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CD84, a new member of the immunoglobulin superfamily, shows high homology with several molecules belonging to the CD2 family of differentiation antigens. By screening a peripheral blood leukocyte cDNA library four CD84 isoforms were obtained differing in their 3' sequence. A reverse transcription-polymerase chain reaction (RT-PCR) analysis confirmed that these isoforms were normally found on leukocytes and a new isoform was identified. To establish the nature of the five isoforms obtained (CD84a, CD84b, CD84c, CD84d and CD84e) the genomic structure of the CD84 gene was determined. Our results show that it is composed of at least eight exons, with an exon coding for the 5' UTR and the leader peptide, two exons coding for each of the two immunoglobulin-like domains, an exon encoding the transmembrane portion and four exons coding for the cytoplasmic domains. The isoforms are generated by several mechanisms: alternative use of exons, reading frame shift, use of a cryptic splice site or absence of splicing. The differential expression of several potentially phosphorylatable residues on the different isoforms could be a way to regulate its possible activity in signal transduction. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between arterial stiffness and low-grade inflammation in subjects with type 1 diabetes without clinical cardiovascular disease.Research Design and Methods: Sixty-eight patients with type 1 diabetes and 68 age- and sex-matched healthy subjects were evaluated. Arterial stiffness was assessed by aortic pulse wave velocity (aPWV). Serum concentrations of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and soluble fractions of tumor necrosis factor-α receptors 1 and 2 (sTNFαR1 and sTNFαR2, respectively) were measured. All statistical analyses were stratified by sex.Results: Subjects with diabetes had a higher aPWV compared with healthy control subjects (men: 6.9 vs. 6.3 m/s, P < 0.001; women: 6.4 vs. 6.0 m/s, P = 0.023). These differences remained significant after adjusting for cardiovascular risk factors. Men with diabetes had higher concentrations of hsCRP (1.2 vs. 0.6 mg/L; P = 0.036), IL-6 (0.6 vs. 0.3 pg/mL; P = 0.002), sTNFαR1 (2,739 vs. 1,410 pg/mL; P < 0.001), and sTNFαR2 (2,774 vs. 2,060 pg/mL; P < 0.001). Women with diabetes only had higher concentrations of IL-6 (0.6 vs. 0.4 pg/mL; P = 0.039). In men with diabetes, aPWV correlated positively with hsCRP (r = 0.389; P = 0.031) and IL-6 (r = 0.447; P = 0.008), whereas in women with diabetes no significant correlation was found. In men, multiple linear regression analysis showed that the following variables were associated independently with aPWV: age, BMI, type 1 diabetes, and low-grade inflammation (R(2) = 0.543). In women, these variables were age, BMI, mean arterial pressure, and type 1 diabetes (R(2) = 0.550).Conclusions: Arterial stiffness assessed as aPWV is increased in patients with type 1 diabetes without clinical cardiovascular disease, independently of classical cardiovascular risk factors. In men with type 1 diabetes, low-grade inflammation is independently associated with arterial stiffness. [ABSTRACT FROM AUTHOR]

