T-cell Subset Profile in Kidney Recipients of Extended or Standard Donors

IntroductionThe usage of extended-criteria donors (ECD) became a routinely accepted manner in the last decade. ECD is a potential risk factor for antibody-mediated rejection. Analysis of lymphocyte subsets might be a complementary diagnostic toolkit because there is limited knowledge about this term.MethodBetween May 12, 2016, and September 4, 2019, a total of 130 patients who had undergone kidney transplant were investigated. Patients were divided in ECD and standard criteria donor (SCD) groups. Blood samples were collected before the operation, then in the first week and after 30, 60, 180, and 365 days. Besides routine laboratory tests, multicolor flow cytometry was performed for lymphocyte subsets.ResultsECD grafts were transplanted to older recipients. The number of CD4+ cells increased in the SCDs from the first week to until the end of first month, and then decreased. The number of CD4+ cells decreased from the beginning of the study until the end of first year to 66% of its original value in ECDs. At the first month, the number of CD19+ cells was higher in SCD compared with ECD cases; the number then decreased in both groups. T-regulatory cells had a drop at the first week that lasted until the first month. A bigger increase in SCD and a moderate increase in ECD group were then observed. The kinetics of CD19+ and CD19+ naive cells are similar in the ECD and SCD groups. In the SCD group, cell count decreased in both CD19+ (13%) and CD19+ naive (12%) between third and sixth month. The count of CD19+ cells decreased by 9%, but the count of CD19+ naive cells increased by 11% between the sixth month and first year.DiscussionThe prolonged postoperative uremic state caused by the poorer initial function, together with an aging immune system, explains the weaker immune response in ECD patients, which may be the cause of the decreased number of memory and regulatory T cells. Older patients with an ECD graft need a tailored, personalized, and less aggressive immunosuppressive treatment.     

Human epididymis protein 4 (HE4) levels inversely correlate with lung function improvement (delta FEV1) in cystic fibrosis patients receiving ivacaftor treatment

Background

We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy.

Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species,polysulfides, and nitroxyl

Experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide (H₂S) signaling pathways are intimately intertwined, with mutual attenuation or potentiation of biological responses in the cardiovascular system and elsewhere. The chemical basis of this interaction is elusive. Moreover, polysulfides recently emerged as potential mediators of H₂S/sulfide signaling, but their biosynthesis and relationship to NO remain enigmatic. We sought to characterize the nature, chemical biology, and bioactivity of key reaction products formed in the NO/sulfide system. At physiological pH, we find that NO and sulfide form a network of cascading chemical reactions that generate radical intermediates as well as anionic and uncharged solutes, with accumulation of three major products: nitrosopersulfide (SSNO⁻), polysulfides, and dinitrososulfite [N-nitrosohydroxylamine-N-sulfonate (SULFI/NO)], each with a distinct chemical biology and in vitro and in vivo bioactivity. SSNO⁻ is resistant to thiols and cyanolysis, efficiently donates both sulfane sulfur and NO, and potently lowers blood pressure. Polysulfides are both intermediates and products of SSNO⁻ synthesis/decomposition, and they also decrease blood pressure and enhance arterial compliance. SULFI/NO is a weak combined NO/nitroxyl donor that releases mainly N₂O on decomposition; although it affects blood pressure only mildly, it markedly increases cardiac contractility, and formation of its precursor sulfite likely contributes to NO scavenging. Our results unveil an unexpectedly rich network of coupled chemical reactions between NO and H₂S/sulfide, suggesting that the bioactivity of either transmitter is governed by concomitant formation of polysulfides and anionic S/N-hybrid species. This conceptual framework would seem to offer ample opportunities for the modulation of fundamental biological processes governed by redox switching and sulfur trafficking.Nitrogen and sulfur are essential for all known forms of life on Earth. Our planet’s earliest atmosphere is likely to have contained only traces of O₂ but rather large amounts of hydrogen sulfide (H₂S) (1). Indeed, sulfide may have supported life long before the emergence of O₂ and NO (2, 3).^* This notion is consistent with a number of observations: H₂S is essential for efficient abiotic amino acid generation as evidenced by the recent reanalysis of samples of Stanley Miller’s original spark discharge experiments (4), sulfide is an efficient reductant in protometabolic reactions forming RNA, protein, and lipid precursors (5), and sulfide is both a bacterial and mitochondrial substrate (6), enabling even multicellular lifeforms to exist and reproduce under conditions of permanent anoxia (7). Thus, although eukaryotic cells may have originated from the symbiosis of sulfur-reducing and -oxidizing lifeforms within a self-contained sulfur redox metabolome (8), sulfide may have been essential even earlier by providing the basic building blocks of life.The chemical reactions of sulfur-centered nucleophiles with a range of nitrogen-containing species have been studied for different reasons and as independent processes for more than a century, and early reports indicated complex reaction mechanisms (9–13). The recent surge of interest in this chemistry in the biological community (13–15) was triggered by a growing appreciation that NO and sulfide exert similar and often interdependent biological actions within the cardiovascular system and elsewhere (NO/H₂S “cross-talk”) (16, 17), resulting in mutual attenuation or potentiation of their responses. This cross-talk is possibly mediated by chemical interactions (18–20), but much of the older chemical work seems to have been forgotten. Recently, low concentrations of sulfide were shown to quench NO-mediated vascular responses through formation of an uncharacterized “nitrosothiol” (RSNO) (18–20), assumed to be thionitrous acid (HSNO) (13–15).A recent report of the detection by MS of the highly unstable HSNO at physiological pH (21) has attracted considerable attention from the biological community, because it could be an intermediate in the reaction of sulfide with RSNOs (22) and a precursor for NO, nitrosonium (NO⁺) equivalents, and nitroxyl (HNO). However, a key aspect of HSNO’s properties that seems to have been overlooked in these discussions is its mobile hydrogen, allowing facile 1,3 hydrogen shift and formation of four isomers with the same chemical equation (13)—a feature described in the seminal studies by Goehring in the 1950s (23) and by Müller and Nonella later on (24, 25) that distinguishes HSNO from all other RSNOs (26). The same feature also contributes to the short half-life of the molecule at ambient temperatures, making it more probable that other yet unknown entities are involved as biological mediators of the NO/H₂S cross-talk. Chemical studies by Seel and Wagner (9, 10) showed that NO readily reacts with HS⁻ in basic aqueous solution or organic solvents under anoxic conditions to form the yellow nitrosopersulfide (SSNO⁻). Accumulation of this product was also observed after reaction of RSNOs with sulfide at pH 7.4 (26, 27); moreover, SSNO⁻-containing mixtures were found to release NO, activate soluble guanylyl cyclase (sGC) (26), and relax vascular tissue (28), although a contribution of other reaction products to these effects cannot be excluded. Meanwhile, other sulfane sulfur molecules, including persulfides (RSSH) and polysulfides (RSS_n⁻ and HS_n⁻), have come to the fore as potential mediators of sulfide’s biological effects (29–31), but little is known about their pathways of formation, prevalence in biological systems, and relationship with NO.In view of this confusion, we sought to carry out an integrative chemical/pharmacological investigation to study the chemical biology of the reaction of NO with sulfide more thoroughly and systematically identify potentially bioactive reaction products. We here report that the NO/H₂S interaction leads to formation of at least three product classes with distinct in vivo bioactivity profiles: nitrosopersulfide (SSNO⁻), polysulfides (HS_n⁻), and dinitrososulfite [ONN(OH)SO₃⁻ or N-nitrosohydroxylamine-N-sulfonate (SULFI/NO)]; all anions at physiological pH. Their formation is accompanied by both scavenging and release of NO and H₂S and formation of nitrous oxide (N₂O), nitroxyl (HNO), nitrite (NO₂⁻), nitrate (NO₃⁻), and various sulfoxy species. These results not only offer an intriguing explanation for the quenching and potentiating effects of sulfide on NO bioavailability but also, provide a novel framework for modulation of fundamental biological processes governed by redox switching and sulfur trafficking. This chemistry is likely to prevail wherever NO and sulfide are cogenerated.     

Measurement of periapical pressure created by occlusal loading

The aim of this study was to develop an in vitro model in which the pressure in the periapical tissues can be measured during loading. Extracted human maxillary central incisors were embedded into resin blocks that had physical characteristics similar to bone and periodontal ligament. Each tooth was loaded with 20, 40, 50, 60, 75, 85, 100, 200, 300 and 450 N vertical forces from the incisal edge of the crown; this procedure was carried out three consecutive times. A minute resistor embedded in the periapical space was used to detect apical pressure changes during occlusal loading. The ratio of apical pressure changes (delta P) to the loading force changes (delta F) was calculated. The periapical pressure detected was in direct proportion to the loading force. The mean value of delta P/delta F was 5.994 kPa/N (SD = 2.04). Direct proportionality was found between the coronal loading and the apical hydrostatic pressure. The (delta P)/(delta F) ratio determined in this study makes it easier to estimate the apical hydrostatic pressure values during occlusal loading of single rooted teeth. In this study the apical pressure generated under occlusal loading was of the same magnitude as that estimated with the finite element method.