Correction to: “Living with COVID”—implications for immunosuppressed and immunocompromised

Clinical Rheumatology -     

Role of chemokines in the pathogenesis of chronic synovitis during rheumatoid arthritis

Chemokines play a central role in the pathogenesis of rheumatoid arthritis (RA) synovitis which is characterised by new blood vessel formation, thickening of the lining layer and infiltration of immune cells. The inflammatory infiltrate is generated by a series of events which include the recruitment of leukocytes from the blood stream into the tissue, their local retention and activation to effector cells. All these processes are finely regulated by the interplay of different cell adhesion molecules (CAMs) and chemoattractant factors called chemokines (CK). CK are a superfamily of small proteins that play a crucial role in immune and inflammatory reactions. These chemoattractant cytokines share structural similarities including four conserved cysteine residues which form disulphide bonds in the tertiary structure of the proteins. CK mediate their effects by binding specific receptors (CK-R) characterised by a domain structure which spans the cell membrane seven times and signal through heterotrimeric GPT-binding proteins. Activation of the CK network results in an amplification of the inflammatory cascade and consequently in the progressive destruction of RA joints. The recognition of the central role of CK in inflammation has paved the way to the development of new agents capable of interfering with CK and CK-R. This review will focus in particular on the role of CK in regulating leukocyte trafficking in RA joints.     

Synovial Tissue Heterogeneity and Peripheral Blood Biomarkers

Rheumatoid arthritis is characterized by multiple pathobiological processes and heterogeneous clinical phenotypes. Not surprisingly, the inflamed synovium harbors an equally complex pathology. This includes variability in infiltrating and resident cell populations, spatial arrangements, and cell–cell interactions, as well as gene expression profiles. Remarkable progress in our understanding of the many facets of tissue heterogeneity has been facilitated by the increasing availability of patients’ material and the development of advanced research technologies. The next challenge is to capitalize on the large amount of data generated to elucidate the specific pathogenic pathways disparately activated in different patients and/or different phases of the disease. When tissue pathology can be reliably explored through noninvasive circulating biomarkers, then the circle will be closed. We attempt to highlight key advances in the understanding of synovial tissue heterogeneity in rheumatoid arthritis and summarize novel perspectives in synovial biomarker discovery in relation to peripheral blood.     

Menarcheal timing in intensively treated girls with type 1 diabetes mellitus

Background and aimPrevious studies on menarcheal age (MA) in type 1 diabetes mellitus (T1DM) have shown conflicting results about the effects of DM, but most lack a control group. The present study design is peculiar in that it covers a study population of 73 intensively treated menarcheal adolescents with premenarcheal onset of T1DM (Group A), whose MA was compared with that recorded in three control populations: the first one consisting of 280 healthy adolescents, the second one consisting of 20 T1DM adolescents with postmenarcheal DM onset (Group B) and the third one represented by the respective mothers.Methods and resultsMA of Group A patients was significantly delayed when compared with the respective mothers, healthy controls and Group B patients. By contrast MA of Group B girls was superimposable to the one of both their respective mothers and healthy controls. In Group A MA was strongly related (p < 0.0005) to HbA1c at the time of menarche and to average HbA1c concentrations during the last years before menarche. In Group A no relationship between patients' and mothers' MAs was found, whilst such a correlation was significant in Group B.Conclusions(a) MA is significantly delayed in girls with premenarcheal presentation of T1DM, even if intensively treated; (b) menarcheal retardation is more severe in the patients with suboptimal metabolic control at the time of menarche; and (c) MA in premenarcheal presenting T1DM is irrespective of maternal MA, age and HbA1c concentrations at DM presentation, body mass index and daily insulin dose at menarche.     

A Hyperlipidemic Rabbit Model Provides New Insights into Pulmonary Zinc Exposure Effects on Cardiovascular Health

This study ascertains the effects of zinc, a major component of particulate matter, on pulmonary and systemic endpoints using hyperlipidemic rabbits to model diet-induced human atherosclerosis. New Zealand White rabbits were fed a normal or cholesterol-enriched diet and then were intratracheally instilled 1×/week for 4 weeks with saline or 16 μg/kg of zinc, equal parts sulfate and oxide. Physiologic responses, blood after each exposure, and terminal bronchoalveolar lavage (BAL) were assessed. Rabbits fed a cholesterol-rich diet developed hyperlipidemia and had consistently higher circulating leukocyte counts than rabbits fed normal chow. Within minutes after zinc instillation, saturation of peripheral oxygen was decreased in hyperlipidemic rabbits and heart rate was increased in hyperlipidemic rabbits with total serum cholesterol levels greater than 200 mg/dl. Total circulating leukocytes levels were increased 24 h after the first zinc instillation, but upon repeated exposures this effect was attenuated. After repeated zinc exposures, BAL fluid (BALF) N-acetylglucosaminidase activity was increased regardless of hyperlipidemic state. Hyperlipidemic rabbits had an increase in BALF-oxidized glutathione and a decrease in serum nitrite. The study elucidates mechanisms by which the zinc metal component of PM drives cardiovascular health effects, as well as the possible susceptibility induced by hyperlipidemia. Furthermore, the study exemplifies the benefits of monitoring circulatory physiology during exposure as well as after exposure. This article was reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. A. P. Carll and N. D. Manzo supported by EPA-CT82947101 and EPA-CT826512010, respectively.     

Fertility ratio in male rats: effects after denervation of two pelvic floor muscles

Fertility ratio is defined here as the proportion of females that a male can impregnate after a constant period of in-polygyny living. This ratio was investigated in male rats after denervation of two pelvic floor muscles, the pubococcygeus and iliococcygeus. Denervation was carried out by transecting the somatomotor branch of the pelvic nerve. The lesion did not modify the sexual behavior of males or their overall fertility, but decreased the weight of the ejaculated seminal plug. Consequently, the number of days living in cohabitation to induce pregnancy was increased in lesioned males (approximately 13 days) compared with intact and sham animals (approximately 5 days). These results showed that the fertility ratio was optimal when intact/sham males cohabited with females for two consecutive estrous cycles, but that lesioned males needed up to four cycles to induce most pregnancies. Two hypotheses are raised by our results. The first is that pelvic floor denervation decreases the forceful tension required to expel the semen from the prostatic urethra to the vagina, then an incomplete seminal plug is expelled. The second is that denervation cut afferent fibers that reflexively promote the continence of the semen deposited in the prostatic urethra during seminal emission, allowing some to leak out before ejaculation. The latter hypothesis can also explain the recovery of the fertility ratio in lesioned males. It could be a compensatory mechanism mediated by the pudendal nerve supply to the coccygeus muscle, the other pelvic floor muscle.