Objective: We compared hair cortisol (HC) with classic tests of the hypothalamic-pituitary-adrenal (HPA) axis in chronic kidney disease (CKD) and assessed its association with kidney and cardiometabolic status., Design and Methods: A cross-sectional study of 48 patients with CKD stages I-IV, matched by age, sex, and BMI with 24 healthy controls (CTR) was performed. Metabolic comorbidities, body composition, and HPA axis function were studied., Results: A total of 72 subjects (age 52.9 ± 12.2 years, 50% women, BMI 26.2 ± 4.1 kg/m 2 ) were included. Metabolic syndrome features (hypertension, dyslipidaemia, glucose, HOMA-IR, triglycerides, waist circumference) and 24-h urinary proteins increased progressively with worsening kidney function (p < 0.05 for all). Reduced cortisol suppression after 1-mg dexamethasone suppression (DST) (p < 0.001), a higher noon (12:00 h pm) salivary cortisol (p = 0.042), and salivary cortisol AUC (p = 0.008) were seen in CKD. 24-h urinary-free cortisol (24-h UFC) decreased in CKD stages III-IV compared with I-II (p < 0.001); higher midnight salivary cortisol (p = 0.015) and lower suppressibility after 1-mg DST were observed with declining kidney function (p < 0.001). Cortisol-after-DST cortisol was >2 mcg/dL in 23% of CKD patients (12.5% in stage III and 56.3% in stage IV); 45% of them had cortisol >2 mcg/dL after low-dose 2-day DST, all in stage IV (p < 0.001 for all). Cortisol-after-DST was lineally inversely correlated with eGFR (p < 0.001). Cortisol-after-DST (OR 14.9, 95% CI 1.7-103, p = 0.015) and glucose (OR 1.3, 95% CI 1.1-1.5, p = 0.003) were independently associated with eGFR <30 mL/min/m 2 ). HC was independently correlated with visceral adipose tissue (VAT) (p = 0.016). Cortisol-after-DST (p = 0.032) and VAT (p < 0.001) were independently correlated with BMI., Conclusion: Cortisol-after-DST and salivary cortisol rhythm present progressive alterations in CKD patients. Changes in cortisol excretion and HPA dynamics in CKD are not accompanied by significant changes in long-term exposure to cortisol evaluated by HC. The clinical significance and pathophysiological mechanisms explaining the associations between HPA parameters, body composition, and kidney damage warrant further study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Boswell, Vega-Beyhart, Blasco, Quintana, Rodríguez, Díaz-Catalán, Vilardell, Claro, Mora, Amor, Casals and Hanzu.)

Background: Diaphragm fiber atrophy has been evidenced after short periods of mechanical ventilation (MV) and related to critical illness-associated diaphragm weakness. Atrophy is described as a decrease in diaphragm fiber cross-sectional area (CSA) in human diaphragm biopsy, but human samples are still difficult to obtain in clinics. In recent years, ultrasound has become a useful tool in intensive care to evaluate diaphragm anatomy. The present study aimed to evaluate the ability of diaphragm expiratory thickness (Tdi) measured by ultrasound to predict diaphragm atrophy, defined by a decrease in diaphragm fiber CSA obtained through diaphragm biopsy (the gold standard technique) in ventilated patients., Methods: Diaphragm biopsies and diaphragm ultrasound were performed in ventilated donors and in control subjects. Demographic variables, comorbidities, severity on admission, treatment, laboratory test results and evolution variables were evaluated. Immunohistochemical analysis to determine CSA and ultrasound measurements of Tdi at end-expiration were performed, and median values of the control group were used as thresholds to determine agreement between them in further analysis. Sensitivity, specificity, and positive and negative predictive values of an ultrasound Tdi cutoff for detecting histologic atrophy were calculated. Agreement between two ultrasound observers was also assessed., Results: Thirty-five ventilated organ donors and 5 ventilated controls were included, without differences in basic characteristics. CSA and Tdi were lower in donors than in controls. All donors presented lower CSA, but only 74% lower Tdi regarding control group thresholds. The cut-off value for lower diaphragm expiratory thickness (Tdi < 1.7 mm) presented a sensitivity of 73%, a specificity of 67%, a positive predictive value of 96% and a negative predictive value of 17% for determining the presence of diaphragm atrophy (CSA < 2851 μm 2 )., Conclusions: Diaphragm atrophy and thickness reduction is associated to MV. While a lower Tdi in diaphragm ultrasound is a good tool for diagnosing atrophy, normal or increased Tdi cannot rule atrophy out showing that both parameters should not be considered as synonymous., (© 2022. The Author(s).)

