Antibody Avidity and Neutralizing Response against SARS-CoV-2 Omicron Variant after Infection or Vaccination.

Background: The recently emerged SARS-CoV-2 Omicron variant exhibits several mutations on the spike protein, enabling it to escape the immunity elicited by natural infection or vaccines. Avidity is the strength of binding between an antibody and its specific epitope. The SARS-CoV-2 spike protein binds to its cellular receptor with high affinity and is the primary target of neutralizing antibodies. Therefore, protective antibodies should show high avidity. This study aimed at investigating the avidity of receptor-binding domain (RBD) binding antibodies and their neutralizing activity against the Omicron variant in SARS-CoV-2 infected patients and vaccinees. Methods: Samples were collected from 42 SARS-CoV-2 infected patients during the first pandemic wave, 50 subjects who received 2 doses of mRNA vaccine before the Omicron wave, 44 subjects who received 3 doses of mRNA vaccine, and 35 subjects who received heterologous vaccination (2 doses of adenovirus-based vaccine plus mRNA vaccine) during the Omicron wave. Samples were tested for the avidity of RBD-binding IgG and neutralizing antibodies against the wild-type SARS-CoV-2 virus and the Omicron variant. Results: In patients, RBD-binding IgG titers against the wild-type virus increased with time, but remained low. High neutralizing titers against the wild-type virus were not matched by high avidity or neutralizing activity against the Omicron variant. Vaccinees showed higher avidity than patients. Two vaccine doses elicited the production of neutralizing antibodies, but low avidity for the wild-type virus; antibody levels against the Omicron variant were even lower. Conversely, 3 doses of vaccine elicited high avidity and high neutralizing antibodies against both the wild-type virus and the Omicron variant. Conclusions: Repeated vaccination increases antibody avidity against the spike protein of the Omicron variant, suggesting that antibodies with high avidity and high neutralizing potential increase cross-protection against variants that carry several mutations on the RBD.

The neutralizing response to SARS-CoV-2 Omicron variants BA.1 and BA.2 in COVID-19 patients and homologous and heterologous vaccinees.

The rapid replacement of Omicron BA.1 by BA.2 sublineage is very alarming, raising the question of whether BA.2 can escape the immunity acquired after BA.1 infection. We compared the neutralizing activity toward the Omicron BA.1 and BA.2 sub-lineages in five groups: COVID-19 patients; subjects who had received two doses of mRNA vaccine; subjects naturally infected with SARS-CoV-2 who had received two doses of mRNA; and subjects who had received three doses of homologous or heterologous vaccine. The results obtained highlight the importance of vaccine boosters in eliciting neutralizing antibody responses against Omicron sub-lineages, and suggest that the adenovirus vectored vaccine elicits a lower response against BA.1 than against BA.2 sub-lineage.

Immune response to SARS-CoV-2 Omicron variant in patients and vaccinees following homologous and heterologous vaccinations.

The SARS-CoV-2 Omicron variant has rapidly replaced the Delta variant of concern. This new variant harbors worrisome mutations on the spike protein, which are able to escape the immunity elicited by vaccination and/or natural infection. To evaluate the impact and susceptibility of different serum samples to the Omicron variant BA.1, samples from COVID-19 patients and vaccinated individuals were tested for their ability to bind and neutralize the original SARS-CoV-2 virus and the Omicron variant BA.1. COVID-19 patients show the most drastic reduction in Omicron-specific antibody response in comparison with the response to the wild-type virus. Antibodies elicited by a triple homologous/heterologous vaccination regimen or following natural SARS-CoV-2 infection combined with a two-dose vaccine course, result in highest neutralization capacity against the Omicron variant BA.1. Overall, these findings confirm that vaccination of COVID-19 survivors and booster dose to vaccinees with mRNA vaccines is the correct strategy to enhance the antibody cross-protection against Omicron variant BA.1.

Serum Neutralizing Activity against B.1.1.7, B.1.351, and P.1 SARS-CoV-2 Variants of Concern in Hospitalized COVID-19 Patients.

