The axial spondyloarthritis clinical phenotype in idiopathic hypoparathyroidism: critical review of concept that muscular hypercontractility can induce enthesopathy lesions.

Idiopathic hypoparathyroidism (iH-PoPT) is a rare condition infrequently associated with axial spondyloarthritis (SpA) which may mimic ankylosing spondylitis (AS). Axial SpA is a unifying clinical term for chronic inflammatory spinal disorders, although biomechanical factors may play a role. The primary objective of this review is to critically describe the iHPoPT/SpA phenotype defined by established criteria and its differentiation from AS. Five databases were comprehensively searched without time limit to retrieve 14 (11M, 3F) iH-PoPT/SpA cases. Their demographic, clinical, laboratory, radiographic, and HLA-B27 status were compared to two national series of AS patients. Mean (SD) onset age of musculoskeletal symptoms [32.5 (9.7)] was significantly older than 943 German AS patients [25.1 (8.5), (p=0.004)] and 842 Spanish AS patients [26.1 (9.7), (p=0.030)]. Radiographic lesions of iHPoPT/SpA differ morphologically from skeletal alterations in hyperparathyroid and hypophosphataemic syndromes which often have inadequate bone mineralisation and decreased bone mineral density (BMD). Clinical musculoskeletal manifestations were greater (p<0.001) in iHPoPT/SpA than AS patients at cervical (62 vs. 10%) and hip (85 vs. 22%) localisations, respectively. Typical AS sacroiliac joint structural lesions of erosions and bony bridging were reported in only 1 iHPoPT/SpA case and HLA-B27 was positive in 2 of 10 tested. The iHPoPT/SpA phenotype may be a natural experiment on the novel concept of how chronic hypocalcaemia of iHPoPT causes axial neuromotor hypercontractility and biomechanically induces the rare SpA association. In iHPoPT/SpA, neuromuscular hyper-contractility may predispose to axial radiographic enthesopathy lesions and contribute knowledge on biomechanical contributions and pathways for further research.

Attenuation of the Induction of TLRs 2 and 4 Mitigates Inflammation and Promotes Neurological Recovery After Focal Cerebral Ischemia.

The intense inflammatory response triggered in the brain after focal cerebral ischemia is detrimental. Recently, we showed that the suppression of toll-like receptors (TLRs) 2 and 4 attenuates infarct size and reduces the expression of pro-inflammatory cytokines in the ischemic brain. In this study, we further examined the effect of unsuppressed induction of TLRs 2 and 4 on the expression of its downstream signaling molecules and pro-inflammatory cytokines 1 week after reperfusion. The primary purpose of this study was to investigate the effect of simultaneous knockdown of TLRs 2 and 4 on M1/M2 microglial polarization dynamics and post-stroke neurological deficits and the recovery. Transient focal cerebral ischemia was induced in young adult male Sprague-Dawley rats by the middle cerebral artery occlusion (MCAO) procedure using a monofilament suture. Appropriate cohorts of rats were treated with a nanoparticle formulation of TLR2shRNA and TLR4shRNA (T2sh+T4sh) expressing plasmids (1 mg/kg each of T2sh and T4sh) or scrambled sequence inserted vector (vehicle control) expressing plasmids (2 mg/kg) intravenously via tail vein immediately after reperfusion. Animals from various cohorts were euthanized during reperfusion, and the ischemic brain tissue was isolated and utilized for PCR followed by agarose gel electrophoresis, real-time PCR, immunoblot, and immunofluorescence analysis. Appropriate groups were subjected to a battery of standard neurological tests at regular intervals until 14 days after reperfusion. The increased expression of both TLRs 2 and 4 and their downstream signaling molecules including the pro-inflammatory cytokines was observed even at 1-week after reperfusion. T2sh+T4sh treatment immediately after reperfusion attenuated the post-ischemic inflammation, preserved the motor function, and promoted recovery of the sensory and motor functions. We conclude that the post-ischemic induction of TLRs 2 and 4 persists for at least 7 days after reperfusion, contributes to the severity of acute inflammation, and impedes neurological recovery. Unlike previous studies in TLRs 2 or 4 knockout models, results of this study in a pharmacologically relevant preclinical rodent stroke model have translational significance.

Microscopic Review of Nasopharyngeal Swabs as a Means of Benchside Quality Assurance.

OBJECTIVE: Nasopharyngeal swabs (NPS) are the collection modality of choice for reverse-transcription polymerase chain reaction (RT-PCR) multiplex array for respiratory viruses. NPS gather both extracellular material and human respiratory epithelial cells and, when used with RT-PCR, have reliable sensitivity for detection of viral infection. GOALS: At our institution, we identified a 1.7% re-order rate within 7-days for NPS destined for RT-PCR respiratory pathogen multiplex, which we hypothesize may be due in part to low confidence in adequate collection. We sought an inexpensive and accessible strategy for benchside quality assurance of NPS adequacy by observing microscopic content of viral transport media. PROCEDURE: For eight-hundred one NPS samples collected during routine clinical practice in November 2019, aliquots of viral transport media were air-dried and safranin-stained on glass slides under a fume hood. We then counted morphologically distinct ciliated columnar epithelial cells (CCEs), which are prevalent in the nasopharynx. RESULTS: Twenty percent of samples negative for respiratory pathogens by RT-PCR (BioFire FilmArray RP2, Cepheid GeneXpert) had no CCEs, while just seven percent of positive samples had no CCEs. Pearson's Chi-squared test was used to compare presence of CCEs between samples that were positive and negative for respiratory pathogens by RT-PCR (p=1.6×10-36). CONCLUSION: We posit that samples without identifiable CCEs have a greater likelihood of inadequate collection. The basic, benchside protocol that we describe here demonstrates potential to reduce unnecessary re-testing when deployed to confirm negative tests despite high clinical suspicion: a strategy which may help conserve NPS reagents.

