Exploring the Link between Plasma Levels of PCSK9, Immune Dysregulation and Atherosclerosis in Patients with Primary Sjögren's Syndrome.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid metabolism contributing to cardiovascular (CV) risk in the general population. The relationship between PCSK9 and CV risk in systemic autoimmune diseases has been poorly explored. We investigated the association between plasma PCSK9, measures of immune-inflammatory status and markers of atherosclerosis in 52 consecutive patients with primary Sjögren's syndrome (pSS) in comparison to healthy controls (HCs). Median plasma PCSK9 levels were significantly higher in pSS patients versus HCs (162 (79-255) vs. 53 (39-99) ng/mL). Significantly higher prevalence of subclinical atherosclerosis and lower of dyslipidaemia (61% vs. 85%, p = 0.042) characterized pSS patients versus HCs. In pSS, no significant correlation emerged between PCSK9 and disease activity, atherosclerosis and lipid levels. In HCs, PCSK9 significantly correlated with lipid levels and atherosclerosis. Interestingly, significantly higher PCSK9 levels were found in HCs with high-to-very-high as compared to low-to-moderate CV risk (p = 0.018) while a non-significant trend towards higher PCSK9 levels was detected in pSS patients with low-to-moderate as compared to high-to-very-high CV risk (p = 0.060). This is the first demonstration that pSS patients, despite lower prevalence of dyslipidaemia and higher CV risk profile, are characterized by a 3-fold increase in PCSK9 levels in comparison to HCs. As PCSK9 does not correlate with measures of CV risk, its role in CV morbidity in pSS needs further investigation.

A tryptophan metabolite prevents depletion of circulating endothelial progenitor cells in systemic low-grade inflammation.

Background: Chronic systemic inflammation reduces the bioavailability of circulating endothelial progenitor cells (EPCs). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme of immune tolerance catalyzing the initial step of tryptophan degradation along the so-called l-kynurenine (l-kyn) pathway, that is induced by inflammatory stimuli and exerts anti-inflammatory effects. A specific relationship between IDO1 activity and circulating EPC numbers has not yet been investigated. Methods: In this study, circulating EPCs were examined in mice treated with low doses of lipopolysaccharide (LPS) to mimic low-grade inflammation. Moreover, the association between IDO1 activity and circulating EPCs was studied in a cohort of 277 patients with variable systemic low-grade inflammation. Results: Repeated low doses of LPS caused a decrease in circulating EPCs and l-kyn supplementation, mimicking IDO1 activation, significantly increased EPC numbers under homeostatic conditions preventing EPC decline in low-grade endotoxemia. Accordingly, in patients with variable systemic low-grade inflammation, there was a significant interaction between IDO1 activity and high-sensitivity C-reactive protein (hs-CRP) in predicting circulating EPCs, with high hs-CRP associated with significantly lower EPCs at low IDO1 activity but not at high IDO1 activity. Interpretation: Overall, these findings demonstrate that systemic low-grade inflammation reduces circulating EPCs. However, high IDO1 activity and l-kyn supplementation limit circulating EPC loss in low-grade inflammation.

The impact of statin therapy on in-hospital prognosis and endothelial function of patients at high-to-very high cardiovascular risk admitted for COVID-19.

Statins may protect against adverse outcomes from Coronavirus disease 2019 (COVID-19) through their pleiotropic effects. Endothelial dysfunction seems to be implicated in the pathophysiology of COVID-19, and can be attenuated by statins. This study assessed the role of preadmission statin therapy and its interaction with endothelial function, measured using flow-mediated dilation (FMD) at hospital admission, in predicting in-hospital outcomes among patients with COVID-19 having high-to-very high cardiovascular (CV) risk. We conducted a retrospective cohort study of hospitalized patients with COVID-19 having high-to-very high CV risk, including a subgroup of patients who underwent FMD assessment. Among 342 patients, 119 (35%) were treated with statins at study baseline. Preadmission statin therapy was independently associated with a 75% risk reduction of intensive care unit admission/in-hospital death (adjusted hazard ratio 0.252, 95% confidence interval 0.122-0.521, p < 0.001). In the subgroup of patients with an FMD assessment (245 patients, 40% statin-treated), preadmission statin therapy was independently associated with higher FMD values (ß = 0.159, p = 0.013). However, preadmission statin therapy × FMD interaction was not associated with in-hospital outcomes (F = 0.002, pinteraction = 0.960). Preadmission statin therapy is associated with better in-hospital outcomes among patients with COVID-19 having high-to-very high CV risk, independent of the endothelium-protective effects of these drugs.