The recent spreading of new SARS-CoV-2 variants, carrying several mutations in the spike protein, could impact immune protection elicited by natural infection or conferred by vaccination. In this study, we evaluated the neutralizing activity against the viral variants that emerged in the United Kingdom (B.1.1.7), Brazil (P.1), and South Africa (B.1.351) in human serum samples from hospitalized patients infected by SARS-CoV-2 during the first pandemic wave in Italy in 2020. Of the patients studied, 59.5% showed a decrease (≥2 fold) in neutralizing antibody titer against B.1.1.7, 83.3% against P.1, and 90.5% against B.1.351 with respect to the original strain. The reduction in antibody titers against all analyzed variants, and in particular P.1 and B.1.351, suggests that previous symptomatic infection might be not fully protective against exposure to SARS-CoV-2 variants carrying a set of relevant spike mutations.

Characterization of antibody response in asymptomatic and symptomatic SARS-CoV-2 infection.

SARS-CoV-2 pandemic is causing high morbidity and mortality burden worldwide with unprecedented strain on health care systems. To investigate the time course of the antibody response in relation to the outcome we performed a study in hospitalized COVID-19 patients. As comparison we also investigated the time course of the antibody response in SARS-CoV-2 asymptomatic subjects. Study results show that patients produce a strong antibody response to SARS-CoV-2 with high correlation between different viral antigens (spike protein and nucleoprotein) and among antibody classes (IgA, IgG, and IgM and neutralizing antibodies). The antibody peak is reached by 3 weeks from hospital admission followed by a sharp decrease. No difference was observed in any parameter of the antibody classes, including neutralizing antibodies, between subjects who recovered or with fatal outcome. Only few asymptomatic subjects developed antibodies at detectable levels.

Circadian rhythm of hydration in healthy subjects and uremic patients studied by bioelectrical impedance analysis.

BACKGROUND: Healthy subjects and patients after successful kidney transplantation show a circadian rhythm for glomerular filtration rate and for the glomerular transport of macromolecules. We aimed to evaluate by bioelectrical impedance analysis (BIA) whether body hydration status also follows a circadian rhythm in patients with impaired renal function. METHODS: The study was conducted on 28 subjects divided into 3 groups: 8 healthy volunteers, 8 patients affected by chronic kidney disease and 12 end-stage renal disease (ESRD) patients on hemodialysis. During 24 h, 9 BIA measurements were taken in every subject every 180 min. RESULTS: BIA findings demonstrate that normal subjects have a circadian rhythm in hydration status that reaches maximum body water content at night, between 21.00 and 23.00 h. In patients with chronic kidney disease, this rhythm, with maximum at night, is maintained. The rhythm is also present in ESRD patients, if the residual diuresis is at least 500 ml/day, while there is no rhythm when residual diuresis is <300 ml/day. CONCLUSIONS: In normal subjects, body hydration status shows a circadian rhythm, which is weakened or lost in oligoanuric patients on dialysis, but partially maintained in subjects with preterminal uremia and in hemodialyzed patients with residual diuresis >500 ml/day.

Oxidative stress, sister chromatid exchanges and apoptosis in the pathogenesis of lymphocytopenia in ESRD patients.

