Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment.

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.

Inflammatory markers and Lp(a) levels as cardiovascular risk factors in androgenetic alopecia.

It is not well-established whether patients with androgenetic alopecia (AGA) show a higher cardiovascular risk and higher prevalence of metabolic syndrome (MS). Therefore, we aimed to analyze the cardiovascular risk and the prevalence of MS by means of a case-control study. We determined lipidic, inflammatory, hormonal and insulin resistance parameters with conventional laboratory methods in 50 male early-onset AGA patients and 50 controls. AGA patients did not show statistical differences for insulin resistance (glucose, insulin, C peptide, HOMA), lipids (total-cholesterol, HDL-cholesterol, tryglicerides) or hormonal parameters (testosterone, free androgen index, sex hormone-binding globulin) P >  0.05, respectively. No differences between groups were observed in prevalence of MS or its components (P >  0.05). AGA patients showed higher levels of fibrinogen, C-reactive protein (CRP) and lipoprotein(a) (Lp(a)) (P = 0.016, P = 0.019 and P = 0.032, respectively). In the unadjusted logistic regression analyses, PCR >4 mg/L, fibrinogen >395 mg/dL and Lp(a) >59 mg/dL increased the risk of AGA, but in the adjusted logistic regression analyses, only PCR >4 mg/L and Lp(a) >59 mg/dL independently increased this risk (OR = 5.83, 95% CI 1.33-25.59 P = 0.020; OR = 3.94 CI 95% 1.08-14.43 P = 0.038). The present study indicates that AGA patients do not show differences in either insulin resistance or prevalence of MS. However, AGA patients show a higher cardiovascular risk characterised by an increase in inflammatory parameters and Lp(a) levels.

Increased circulating endothelial cells and microparticles in patients with psoriasis.

INTRODUCTION: Psoriasis is a chronic pathology characterized by increased inflammation that can be associated with changes in the vascular endothelium. We quantified the levels of circulating endothelial cells (CECs) and microparticles (MPs) in patients with psoriasis in order to analyze their relationship with endothelial and inflammation markers, subclinical atherosclerosis and microcirculation. METHODS: We studied 20 patients and 20 controls. Circulating markers of endothelial damage (CEC, MPs and von Willebrand factor, vWF) and inflammation (E-selectin, E-sel; Interleukin-6, IL-6 and C-reactive protein, CRP) were determined. Subclinical atherosclerosis was assessed by carotid ultrasound to obtain intima-media thickness. Microcirculation was evaluated by nailfold capillaroscopy. RESULTS: CECs, MPs, vWF, CRP and E-sel levels were significantly elevated in patients when compared with controls (p <  0.05). Ninety-four and fifty-three percentage of patients had CEC and MP levels higher than 99th percentile in controls. Forty-seven percent of patients simultaneously showed increased CEC and MP levels. MPs correlate with the inflammatory markers and with the intima-media thickness. CECs correlate with the capillaries loops per mm (p <  0.05). CONCLUSION: Psoriasis patients show elevated CECs and MPs, as a sign of endothelial dysfunction, which correlates with inflammatory markers as well as subclinical atherosclerosis and some capillaroscopy findings.

Haematological, biochemical and inflammatory parameters in inactive Behçet's disease. Its association with red blood cell distribution width.

Red blood cell distribution width (RDW) has been shown to be associated with disease activity in several inflammatory disorders. However only one study to show this has been conducted in patients with Behçet's disease (BD). The aim of the present study was to analyse the association of RDW with BD and its main complications; i.e.; thrombosis and posterior uveitis. A second aim was to analyse the possible correlation between RDW and both haematological and inflammatory parameters. Eighty-nine patients with BD (48 males/41 females) and 94 controls (49 males/45 females) were included in the study. Patients were in an inactive phase of the disease, showing only minimum activity. RDW was statistically higher in patients than in controls (14.02 ± 1.32 vs. 13.15 ± 0.75; p < 0.001) as were CRP, fibrinogen, leucocytes and neutrophils (p < 0.001). No differences in haematimetric indices (MCV, MCH, MCHC) were observed (p > 0.05). RDW correlated negatively with haemoglobin, MCH and MCHC (p < 0.05), and directly with homocysteine (p < 0.01). No correlation was found between RDW and the several inflammatory parameters analysed (p > 0.05). The multivariate regression analysis revealed that haemoglobin and homocysteine were independent predictors of RDW (beta coefficient: -0.310; p = 0.003, beta coefficient: 0.379; p < 0.001, respectively). RDW >14 was associated with neither thrombosis nor uveitis (p = 0.935; p = 0.553, respectively). Our results indicate that BD patients show increased RDW when compared with controls. This increase seems to be related with haematimetric indices and with homocysteine levels. Lack of correlation with inflammatory markers may be due to the fact that patients were in an inactive phase of the disease.