Thyroid-Stimulating Hormone Predicts Total Cholesterol and Low-Density Lipoprotein Cholesterol Reduction during the Acute Phase of COVID-19.

A complex dysregulation of lipid metabolism occurs in COVID-19, leading to reduced total cholesterol (TC), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) levels, along with a derangement of thyroid function, leading to reduced thyroid-stimulating hormone (TSH) levels. This study aimed to explore the association between TSH levels during COVID-19 and the variation (Δ) of lipid profile parameters in the period preceding (from 1 month up to 1 year) hospital admission due to COVID-19. Clinical data of 324 patients (mean age 76 ± 15 years, 54% males) hospitalized due to COVID-19 between March 2020 and March 2022 were retrospectively analyzed. The association between TSH levels at hospital admission and either Δ-TC, Δ-LDL-C, or Δ-HDL-C over the selected time frame was assessed through univariable and multivariable analyses. TSH levels were below the lower reference limit of 0.340 µUI/mL in 14% of COVID-19 patients. A significant reduction of plasma TC, LDL-C, and HDL-C was recorded between the two time points (p < 0.001 for all the comparisons). TSH was directly associated with Δ-TC (rho = 0.193, p = 0.001), Δ-LDL-C (rho = 0.201, p = 0.001), and Δ-HDL-C (rho = 0.160, p = 0.008), and inversely associated with C-reactive protein (CRP) (rho = −0.175, p = 0.004). Moreover, TSH decreased with increasing COVID-19 severity (p < 0.001). CRP and COVID-19 severity were inversely associated with Δ-TC, Δ-LDL-C, and Δ-HDL-C (p < 0.05 for all associations). A significant independent association was found between TSH and either Δ-TC (ß = 0.125, p = 0.044) or Δ-LDL-C (ß = 0.131, p = 0.036) after adjusting for multiple confounders including CRP and COVID-19 severity. In conclusion, lower levels of TSH may contribute to explain TC and LDL-C reduction in the acute phase of COVID-19.

The HACOR Score Predicts Worse in-Hospital Prognosis in Patients Hospitalized with COVID-19.

Non-invasive respiratory support (NIRS) is widely used in COVID-19 patients, although high rates of NIRS failure are reported. Early detection of NIRS failure and promptly defining the need for intubation are crucial for the management of patients with acute respiratory failure (ARF). We tested the ability of the HACOR score¸ a scale based on clinical and laboratory parameters, to predict adverse outcomes in hospitalized COVID-19 patients with ARF. Four hundred patients were categorized according to high (>5) or low (≤5) HACOR scores measured at baseline and 1 h after the start of NIRS treatment. The association between a high HACOR score and either in-hospital death or the need for intubation was evaluated. NIRS was employed in 161 patients. Forty patients (10%) underwent intubation and 98 (25%) patients died. A baseline HACOR score > 5 was associated with the need for intubation or in-hospital death in the whole population (HR 4.3; p < 0.001), in the subgroup of patients who underwent NIRS (HR 5.2; p < 0.001) and in no-NIRS subgroup (HR 7.9; p < 0.001). In the NIRS subgroup, along with the baseline HACOR score, also 1-h HACOR score predicted NIRS failure (HR 2.6; p = 0.039). In conclusion, the HACOR score is a significant predictor of adverse clinical outcomes in patients with COVID-19-related ARF.

The detrimental impact of elevated Ferritin to Iron ratio on in-hospital prognosis of patients with COVID-19.

BACKGROUND: Acute viral infections, including coronavirus disease 2019 (COVID-19), are characterized by the dysregulation of iron metabolism, resulting in high serum ferritin and low iron levels. RESEARCH DESIGN AND METHODS: This study aimed to evaluate the prospective impact of iron metabolism dysregulation, as expressed by serum Ferritin-to-Iron Ratio (FIR), on the in-hospital prognosis of patients with COVID-19. Serum levels of ferritin and iron, as well as other iron metabolism markers and recognized prognostic indicators of COVID-19 severity, were measured in 362 patients consecutively hospitalized for COVID-19. The prospective relationship between FIR and the risk of the composite outcome of intensive care unit (ICU) admission/in-hospital death was analyzed. RESULTS: In the population examined (mean age 74 ± 15 years, males 55%), the rates of radiographic signs of pneumonia, respiratory distress, and the need for noninvasive ventilation were higher in patients with high FIR (≥29.2, the 75th percentile) than in those with low FIR (<29.2, the 75th percentile) (p < 0.05 for all comparisons). High FIR was associated with a 1.7-fold (HR 1.709, 95% CI 1.017-2.871, p = 0.043) higher risk of ICU admission/in-hospital death. CONCLUSIONS: Increasing FIR values significantly and independently predicts worse in-hospital prognosis in hospitalized patients with COVID-19.