Background: Bovine besnoitiosis, an emerging disease in Europe that can be transmitted by vectors, is caused by the apicomplexan Besnoitia besnoiti. Bovine besnoitiosis is difficult to control due to the complexity of its diagnosis in the acute stage of the disease, poor treatment success and chronically asymptomatic cattle acting as parasite reservoirs. When serological prevalence is low, detection and specific culling of seropositive cattle is feasible; however, economic considerations preclude this approach when serological prevalence is high. The aims of this study were to evaluate the accuracy of detection of super-spreaders in highly infected herds and to test their selective elimination as a new control strategy for bovine besnoitiosis., Methods: Previous real-time PCR analyses performed on skin tissues from 160 asymptomatic animals sampled at slaughterhouses showed that the tail base was the best location to evaluate the dermal parasite DNA load. All seropositive animals (n = 518) from eight dairy or beef cattle farms facing a high serological prevalence of besnoitiosis were sampled at the tail base and their skin sample analysed by real-time PCR. A recommendation of rapid and selective culling of super-spreaders was formulated and provided to the cattle breeders. Subsequent serological monitoring of naïve animals was used to evaluate the interest of this control strategy over time., Results: Among the 518 seropositive animals, a low proportion of individuals (14.5%) showed Cq values below 36, 17.8% had doubtful results (36 < Cq ≤ 40) and 67.8% had negative PCR results. These proportions were grossly similar on the eight farms, regardless of their production type (beef or dairy cattle), size, geographical location or history of besnoitiosis. Within two weeks of the biopsy, the rapid culling of super-spreaders was implemented on only three farms. The numbers of newly infected animals were lower on these farms compared to those where super-spreaders were maintained in the herd., Conclusions: Real-time PCR analyses performed on skin biopsies of seropositive cattle showed huge individual variabilities in parasite DNA load. The rapid culling of individuals considered as super-spreaders seems to be a new and encouraging strategy for bovine besnoitiosis control.

Background and Objectives: The most accurate technology to detect and diagnose subepithelial tumors (SETs) is the endoscopic ultrasonography (EUS) combined with puncture techniques, such as the endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) or the endoscopic ultrasonography-guided fine-needle biopsy. Going further in the improvement of the results of tumor samples obtained endoscopically to diagnose the SETs, the canalization technique guided by miniprobes (MPs) to obtain biopsies of SET could be an alternative to EUS-FNA. The objective of this study is to analyze the results of samples obtained by this procedure., Materials and Methods: A multicenter, retrospective study of a review of a database of 32 consecutive patients with a SET in the digestive tract, from 2000 to 2015 was conducted. All patients underwent EUS-performed by MP, to define the size, internal echostructure, and layer of origin of tumor. Once the echostructure was defined, it proceeded to the canalization technique to arrive to the tumor tissue., Results: The average diameter of SETs in this series (32 patients) was about 21.6±11 mm (range: 5-41 mm). The diagnostic accuracy was 28/32, 87.50% (Confidence interval 95%: 76.04%-98.99%), and there were no major complications. All procedures were performed on outpatients, none of which required additional hospitalization. The 50% of patients were operated or endoscopically resected and in all cases, the previous pathological diagnosis was confirmed., Conclusions: This is a feasible, safe, and effective procedure that allows to access to inside of SET to obtain deep biopsies. Tumor samples obtained by deep biopsy, with prior performing of the canalization technique guided by MP, were sufficient for histopathological and immunohistochemical diagnosis and similar to those obtained with other known methods (FNA Trucut, ProCore ® , etc.). However, more prospective comparative studies with a larger number of patients and different specialists carrying out the procedure to reach a higher statistical significance are necessary., Competing Interests: There are no conflicts of interest