BACKGROUND: In end-stage renal disease (ESRD) patients on hemodialysis (HD) there may be a link between oxidative stress, genomic damage and the tendency of peripheral lymphocytes to die by apoptosis. Our aim was to verify this hypothesis, and to ascertain whether the link, if present, could explain lymphopenia in uremic patients. METHODS: The series investigated comprised 55 participants: 30 HD patients on regular maintenance acetate-free bio-filtration (AFB) and 25 age-matched healthy volunteers. One blood sample was drawn from the cubital vein of each participant. In HD patients, samples were drawn 3 times: predialytic, postdialytic and interdialytic (24 hours after the end of the session). Thiobarbituric acid reactants (TBARs), sister chromatid exchange (SCE) rate, high frequency cells (HFCs), total circulating lymphocytes and the percentage of circulating apoptotic lymphocytes were assayed in all samples. A statistical analysis of the findings was made using multiple and linear regression. RESULTS: In AFB patients, TBAR levels appeared higher than in controls, even at baseline (2.15 +/- 0.5 micromol/L vs. 1.20 +/- 0.4 micromol/L; p < 0.05). The highest peak occurred at the end of the session (3.2 +/- 0.4 micromol/L; p < 0.05 vs. basal), and a prompt return to basal values was observed 24 hours later (2.2 +/- 0.6 micromol/L, p < 0.5 vs. basal). In AFB patients, the per-centages of HFCs (8.63% vs. 3%; p < 0.05), SCE (6 +/- 0.6 vs. 4.65 +/- 2.18; p < 0.04) and apoptotic lymphocytes (3-fold) were greater than in controls, even at baseline, whereas the values for total lymphocytes were lower (1,140 +/- 652 vs. 1,590 +/- 822). After an AFB session the differences between patients and control values appeared greater (HFCs, 16.81%, p < 0.04 vs. basal; SCE, 7.02 +/- 1.2, p < 0.03; apoptotic lymphocytes 3.5-fold greater than control values). Twenty-four hours later, a further increase was observed in the expression of genomic damage (HFCs, 50%, p < 0.05 vs. basal; SCE, 9.82 +/- 2.1, p < 0.03) and the percentage of apoptotic lymphocytes (4.7-fold greater than control values), while the lowest peak occurred for total circulating lymphocyte count (997 +/- 854, p < 0.04). At linear regression, a strong positive correlation was found between HFCs and TBARs at the beginning and at the end of the AFB session(r = 0.7, p < 0.03). With multiple regression analysis, a strong positive correlation was found between TBAR levels at the end of AFB session, HFC rate and apoptotic lymphocytes at 24 hours, with the last as the dependent variable (multiple r = 0.8, TBARs, beta = 0.51, p < 0.04; HFCs, beta = 0.43, p < 0.03). DISCUSSION AND CONCLUSIONS: An AFB session has an immediate impact, causing an increase in TBAR levels, genomic da-mage and lymphocytic apoptosis. Twenty-four hours after the session there was a further expression of genomic damage, and an increase in apoptosis, while the peak for lymphocytes dropped sharply. Our findings indicate that lymphopenia affecting end-stage renal disease (ESRD) patients may be strictly related to genomic damage exerted, at least in part, by TBARs, and to a dysregulation in programmed cell death.

Osteoprotegerin, IL-6, IL-1, TNF-alpha and TGF-beta concentrations during acetate-free biofiltration.

To ascertain the effect of acetate-free biofiltration (AFB), performed with polyacrilonitrile filters, on serum concentrations of osteoprotegerin (OPG) and other bone-acting cytokines (interleukin (IL) IL-1, IL-6, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta)) in end-stage renal disease (ESRD) patients, we evaluated these parameters during an AFB session and 24 hr after it ended. In second time we verified the existence of eventual correlations among serum levels of all these cytokines at different times. We investigated 48 subjects: 24 healthy volunteers (controls) (12 females, 12 males, mean age 55 +/- 9 yrs) and 24 ESRD patients (12 females, 12 males, mean age 58 +/- 6.7 yrs, mean dialytic age 2.7 +/- 1.6 yrs, residual glomerular filtration rate (GFR) 2.3 +/- 0.6 ml/min). All dialyzed patients received regular AFB with polyacrilonitrile filters for 4 hr thrice-weekly. Statistical analysis showed significant increase in basal serum OPG, IL-6 and TNF-alpha concentrations in dialyzed patients compared to controls, while it did not show significant variations for the other cytokines. During the dialytic session, OPG and TGF-beta concentrations did not show significant variations, while serum TNF-alpha, IL-6 and IL-1 levels significantly decreased from the 1st hour of AFB. None of the cytokines showed significant differences between basal and interdialytic values. We did not find correlations between OPG, IL-1, IL-6, TNF-alpha and TGF-beta concentrations during hemodialytic sessions and during the interdialytic interval. It is our opinion that the lack of correlation between serum concentrations, observed in our study, could not exclude the presence of local interferences between OPG and the other cytokines.