Low Brachial Artery Flow-Mediated Dilation Predicts Worse Prognosis in Hospitalized Patients with COVID-19.

BACKGROUND: Endothelial injury can be induced by coronavirus disease 2019 (COVID-19) and seems to exert a crucial pathogenic role in its most severe clinical manifestations. We aimed to investigate the association between brachial artery flow-mediated dilation (bFMD), a potential clinical and non-invasive measure of endothelial function, and in-hospital prognosis of COVID-19 patients. METHODS: Brachial artery flow-mediated dilation was assessed in hospitalized COVID-19 patients within 48 h of hospital admission. The association between bFMD and either intensive care unit (ICU) admission or in-hospital death was explored using univariable and multivariable analyses. RESULTS: Four hundred and eight patients were enrolled. Significantly lower bFMD values emerged in COVID-19 patients with either radiographic signs of pneumonia, respiratory distress, or the need for non-invasive ventilation compared with patients without these signs (p < 0.001, p = 0.001, and p < 0.001, respectively). Forty-two (10%) patients were admitted to the ICU, 76 (19%) patients died, and 118 (29%) patients met the composite endpoint of ICU admission/in-hospital death. At unadjusted Cox regression analysis showed that low bFMD (<4.4%, the median value) was associated with a higher risk for the composite endpoint of ICU admission/in-hospital death compared with high bFMD (≥4.4%, the median value) (HR 1.675, 95% CI 1.155-2.428, p = 0.007). Multi-adjusted Cox regression analyses showed that low bFMD was independently associated with a 1.519- to 1.658-fold increased risk for the composite endpoint of ICU admission/in-hospital death. CONCLUSIONS: Low bFMD predicts an unfavorable in-hospital prognosis in COVID-19 patients. The measurement of bFMD may be clinically useful in the prognostic stratification of COVID-19 patients upon hospital admission.

Prevalence of vitamin D deficiency and its prognostic impact on patients hospitalized with COVID-19.

OBJECTIVES: Although hypovitaminosis D appears to be highly prevalent in patients with coronavirus disease 2019 (COVID-19), its impact on their prognosis remains unclear. METHODS: In this study, serum 25-hydroxyvitamin D (Vit-D) level was measured in 200 patients hospitalized with COVID-19. The association between Vit-D and the composite endpoint of intensive care unit (ICU) admission/in-hospital death was explored using univariable and multivariable analyses. Also, serum Vit-D level in patients with COVID-19 was compared with that in age- and sex-balanced COVID-19-negative controls (i.e., 50 inpatients with sepsis). RESULTS: Serum Vit-D level was comparable between patients with COVID-19 and COVID-19-negative inpatients with sepsis (P = 0.397). No significant differences were found in serum Vit-D level according to COVID-19 severity at the time of hospital admission (P = 0.299). Incidence rates of the composite endpoint of ICU admission/in-hospital death did not differ significantly between patients with either Vit-D deficiency (i.e., Vit-D <20 ng/mL) or severe Vit-D deficiency (i.e., Vit-D <12 ng/mL) and those without (31% vs 35% with P = 0.649, and 34% vs 30% with P = 0.593, respectively). Vit-D level and status (i.e., Vit-D deficiency and severe Vit-D deficiency) were not prospectively associated with the risk of the composite endpoint of ICU admission/in-hospital death (P > 0.05 for all Cox regression models). CONCLUSIONS: Regardless of the potential usefulness of Vit-D measurement to guide appropriate supplementation, Vit-D does not appear to provide helpful information for the stratification of in-hospital prognosis in patients with COVID-19.

Noncontact Body Temperature Measurement: Uncertainty Evaluation and Screening Decision Rule to Prevent the Spread of COVID-19.