The aim of this study was to investigate the relationship between advanced glycation end products (AGEs) and arterial stiffness (AS) in subjects with type 1 diabetes without clinical cardiovascular events. A set of 68 patients with type 1 diabetes and 68 age- and sex-matched healthy subjects were evaluated. AGEs were assessed using serum concentrations of N-carboxy-methyl-lysine (CML) and using skin autofluorescence. AS was assessed by aortic pulse wave velocity (aPWV), using applanation tonometry. Patients with type 1 diabetes had higher serum concentrations of CML (1.18 vs 0.96 μg/ml; P=0.008) and higher levels of skin autofluorescence (2.10 vs 1.70; P<0.001) compared with controls. These differences remained significant after adjustment for classical cardiovascular risk factors. Skin autofluorescence was positively associated with aPWV in type 1 diabetes (r=0.370; P=0.003). No association was found between CML and aPWV. Skin autofluorescence was independently and significantly associated with aPWV in subjects with type 1 diabetes (β=0.380; P<0.001) after adjustment for classical cardiovascular risk factors. Additional adjustments for HbA1c, disease duration, and low-grade inflammation did not change these results. In conclusion, skin accumulation of autofluorescent AGEs is associated with AS in subjects with type 1 diabetes and no previous cardiovascular events. These findings indicate that determination of tissue AGE accumulation may be a useful marker for AS in type 1 diabetes., (© 2014 Society for Endocrinology.)

Aim: To assess the role of iron overload in type 2 diabetic men with hyperferritinemia., Methods: 150 men were recruited from a genetic screening programme for hereditary hemocromatosis (HH) and were tested for type 2 diabetes, other components of the metabolic syndrome, beta cell function (BCF), insulin sensitivity, high-sensitivity C-reactive protein and iron overload., Results: Fifty-one men had type 2 diabetes. They were older (p=0.017) and 99 had lower BCF (p<0.001) than non-diabetic men. None of the iron overload indexes was associated with diabetes., Conclusions: Our findings dispute a role of iron overload in the pathogenesis of type 2 diabetes., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Thalidomide and its analogs are effective agents in the treatment of multiple myeloma. Since gelatinases (matrix metalloproteinases-2 and -9) play a crucial role in tumor progression, we explored the effect of thalidomide on gelatinase production by malignant B lymphoid cell lines., Design and Methods: We investigated the effect of therapeutic doses of thalidomide on integrin-mediated production of gelatinases by malignant B lymphoid cell lines by gelatin zymography, western-blot, reverse transcriptase polymerase chain reaction and invasive capacity through Matrigel-coated Boyden chambers. We also explored the effect of thalidomide on the activation status of the main signaling pathways involved in this process., Results: Thalidomide strongly inhibited gelatinase production by B-cell lines and primary myeloma cells in response to fibronectin, the most efficient gelatinase inducer identified in lymphoid cells. Thalidomide disrupted integrin-mediated signaling pathways involved in gelatinase induction and release, such as Src and MAP-kinase ERK activation, resulting in decreased cell motility and invasiveness. Unexpectedly, treatment with thalidomide elicited an increase in fibronectin-induced Akt phosphorylation through phosphoinositide 3-kinase-independent pathways since thalidomide decreased fibronectin-induced phosphoinositide 3-kinase phosphorylation and reversed the inhibition of Akt phosphorylation achieved by the phosphoinositide 3-kinase inhibitors wortmannin and LY294002., Conclusions: Disruption of integrin-mediated signaling may be an important mechanism through which thalidomide and its analogs impair tumor cell interactions with the microenvironment. The unexpected effects of thalidomide on Akt activation indicate the need for further studies to elucidate whether the interference with Akt downstream effects would synergize with the anti-tumor activity of thalidomide.