Relationship between IL-18 and sICAM-1 serum levels in patients affected by coeliac disease: preliminary considerations.

OBJECTIVES: Cytokine production from activated T cells play a pathogenetic role in mucosal lesions of coeliac disease (CD). Active interleukin (IL)-18 is expressed in the small intestinal mucosa in CD but not in healthy controls. IL-18 enhances intercellular adhesion molecule-1 (ICAM-1) expression. We analyzed IL-18 serum levels in CD patients before and after gluten-free diet and the possible correlation with soluble ICAM-1 (sICAM-1) serum levels. METHODS: The study comprises ten CD patients before and after gluten free diet and ten healthy controls. Serum IL-18 and sICAM-1 levels were assayed by immunoenzymatic methods. RESULTS: Serum IL-18 and sICAM-1 levels were significantly higher in patients with CD before diet with respect to healthy controls (P<0.05), with a highly significant correlation between the two parameters (Rho=0.800, P=0.0167). Gluten free diet significantly reduces IL-18 and sICAM-1. CONCLUSION: Our findings show that IL-18 serum concentrations correlated with the clinical status of CD patients suggesting a role for this cytokine in the pathophysiology of this disease.

Aquaporin-2 water channels in spontaneously hypertensive rats.

Vasopressin (AVP), an antidiuretic hormone, is known to induce hypervolemia and to regulate the renal expression of aquaporin-2 (AQP2) water channels, but it is not yet known whether the latter are involved in the pathogenesis of essential hypertension. The aim of the present study was therefore to make a comparative study of blood pressure (BP), urinary volume (UV), urinary osmolarity (uOsm), urinary AQP2 (uAQP2), and plasma AVP levels (PAVP) in male spontaneously hypertensive rats (SHR; n = 30) at 3, 7, and 12 weeks of age and in male Wistar-Kyoto rats (WKY, n = 30), also after the subcutaneous administration of OPC-31260 (OPC), a human AVP V(2) receptor antagonist. At 3 weeks, SHR had markedly higher uOsm and lower UV levels than WKY. At 7 weeks, SHR were hypertensive, showing increased uAQP2, PAVP, and uOsm levels and a decreased UV. At 12 weeks, no significant changes were observed in this condition. At 7 and 12 weeks of age, OPC-treated WKY rats showed significant reduction in BP and uOsm and increase in UV with respect to untreated animals. From 3 weeks of age, OPC-treated SHR presented significantly lower BP levels, higher UV levels, and lower uOsm than untreated animals. In treated WKY and SHR, uAQP2 levels were lower than in untreated animals. The PAVP appeared to be higher in OPC-treated rats from both strains. These findings suggest that AVP and the AQP2 are involved in the pathogenesis of hypertension in SHR.

Recombinant human erythropoietin (rHuEPO): more than just the correction of uremic anemia.

Hematopoiesis is controlled by numerous interdependent humoral and endocrine factors. Erythropoietin (EPO), a hydrophobic sialoglycoproteic hormone, plays a crucial role in the regulation of hematopoiesis, and induces proliferation, maturation and differentiation of the erythroid cell line precursors. Thanks to recombinant DNA techniques, different recombinant hormones can now be produced at low cost and in large amounts. This has led to greater understanding of the pathophysiological factors regulating hematopoiesis. This in turn, hasprompted the search for new therapeutic approaches. EPO might also be used to treat patients with different types of anemia: uremics, newborns, patients with anemia from cancer or myeloproliferative disease, thalassemia, bone marrow transplants, chronic infectious diseases. Besides erythroid cells, EPO affects other blood cell lines, such as myeloid cells, lymphocytes and megakaryocytes. It can also enhance polymorphonuclear cell phagocytosis and reduce macrophage activation, thus modulating the inflammatory process. Hematopoietic and endothelial cells probably have the same origin, and the discovery of eyrthropoietin receptors also on mesangial, myocardial and smooth muscle cells has prompted research into the non-erythropoietic function of the hormone. EPO has an important, direct, hemodynamic and vasoactive effect, which does not depend only on an increase in hematocrit and viscosity. Moreover, EPO and its receptors have been found in the brain, suggesting a role in preventing neuronal death. Finally, the recently discovered interaction between EPO and vascular endothelial growth factor (VEGF), and the ability of EPO to stimulate endothelial cell mitosis and motility may be of importance in neovascularization and wound healing.