The need to measure body temperature contactless and quickly during the COVID-19 pandemic emergency has led to the widespread use of infrared thermometers, thermal imaging cameras and thermal scanners as an alternative to the traditional contact clinical thermometers. However, limits and issues of noncontact temperature measurement devices are not well known and technical-scientific literature itself sometimes provides conflicting reference values on the body and skin temperature of healthy subjects. To limit the risk of contagion, national authorities have set the obligation to measure body temperature of workers at the entrance to the workplace. In this paper, the authors analyze noncontact body temperature measurement issues from both clinical and metrological points of view with the aim to (i) improve body temperature measurements accuracy; (ii) estimate the uncertainty of body temperature measurement on the field; (iii) propose a screening decision rule for the prevention of the spread of COVID-19. The approach adopted in this paper takes into account both the traditional instrumental uncertainty sources and clinical-medical ones related to the subjectivity of the measurand. A proper screening protocol for body temperature measurement considering the role of uncertainty is essential to correctly choose the threshold temperature value and measurement method to access critical places during COVID-19 pandemic emergency.

Gliadin activates HLA class I-restricted CD8+ T cells in celiac disease intestinal mucosa and induces the enterocyte apoptosis.

BACKGROUND & AIMS: The extensive infiltration of CD8(+) T cells in the intestinal mucosa of celiac disease (CD) patients is a hallmark of the disease. We identified a gliadin peptide (pA2) that is selectively recognized by CD8(+) T cells infiltrating intestinal mucosa of HLA-A2(+) CD patients. Herein, we investigated the phenotype, the tissue localization, and the effector mechanism of cells responsive to pA2 by using the organ culture of CD intestinal mucosa. The target of pA2-mediated cytotoxicity was also investigated by using the intestinal epithelial cell lines Caco2 and HT29, A2(+) and A2(-), respectively, as target cells. METHODS: Jejunal biopsy specimens from CD patients were cultured in vitro with pA2, and cellular activation was evaluated by immunohistochemistry and cytofluorimetric analysis. Cytotoxicity of pA2-specific, intestinal CD8(+) T cells was assayed by granzyme-B and interferon-gamma release and by apoptosis of target cells. RESULTS: pA2 challenge of A2(+) CD mucosa increased the percentage of CD8(+)CD25(+) and of CD80(+) cells in the lamina propria, the former mainly localized beneath the epithelium, as well as the number of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive cells (TUNEL(+)) in the epithelium. Intraepithelial CD3(+) cells and enterocyte expression of Fas were also increased. CD8(+)CD25(+) and CD8(+)FASL(+) T cells were significantly increased in cell preparations from biopsy specimens cultured with pA2. CD8(+) T-cell lines released both granzyme-B and interferon-gamma following recognition of pA2 when presented by Caco2 and not by HT29. CONCLUSIONS: These data indicate that gliadins contain peptides able to activate, through a TCR/HLA class I interaction, CD8-mediated response in intestinal CD mucosa and to induce the enterocyte apoptosis.

Paroxysmal nocturnal hemoglobinuria: significant association with specific HLA-A, -B, -C, and -DR alleles in an Italian population.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the expansion of a PIG-A mutated hematopoietic stem cell. An immune-mediated origin has been suggested for this disease. Because HLA genes represent a susceptibility factor for autoimmunity, we investigated HLA genotype in 42 Italian PNH patients compared with 301 control subjects of the same ethnic origin. A significantly increased frequency of the HLA class I alleles A*0201 (p < 0.05), B*1402 (p < 0.001), and Cw*0802 (p < 0.005), and of the HLA class II DRB1*1501 (p < 0.01) with the linked DQB1*0602 (p

Functional interaction of common gamma-chain and growth hormone receptor signaling apparatus.

We previously reported on an X-linked SCID (X-SCID) patient, who also had peripheral growth hormone (GH) hyporesponsiveness and abnormalities of the protein phosphorylation events following GH receptor (GHR) stimulation. In the present study, we examined a potential role of common cytokine receptor gamma-chain (gammac) in GHR signaling using EBV-transformed lymphocytes from healthy subjects and gammac-negative X-SCID patients. We demonstrated that the proliferative response to GH stimulation of the B cell lines of gammac-negative patients was impaired despite a comparable cellular expression of GHR molecules to controls. In patients, after GH stimulation, no phosphorylation of STAT5 was observed. In addition, the molecule localization through confocal microscopy revealed that in B cell lines of patients no nuclear translocation of STAT5b following GH stimulation occurred differently from controls. Biochemical analysis of the nuclear extracts of gammac-negative cell lines provided further evidence that the amount of STAT5b and its phosphorylated form did not increase following GH stimulation. In patients, cells reconstituted with wild-type gammac abnormal biochemical and functional events were restored resulting in nuclear translocation of STAT5. Confocal experiments revealed that GHR and gammac were colocalized on the cell membrane. Our study demonstrates the existence of a previously unappreciated relationship between GHR-signaling pathway and gammac, which is required for the activation of STAT5b in B cell lines. These data also confirm that growth failure in X-SCID is primarily related to the genetic alteration of the IL2RG gene.