Preclinical biomarker associations with both incident rheumatoid arthritis and its subsequent mortality: sex effects in a 41-year, community-based, case-control cohort study.

OBJECTIVES: To identify sex effects and preclinical serum biomarker associations with both incident rheumatoid arthritis (RA) and its subsequent mortality, using a 41-year, community-based, case-control cohort. METHODS: After cohort entry in 1974, incident RA cases (n=54) had clinical onsets between 1977 and 1994. Cohort control (CN) subjects were individually matched on entry to cases (4 CN:1 RA, n=216). All subjects were followed for survival from 1995 through 2015. Ranks (1-5) of preclinical z-scores within each set of 1 RA and 4 matched CN were analysed for associations with incident RA and mortality. Survival was evaluated using Cox proportional hazards models. RESULTS: Preclinical serum IgG RF z-score ranks associated with incident RA in 90 males (18 RA, 72 CN). Cigarette smoking, androstenedione, pregnenolone, and sIL-2Rα ranks associated with incident RA in 180 females (36 RA, 144 CN). Total percentile mortality was greater (p=0.003) in RA (70.4) vs. CN (49.9) and equivalently increased in female RA (69.4) vs. CN (49.3) and in male RA (72.2) vs. CN (43.1) subjects. Percentile respiratory-related CODs were greater (p=0.009) only in the female RA cases (16.7) vs. CN (3.5). Ranks of preclinical hsCRP (p=0.028) and sIL-2Rα (p=0.030) independently associated with 140 total deaths, as did sTNF-R1 (p=0.003) and hsCRP (p=0.005) with 50 CVD deaths. Latter biomarker association were significant in females. Therapy responses in 1995 significantly associated with subsequent mortality. CONCLUSIONS: Sex effects were important in preclinical biomarker associations with incident RA, total and CVD mortality as well as occurrence of respiratory deaths.

Increased mortality of incident rheumatoid arthritis versus matched non-RA control subjects: a community-based long-term prospective cohort study.

OBJECTIVES: This study aimed to critically investigate all-cause and major-cause mortality of incident rheumatoid arthritis (RA) cases versus matched non-RA comparison (CN) subjects in a long-term prospective cohort. METHODS: Baseline 1974 cohort entry demographic and serum biomarker data on 54 incident RA patients and 216 matched CN subjects were related to their mortality from 1995 through 2015. Mortality of RA patients was also analysed by 3 categories of course responses to therapy assigned by the sole community rheumatologist in 1995 (19 good, 23 fair, and 12 limited). Cox proportional hazards regression models including baseline covariates were used to determine survival from all-causes, cardiovascular disease (CVD), respiratory-related, malignancies, and other causes of death (CODs). RESULTS: Total deaths occurred in 38 (70.4 percent) of 54 RA and 102 (47.7 percent) of 216 CN (p=0.003). Total mortality remained greater (p=0.011) in RA versus CN subjects after adjustment for baseline demographic covariates (HR= 1.66, 95% CI 1.12-2.46). Respiratory-related CODs were also greater (p=0.047) in RA versus CN (HR= 2.69, 95% CI 1.02-7.14) subjects. The RA patients' responses to therapy in 1995 significantly (p=0.004) predicted total mortality. Baseline serum immunological and steroid biomarkers independently predicted total, CVD, and other and unknown CODs. Pre-clinical (1974) ranked biomarker z-score values (1 = lowest, 5 = highest) within matched sets of 1 RA and 4 CN study subjects independently associated with mortality from 1995 through 2015, for both total (CRP, p=0.028 and sIL-2Rα, p=0.030) and CVD (CRP, p=0.005 and sTNF-R1, p=0.003) deaths. CONCLUSIONS: Total mortality and respiratory-related CODs were greater in incident RA versus CN subjects. The 35 RA cases who had fair or limited course responses to rheumatologist's therapy had greater mortality than their matched CN, whereas the 19 good RA responders had equivalent survival to CN subjects. The independent CRP and sTNF-R1 biomarker associations with CVD deaths were enhanced by a gradient of their dichotomous z-score values in survival models.

Sexual Dimorphisms of Adrenal Steroids, Sex Hormones, and Immunological Biomarkers and Possible Risk Factors for Developing Rheumatoid Arthritis.

Innate immunity and immunological biomarkers are believed to be interrelated with sex hormones and other neuroendocrine factors. Sexual dimorphism mechanisms may be operating in certain rheumatic and inflammatory diseases which occur more frequently in women than men, as rheumatoid arthritis (RA). Less data have been available on altered interrelations of the combined neuroendocrine and immune (NEI) systems as risk factors for development of certain diseases. In this study, serological interrelations of NEI biomarkers are analyzed before symptomatic onset of RA (pre-RA) versus control (CN) subjects, stratified by sex. Sexual dimorphism was found in serum levels of acute serum amyloid A (ASAA), soluble interleukin-2 receptor alpha (sIL-2Rα), and soluble tumor necrosis factor receptor 1 (sTNF-R1). Multiple steroidal and hormonal (neuroendocrine) factors also showed highly (p < 0.001) significant sexual dimorphism in their assayed values, but less for cortisol (p = 0.012), and not for 17-hydroxyprogesterone (p = 0.176). After stratification by sex and risk of developing RA, differential NEI correlational patterns were observed in the interplay of the NEI systems between the pre-RA and CN groups, which deserve further investigation.