Correlation between quality of life assessment and a personality neurobiologic model in dialyzed patients.

The Short Form 36 Health Survey (SF-36) is a self-administered scoring system that has been widely used and validated as a quality of life (QOL) assessment tool. In our study, a cluster analysis of SF-36 scores was performed in 50 healthy volunteers (controls) and 50 neurobiologically asymptomatic patients on maintenance hemodialysis (MHD). Firstly, we assayed the tendency to form clusters from each of the investigated dimensions. Statistic analysis was performed using the Student's t-test for independent measurements and multiple regression analysis. Secondly, we attempted to evaluate if the MHD to apply to both groups a general psychobiological personality model developed by Cloninger in 1987. Cloninger describes three independent personality dimensions: novelty seeking (NS), harm avoidance (HA)and reward dependence (RD). Each personality dimension would be the expression of hereditary variations integrating the three main brain systems, respectively: dopaminergic, serotoninergic and noradrenergic. Finally, we then aimed to investigate possible interferences among the seric concentrations of the neuromodulators and SF-36 scores, in the attempt to identify, using a simple approach, the complex personality structure of MHD patients. QOL self-assessment and seric neuromodulators were measured in both groups, choosing an interdialytic day for MHD patients. We found that MHD patients perceived a significant worsening in their QOL in all investigated dimensions with respect to the controls. In addition, they showed significantly lower dopamine and serotonine concentrations and significantly higher noradrenaline concentrations. Therefore, our study, confirmed data reported previously in the literature, that cluster analysis of SF-36 scores provides different results in the MHD population in comparison to normal subjects. In fact, comparing the hierarchical trees of both groups, it appeared evident that in MHD patients, cluster dimensions were greater than in the controls. In cluster compositions showed differences between the two groups. In fact, in MHD patients there were only a few of the clusters that were observed in the controls (mental health and social functioning, vitality and general health), while role-physical and role-emotional dimensions aligned outside the hierarchical tree, with a considerable linkage distance. In our opinion, it is fascinating that the three Cloninger neuromodulators could suggest that HD patient personalities are potentially cyclothymiac, altering the disposition of the two role functions inside the hierarchical tree.

ICAM-1 in maternal serum and amniotic fluid as an early marker of preeclampsia and IUGR.

OBJECTIVE: To determine if plasma and amniotic fluid levels of intercellular adhesion molecule-1 (ICAM-1) at 16 weeks' gestation could be predictive of preeclampsia or intrauterine growth retardation (IUGR). STUDY DESIGN: A retrospective analysis was undertaken in 44 serum samples stored for Down's syndrome screening at 16 weeks' gestation and 44 amniotic fluid samples obtained by midtrimester amniocentesis. RESULTS: No significant difference was found between women who subsequently developed preeclampsia or IUGR and the control group. CONCLUSION: This study failed to demonstrate that ICAM-1 may be an early serum marker of preeclampsia or an amniotic fluid marker of IUGR.

Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt-sensitive hypertension.