Introduction and Objectives: Several guidelines on the treatment of cardiovascular risk factors base their recommendations on the assertion that diabetes mellitus (DM) is a coronary heart disease (CHD) or cardiovascular disease (CVD) risk equivalent. To date, no systematic review of studies substantiating this assertion has been carried out., Methods: A systematic search of the PubMed database up to February 2006 was performed to identify prospective studies meeting the following criteria: a) follow-up was >5 years; b) groups of subjects with DM and without CHD (i.e., DM+CHD-), without DM and with CHD (DM-CHD+), and without either DM or CHD (DM-CHD-) were all included; and c) data on CHD or CVD mortality was reported. The characteristics of the studies were assessed, and data were combined separately for men and women using a random effects model and taking the DM-CHD- group as a reference., Results: In total, 13 studies met the inclusion criteria. Overall, CHD mortality was non-significantly lower in DM+CHD- men than in DM-CHD+ men, hazard ratio [HR] (95% confidence interval [CI]), 3.06 (2.45-3.83) vs 4.28 (3.24-5.66), respectively (P=.066); as was CVD mortality, HR (95% CI), 2.55 (2.00-3.26) vs 3.61 (2.81-4.62), respectively (P=.051). In women, there was no significant difference between the DM+CHD- and DM-CHD+ groups with regard to either CHD mortality, HR (95% CI), 4.68 (3.40-6.45) vs 3.51 (1.75-7.04), respectively (P=.42), or CVD mortality, HR (95% CI), 4.70 (4.23-5.22) vs 3.39 (1.51-9.02), respectively (P=.59)., Conclusions: The findings of this meta-analysis support the view that women in the DM+CHD- group have similar CHD and CVD mortality to those in the DM-CHD+ group, whereas men in the DM+CHD- group demonstrated a non-significant trend towards lower CHD and CVD mortality than those in the DM-CHD+ group.

Background and Objective: Subjects with diabetes mellitus (DM) are at high risk of cardiovascular events. However, their cardiovascular risk varies according to several clinical characteristics like age, sex, ethnicity, type and duration of the DM, quality of glycemic control, type of hypoglycemic treatment, or the presence of nephropathy or previous cardiovascular events. It is not known if these characteristics have been sufficiently reported in clinical trials on hypertension including subjects with DM., Material and Method: We analyzed randomized controlled clinical trials about treatment of hypertension published before May 2003 with the following characteristics: a) inclusion of subjects with DM and b) a primary end-point including at least one of the following events: myocardial infarction, cerebrovascular disease or total mortality. In these trials we evaluated the above-mentioned clinical characteristics concerning cardiovascular risk., Results: Sixteen trials were eventually analyzed. These trials were classified into: a) trials designed only for subjects with DM (RENAAL, UKPDS 38, UKPDS 39, IDNT); b) trials with a subgroup analysis for subjects with DM (SHEP, Syst-Eur, MICRO-HOPE, HOT, STOP-2, LIFE), and c) trials without a subgroup analysis for subjects with DM (CAPP, NORDIL, INSIGHT, ALLHAT, SANBPSG, CONVINCE). All these trials included a total of 33984 subjects with DM, most of them > or = 55 years old. The percentage of women evaluated ranged from 33.5 to 71.9% although in 2 trials no data were found regarding this percentage (12.5%). There was no information on ethnicity in 10 trials (62.5%), on the type of DM in 7 (43.8%), on the duration of the disease in 13 (81.3%), on the degree of glycemic control in 10 (62.5%), on the type of hypoglycemic treatment in 11 (68.8%), on the presence or absence of nephropathy in 11 (68.8%) and on the presence or absence of previous cardiovascular events in 3 (18.8%). Trials without subgroup analysis for subjects with DM had a lower reporting of the clinical characteristics of the subjects evaluated than the rest of the trials., Conclusions: The reporting of relevant clinical characteristics of cardiovascular risk in subjects with DM in the main clinical trials on hypertension is low, diminishing their external validity. To optimize the therapeutic recommendations in the treatment of hypertension in DM these deficiencies should be overcome.