High number of circulating CD34+ cells in patients with myelophthisis.

Six patients with bone marrow micrometastases from solid cancers presented with increased numbers of circulating CD34+ cells; the CD34+ cell counts were very high in some cases. By contrast, no patient with metastatic cancer without bone marrow involvement showed raised numbers of circulating hemopoietic progenitors.

Allelic distribution of human leucocyte antigen in historical and recently diagnosed tuberculosis patients in Southern Italy.

This study addresses the analysis of the human leucocyte antigen (HLA) allele distribution in 54 historical and in 68 recently diagnosed tuberculosis (TB) patients. The historical cohort was characterized by the presence of large fibrocavernous lesions effectively treated with therapeutic pneumothorax during the period 1950-55. Patients and healthy controls enrolled in the study were from the Campania region of southern Italy. No significant association between HLA alleles and TB in the population of recently diagnosed TB patients was observed. On the contrary, among the historical TB patients there was a strong association with an increased frequency of the HLA-DR4 allele alone and/or in the presence of the HLA-B14 allele (P = 0.000004; Pc = 0.0008), as well as with a decreased frequency of the HLA-A2+,-B14-,DR4- allele association (P = 0.00005; Pc = 0.01). In order to exclude any interference from age-related factors, these results were confirmed by comparing the historical cohort of TB patients with an age-matched healthy control population of the same ethnic origin (P = 0.00004; Pc = 0.008; and P = 0.0001; and Pc = 0.02, respectively).

Celiac disease association with CD8+ T cell responses: identification of a novel gliadin-derived HLA-A2-restricted epitope.

One of the diagnostic hallmarks of the histological lesions associated with celiac disease is the extensive infiltration of the small intestinal epithelium by CD8(+) T cells of unknown Ag specificity. In this study, we report recognition of the gliadin-derived peptide (A-gliadin 123-132) by CD8(+) T lymphocytes from celiac patients. A-gliadin 123-132-specific IFN-gamma production and cytotoxic activity were detected in PBMCs derived from patients on gluten-free diet, but not from either celiac patients on gluten-containing diet or healthy controls. In contrast, A-gliadin 123-132-specific cells were isolated from small intestine biopsies of patients on either gluten-free or gluten-containing diets. Short-term T cell lines derived from the small intestinal mucosa and specific for the 123-132 epitope recognized human APC pulsed with either whole recombinant alpha-gliadin or a partial pepsin-trypsin gliadin digest. Finally, we speculate on a possible mechanism leading to processing and presentation of class I-restricted gliadin-derived epitopes in celiac disease patients.

Clinical and genetic aspects of psoriatic arthritis "sine psoriasis".

OBJECTIVE: To characterize the clinical pattern of psoriatic arthritis (PsA) sine psoriasis. METHODS: Fifty-seven patients (31 men, 26 women, mean age 46.32 +/- 14.12 yrs) with undifferentiated spondyloarthropathy (SpA) were studied. Two subsets were defined: (1) 21 patients with familial psoriasis (12 men, 9 women, mean age 49.29 +/- 14.17 yrs); (2) 36 patients without familial psoriasis (19 men, 17 women, mean age 44.58 +/- 14.00 yrs). The prevalence of the following clinical variables was evaluated: low back pain, enthesopathy, dactylitis, distal interphalangeal (DIP) arthritis, spinal involvement, and discitis. In all patients the following HLA haplotypes were tested: B7, B13, B17, B18, B27, B38, Cw6, and DR7. RESULTS: Dactylitis and DIP arthritis were markedly present in the articular subset with familial psoriasis (p < 0.0001) that also showed a high frequency rate of HLA-Cw6 (p < 0.0001 vs controls and patients without familial psoriasis). HLA-B27 was markedly frequent in patients without familial psoriasis (p < 0.0001 vs controls and p = 0.019 vs patients with familial psoriasis). In addition, in patients with familial psoriasis the log-linear model showed that the presence of HLA-Cw6 was related to the presence of DIP arthritis as well as dactylitis (likelihood ratio chi-square change of 5.891 and p = 0.015). CONCLUSION: A subset of patients with PsA "sine psoriasis" is identified by the occurrence of a SpA with dactylitis and/or DIP arthritis, presence of HLA-Cw6, and familial psoriasis in first or second-degree relatives.