Abnormal renal reabsorption of sodium (Na(+)) is likely to play a role in the pathogenesis of salt-sensitivity. In the kidney, chloride channels CLC-Ka (gene CLCNKA) and CLC-Kb (gene CLCNKB) and their subunit Barttin (gene BSND) have important effects on the control of Na(+) and water homeostasis. We investigated if single nucleotide polymorphisms (SNPs) or haplotypes within CLCNKA, CLCNKB and BSND loci affect salt-sensitivity in hypertensive subjects. Associations between blood pressure (BP) change after Na(+)-load and 15 SNPs spanning the length of CLCNKA and CLCNKB and six SNPs spanning the length of BSND were studied in 314 never treated essential hypertensives who underwent an i.v. infusion of saline (300 mm NaCl in 2 l H(2)O in 120 min). Four SNPs were significantly associated with BP change after Na-load. Rs848307 (P = 0.0026) and rs1739843 (P = 0.0023) map upstream the 5' of CLCNKA. Non-coding Rs1010069 (P = 0.0006) and non-synonymous rs1805152 (Thr447Ala; P = 0.0078) map within CLCNKA. Moreover, basal plasma renin activity and heart rate (measured before Na-load) were significantly lower in patients carrying the alleles associated with the larger mean BP increase after Na-load, indicating that such alleles are associated with chronic volume expansion. This study supports the candidacy of CLCNKA as a new susceptibility gene for salt-sensitivity.

Cleavage of p21/WAF1/CIP1 by proteinase 3 modulates differentiation of a monocytic cell line. Molecular analysis of the cleavage site.

Proteinase 3 (PR3), also called myeloblastin, is involved in the control of myeloid cell growth, but the underlying molecular mechanisms have not been elucidated. In U937/PR3, stably transfected with PRCRSV/PR3 to overexpress PR3, PMA-induced p21 expression was significantly decreased as compared with control U937, and this phenomenon was reversed in the presence of the serine proteinase inhibitor, pefabloc. Conversely, when PR3 was inactivated by small interfering RNA, p21 protein was increased, and PMA-induced monocytic differentiation was potentiated. Mass spectrometry analysis identified Ala45 as the primary cleavage site on p21, and the recombinant mutated p21A45R, generated by site-directed mutagenesis and expressed in Escherichia coli, was resistant to in vitro PR3 cleavage. The U937 cells were then stably transfected with either PRCRSV/p21 or PRCRSV/p21A45R, to ectopically express wild type p21 or PR3-resistant p21, respectively. In U937/p21A45R treated with PS-341, a selective proteasome inhibitor, a significant decrease in the S phase and a blockade in the G0-G1 phase of cell cycle were observed when compared with U937/p21 or control U937. This suggested that both PR3 and the proteasome are efficiently involved in the proteolytic regulation of p21 expression in myeloid cells. Moreover, PMA-induced p21 expression was more pronounced in U937/p21A45R compared with U937/p21 and was concomitant with the morphological features of early differentiation. Our data demonstrated that p21 is one specific target of PR3 and that PR3-mediated p21 cleavage prevents monocytic differentiation.

Beta4 integrin and laminin 5 are aberrantly expressed in polycystic kidney disease: role in increased cell adhesion and migration.

Extracellular matrix alterations have been suggested to be part of the early events occurring in Autosomal Dominant Polycystic Kidney Disease (ADPKD), a disease characterized by formation of renal cysts and progressive renal failure. Here we report that cDNA array analysis identified beta(4) integrin aberrant expression in ADPKD cells. Furthermore, laminin 5 (Ln-5), the main alpha(6)beta(4) integrin ligand, was also found to be abnormally expressed in ADPKD. Studies performed with ADPKD cyst-lining epithelial cells (CC) by comparison with normal tubular cells indicate that integrin alpha(6)beta(4)-Ln-5 interactions are involved in cellular events of potential importance for cystogenesis: 1) laminin 5 is a preferential adhesion substrate for CC, mainly through alpha(6)beta(4) interaction, 2) CC increased haptotactic and chemotactic motility depends on the presence of Ln-5 and requires integrin alpha(3)beta(1) cooperation, and 3) CC haptotactic or chemotactic migration is specifically increased by mAb-mediated beta(4) integrin ligation, through an alpha(3)beta(1) integrin-dependent and independent pathway, respectively. These results highlight the role of Ln-5 and alpha(6)beta(4) integrin in adhesive and motility properties of cyst-lining epithelial cells, and further suggest that integrins and extracellular matrix modifications may be of general relevance to kidney epithelial cell cyst formation.