Objective: Ghrelin is a gastric peptide that plays a role in appetite stimulation, energy balance and possibly in insulin resistance. Hyperthyroidism is a situation where negative energy balance and insulin resistance coexist, while in hypothyroidism a positive energy balance and normal insulin sensitivity predominate. We investigated ghrelin levels and their relationship with hunger, food intake and both anthropometric and insulin resistance parameters in patients with thyroid dysfunction., Design and Methods: We studied 24 hyperthyroid and 17 hypothyroid patients before and after normalisation of thyroid hormone levels and their respective body mass index (BMI)-matched control group. We measured plasma ghrelin levels, homeostasis model assessment of insulin resistance (HOMA-IR) index, a hunger score, mean three-day calorie intake and anthropometric parameters., Results: In hyperthyroidism, HOMA-IR index was higher (3.21 +/- 0.60 vs 1.67 +/- 0.15 mMmU/l; P = 0.014, t test for independent data) and ghrelin levels were lower (463.6 +/- 36.4 vs 561.1 +/- 32.1 pg/ml; P = 0.041, Mann-Whitney U-test) than in its control group and both normalised after treatment (HOMA-IR: 2.28 +/- 0.38 mMmU/l; P = 0.106, t test for independent data, and ghrelin: 539.7 +/- 45.4 pg/ml; P = 0.549, Mann-Whitney U-test). Glucose, as a component of HOMA-IR index was the only predictor for ghrelin levels (beta = -0.415, P = 0.044, stepwise multiple regression analysis). In hypothyroidism, HOMA-IR index and ghrelin levels were similar to those in its control group both before and after treatment. In both thyroid dysfunction states, no correlations were observed between changes in ghrelin levels and in free T4, free T3, anthropometric parameters, total calorie intake and hunger score., Conclusions: In thyroid dysfunction states, ghrelin levels seemed to be in relation to insulin resistance and not to energy balance and food intake regulation, as seen in other physiological and pathological states.

The systemic vasculitides include a group of diseases with highly heterogeneous organ distribution and disease expression patterns. The mechanisms mediating tissue targeting in systemic vasculitis are largely unknown. Mechanical forces may contribute to the distribution of lesions in immune complex-mediated vasculitis. The site at which the antigen is encountered may be crucial in determining the location of inflammatory infiltrates in some vasculitides. Co-existence of different immunopathogenic mechanisms with variable dominance may generate diversity in disease presentation patterns. Heterogeneous and incompletely understood triggering mechanisms attract inflammatory cells to the site of interest through sophisticated molecular mechanisms: interplay between leukocyte receptors and endothelial ligands, and interactions between chemokines and chemokine receptors. Even with a similar distribution of lesions, patients with vasculitis may display highly variable clinical manifestations. Variations in genes involved in immune response might determine the severity of disease, the intensity of the systemic inflammatory response, the degree of vessel occlusion and the response to therapy., (Copyright 2001 Harcourt Publishers Ltd.)

T-lymphocyte migration into tissues requires focal degradation of the basement membrane. In this study, we show that transient adherence to fibronectin induces the production of activated forms of matrix metalloproteinase-2 (MMP-2) and MMP-9, as well as downregulation of tissue inhibitor of metalloproteinase-2 (TIMP-2) by T-cell lines. MMP-2 activation was likely achieved by inducing a coordinated expression of membrane-type matrix metalloproteinase-1 (MMP-14), a major activator of MMP-2. Blocking monoclonal antibodies against alpha4, alpha5, and alphav integrins strongly reduced MMP-2 and MMP-9 production induced by fibronectin. Disrupting actin cytoskeleton organization by cytochalasin D strongly enhanced fibronectin-induced MMP-2 and MMP-9 expression. Inhibiting Src tyrosine kinases with herbimycin A reduced MMP-2 and MMP-9 production with no effect on cell attachment. By contrast, G-protein inhibition by pertussis toxin, or transfection with a dominant negative mutant of Ha-Ras strongly increased fibronectin-induced MMP-2 and MMP-9. Inhibition of PI3 kinase, MAPkinase (MEK1), or p38 MAPkinase by wortmannin, PD 98059, or SB 202190, respectively, strongly promoted fibronectin-induced MMP2 and MMP-9. Cells at high density lost their ability to synthesize MMP-2 and MMP-9 in response to fibronectin and MMP expression was restored by transfection with a dominant-negative mutant of Ha-Ras or by treatment with wortmannin, PD 98059, or SB 202190. Our findings suggest that adhesion to fibronectin transduces both stimulatory (through Src-type tyrosin kinases) and inhibitory signals (through Ras/MAPKinase signaling pathways) for MMP-2 and MMP-9 expression by T lymphocytes and that their relative predominance is regulated by additional stimuli related to cell adhesion, motility, and growth.