glycolic acid) polymers have been considered as a new delivery system for single-dose tetanus toxoid (TT) vaccines. One of the most critical properties of the proposed vaccines is the loading and distribution of TT as this will have a profound effect on immunogenicity. As the concentration of TT in microspheres is very low sensitive assay methods are required. An assay incorporating monoclonal antibody (MAb) recognizing a neutralizing epitope and cross-reacting with TT was developed (MAp capture ELISA) which provided a sensitivity of 0.001 Lf/ml. An extraction procedure was devised which did not destroy the antigenicity and gave a recovery of 90.6 +/- 3.39% when applied to different preparations. The extracted TT was then quantified by MAb capture ELISA which was estimated to be 250-fold more sensitive than single-site ELISA for toxoid. The loading of 20 microspheres preparations (12 filled and 8 placebo) was determined by both protein micro-BCA assay and the developed assay for TT. The TT content obtained for the 12 filled microspheres preparations from different sources varied up to 400-fold (range 0.01-4.0 Lf/mg microspheres). The utility of the MAb capture ELISA for detection of total antigenic content in microspheres was confirmed by the observation that the determine TT loading correlated with the theoretical loading predicted from the protein content for the best preparations. Preparations with high loading gave the greatest peak response. There was no relationship between dose and the in vivo immunogenic response, suggesting that encapsulated vaccines with differential loading, release properties and presence of excipients will have different response curves in vivo. Hence, the present assay, when combined with information on toxoid release rate and presence and effect of excipients may be of value in predicting in vivo response.

Immunological detection of Clostridium botulinum toxin type A in therapeutic preparations.

The potent neurotoxins produced by strains of Clostridium botulinum act by blocking the release of acetylcholine from peripheral nerve junctions. This specific action of the botulinum neurotoxins is now being exploited therapeutically to treat a variety of conditions involving involuntary muscle spasms. We aimed to develop a sensitive and specific enzyme-linked immunosorbent assay (ELISA) which may be used in parallel with the currently accepted mouse bioassay test for the determination of botulinum neurotoxin type A in therapeutic preparations. High titre polyclonal antitoxins and their biotin derivatives, highly labelled horseradish peroxidase (HRP)-antibody conjugates, and streptavidin-biotin-HRP complexes were prepared and used in a sandwich ELISA for the detection of pure neurotoxin and neurotoxin in therapeutic material. The ELISA utilized either a monoclonal or polyclonal antibody as capture agent and HRP-labelled IgG or F(ab')2 fragment as second antibody. The limit of detection was 4-8 pg of purified toxin/ml (gcv < 13%), equivalent to 1-2 mouse bioassay units/ml. The assay was used to evaluate therapeutic preparations and the results compared with the mouse bioassay. The lower limit of detection for a therapeutic preparation of BoTxA was 2-5 mouse bioassay units/ml. Although across different manufacturers and bulk products there was no correlation between immunologically detected neurotoxin and its biological activity in different therapeutic preparations (r = -0.44, p = 0.34, n = 8), the assay could be used to quantify neurotoxin in therapeutic preparations derived from the same bulk concentrate and manufacturer. The assay is relatively simple, and may be readily adapted to routine monitoring of BoTxA content in therapeutic preparations.

Placental and fetal hepatic growth are selectively inhibited by prolonged reductions of uterine blood flow in pregnant sheep.

Experiments were conducted in eight pregnant sheep to determine the effect on fetal growth of mechanical restriction of uterine blood flow (RUBF) between 120 days and 134 days gestation. Uterine blood flow measured in the middle uterine arteries was 40% less in RUBF animals compared with control animals at the end of the experimental period. There was no change in fetal blood gases, bodyweights, or organ weights between the two groups of animals. The rate of DNA synthesis in the right lobe of the liver was significantly less in RUBF animals (581 +/- 34 dpm micrograms-1 DNA) compared with control animals (845 +/- 44 dpm microgram-1 DNA). There was no difference in the rate of DNA synthesis in the left lobe of the liver or in any of the other organs examined. Autoradiographic examination of the placental cotyledons demonstrated that most DNA synthesis in the placenta was occurring in fetal trophoblastic cells and there was a 40% reduction in the nuclear-labelling index of placental trophoblast cells. These studies show that mild mechanical reductions in uterine blood flow in pregnant sheep results in the selective inhibition of growth in the right lobe of the fetal liver and the placental trophoblastic cells. The mechanism underlying this close association remains to be determined.

Prolonged hypoxia induced by the reduction of maternal uterine blood flow alters insulin-like growth factor-binding protein-1 (IGFBP-1) and IGFBP-2 gene expression in the ovine fetus.

Insulin-like growth factors (IGF-I and IGF-II) are potent mitogenic and differentiating peptides which are synthesized by many fetal tissues. In the circulation and tissue fluids, IGFs are bound to binding proteins (BPs) which not only function as carrier proteins, but also inhibit or modulate the biological actions of IGFs. We have previously shown that prolonged hypoxia in the ovine fetus induced by the reduction of maternal uterine blood flow for 24 h causes a reduction in the DNA synthesis rate in selected fetal tissues. To determine if this effect is due to alterations in the local synthesis of tissue IGFs and their binding proteins or to changes in systemic concentrations of IGFs and IGFBPs, we have investigated the abundance of mRNAs encoding IGFs and IGFBPs in selected tissues and changes in plasma IGFs and IGFBPs. Ovine fetuses (115-120 days gestation; n = 6) underwent 24 h of hypoxia by the reduction of maternal uterine blood flow (RUBF). Controls (n = 6) underwent the same surgical procedure without RUBF. Serial plasma samples were collected before, during, and after the experiment, and tissues were collected at the end of 24 h. Mean plasma IGF-I and IGF-II concentrations tended to be lower in hypoxic fetuses than in controls during the course of hypoxia, but these differences were not statistically significant. Tissue mRNA levels for IGF-I and IGF-II in lung, muscle, thymus, and kidney were similar in control and hypoxic fetuses after 24 h of hypoxia. The relative abundance of liver IGF-I and IGF-II mRNAs was lower in hypoxic fetuses, but only IGF-I mRNA levels were significantly different from the control values (P < 0.05). Compared to control fetuses, IGFBP-1 mRNA levels in the liver of hypoxic fetuses were increased 3- to 7-fold, and IGFBP-1 mRNA expression was induced in kidneys of some hypoxic fetuses (two of six). In addition, IGFBP-2 mRNA levels were decreased in the liver (50%) and kidney (30%) of hypoxic fetuses. The increase in liver IGFBP-1 mRNA abundance and the decrease in liver and kidney IGFBP-2 mRNA abundance were accompanied by an increase in IGFBP-1 levels and a decrease in IGFBP-2 levels in fetal plasma. No changes were observed in either plasma levels or tissue mRNA abundance for IGFBP-3. Analysis of the time course of changes in plasma revealed that the changes in IGFBP-1 and IGFBP-2 occurred within 4 h of hypoxia.(ABSTRACT TRUNCATED AT 400 WORDS)