In vitro effect of fluticasone propionate on interleukin 8 production by monocytes obtained from patients affected by moderate-severe allergic asthma.

BACKGROUND: Interleukin-8 (IL-8), a potent chemotactic and activating factor for neutrophils and eosinophils, may be a crucial factor in severe asthma. The aim of this study was to evaluate the effect of fluticasone propionate (FP), a corticosteroid with potent anti-inflammatory activity, on the in vitro release of IL-8 by monocytes obtained from asthmatic patients. METHODS: Monocytes from 15 non-atopic healthy donors and from 15 patients affected by moderate-severe allergic asthma were isolated and incubated (37 degrees C, 5% CO(2)) for 24 h with varying combinations of lipopolysaccharide (LPS) from Escherichia coli (1 microg/ml) and FP (100 nmol/l). IL-8 concentration in the culture supernatant was measured by an immuno-enzymatic method (ELISA). RESULTS: A highly significant inverse correlation between FEV1 (forced expiratory volume) values before withdrawal and in vitro IL-8 production by unstimulated monocytes from asthmatic patients was observed (Rho = -0.787; p = 0.0032). IL-8 production by either LPS-stimulated or unstimulated monocytes from asthmatic subjects was statistically increased compared to monocytes from healthy donors (p < 0.05). FP addition reduced IL-8 production by monocytes from asthmatic patients and also from healthy donors (p < 0.05). CONCLUSIONS: The partial IL-8 inhibition by FP could be closely related to the anti-inflammatory activity of this corticosteroid. Based on these results, we propose that the clinical improvement of asthma, observed following FP administration, may depend, at least in part, on the ability of this drug to modulate cytokine production by monocytes.

Interleukin-18 and CD30 serum levels in patients with moderate-severe depression.

Interleukin-18 (IL-18), a pro-inflammatory cytokine that plays an important role in the T-cell-helper type 1 response, is a new member of the family of cytokines produced in the brain. CD30 is a marker of T-cell-helper type 2 lymphocytes. We evaluated IL-18 and CD30 serum levels in 10 patients affected by moderate-severe depression (MSD). We demonstrated for the first time that serum IL-18 levels of MSD patients were significantly higher than those of healthy donors. On the contrary, no significant difference was found between serum CD30 levels of MSD patients compared with those of healthy donors. These data strengthen the hypothesis that MSD disease is associated with an inflammatory response, mainly T-cell-helper type 1, and suggest an important role for IL-18 in the pathophysiology of MSD.

Effect of a prostacyclin analogue, iloprost, on urinary aquaporin-2 excretion in humans.

The regulation of aquaporin-2 (AQP2) water channel excretion in the collecting duct depends mainly on the action of vasopressin (AVP). Recently, however, other regulatory factors have been identified: atrial natriuretic factor, oxytocin and prostaglandins. In healthy volunteers (5 males, 5 females; mean age 23 +/- 3 years) we therefore evaluated the effect of a stable analogue of prostacyclin-2 (PGI(2)), iloprost, on renal function and on the urinary excretion of AQP2 (U-AQP2). After 6 h of iloprost infusion, U-AQP2 increased from 0.8 +/- 0.15 to 1.8 +/- 0.2 pmol/mg creatinine (p < 0.001), while the urinary flow rate increased from 1.4 +/- 0.2 to 1.8 +/- 4 (p < 0.01). No significant change was found in the AVP serum concentration, with a basal value of 3.17 +/- 0.12 vs. 3.15 +/- 0.12 pg/ml after 6 h of prostacyclin infusion. All the values returned to pre-study levels after a recovery period of 6 h. In conclusion, the PGI(2) analogue, iloprost, can induce U-AQP2 excretion independent of AVP.