Hemorheological profile in primary and secondary Raynaud's phenomenon. Influence of microangiopathy.

Raynaud's phenomenon (RP) is an episodic peripheral circulatory disorder characterized by local artery spams in subjects exposed to cold or emotional stress. It is not well-established whether RP patients show an altered rheological profile, mostly due to patient classification and clinical severity. We aimed to compare the hemorheological profile in patients with primary and secondary RP with a healthy control group. Eighteen primary RP, 22 secondary RP and 22 healthy controls, were included in the study. RP patients were also divided according to the presence of digital ulcers (7 with, 33 without). Biochemical and hemorheological variables were analyzed, including glucose, triglycerides, total-cholesterol, immunoglobulins, fibrinogen, plasma viscosity, erythrocyte aggregation, erythrocyte deformability and blood viscosity. Age was higher in secondary RP as compared with primary (p = 0.049), while glucose, triglycerides IgA, IgG and plasma viscosity were higher in secondary RP than in healthy subjects (p < 0.05). RP patients with digital ulcers presented higher IgA (p = 0.012), lower erythrocyte aggregation time (p = 0.008) and a trend for higher fibrinogen levels and plasma viscosity (p = 0.064, p = 0.069, respectively). The results of the present study indicate that secondary RP patients show a mild impairment of the rheological profile that aggravates with microangiopathy severity.

Homocysteine levels in patients with primary and secondary Raynaud's phenomenon. Its association with microangiopathy severity.

The association between hyperhomocysteinemia (HHcy) and Raynaud's phenomenon (RP) remains a matter of debate. In 18 primary RP, 23 secondary RP and 41 controls, we investigated homocysteine (Hcy) levels along with biochemical and inflammatory parameters. The Hcy levels in both primary and secondary RP were elevated when compared with controls (p < 0.05 and p < 0.01, respectively). As age was higher in secondary RP as compared with controls (p < 0.01), both primary and secondary RP were age-matched with a corresponding control group, and with Hcy maintaining its statistical significance (p < 0.05). No differences in creatinine, B12 vitamin or folic acid were observed between groups (p > 0.05), or in the prevalence of cardiovascular risk factors (p > 0.05). When patients were classified according to presence or absence of digital ulcers, as a sign of microangiopathy severity, the former showed higher Hcy levels than the latter (p = 0.035). Our results indicate that both primary and secondary RP patients show a mild increase in Hcy levels, which is not related to age, vitamin deficiencies or impaired renal function, but is related to microangiopathy severity. Therefore the association of HHcy and RP suggest that Hcy may contribute to endothelial dysregulation, which characterizes this disease. Specific studies should be designed to elucidate the pathogenesis of HHcy in these patients.

Erythrocyte deformability and psoriasis.

Psoriasis, a systemic immunomediated disorder, is associated with increased cardiovascular risk, although the contribution of rheological alteration to this risk has been seldom analyzed. We have determined erythrocyte deformability in 91 patients with psoriasis and in 101 sex- and age-matched control subjects by means of the Rheodyn SSD, along with hematological, biochemical and inflammatory parameters. Although psoriatic patients showed higher BMI, waist, triglyceride, C-reactive protein levels, neutrophils count and lower HDL-cholesterol (P < 0.001), no differences in the elongation index and in any of the shear stresses tested (12, 30, 60 Pa) were observed (P > 0.05). The results of the present study indicate that patients with psoriasis do not present impaired erythrocyte deformability. Therefore this rheological parameter does not seem to be involved in the higher cardiovascular risk characterizing these patients.

Psoriasis and hemorheology. Influence of the metabolic syndrome.

Psoriasis is a systemic inflammatory disorder with increased cardiovascular risk which has been partly attributed to the increased prevalence of the metabolic syndrome (MS). However, the contribution of rheological alterations to cardiovascular risk has been scarcely investigated. In 91 psoriasis patients and in 101 healthy volunteers, we determined the rheological profile (fibrinogen, blood viscosity and erythrocyte aggregation), along with lipidic and inflammatory parameters. Patients showed statistically higher BMI, waist, triglycerides, insulin, c-reactive protein (CRP), neutrophils, lower HDL-cholesterol and a higher MS prevalence (p<0.05). When subjects with MS were excluded from the study, patients with psoriasis still showed a worse inflammatory, lipidic and rheological profile in the above-mentioned variables compared with controls without MS (p<0.05). The logistic regression analysis revealed that abdominal obesity and fibrinogen>384 mg/dL were independent predictors of psoriasis (OR 3.75 95% CI 1.77-7.94, p<0.001; OR 2.95 95% CI 1.14-7.64, p=0.025), respectively. Patients on biologics, showed less inflammation and a better rheological profile than those not on biological treatment. In conclusion, patients with psoriasis show an altered rheological profile, which may contribute to increased cardiovascular risk. Although the presence of MS worsens this profile, psoriasis per se shows rheological alterations due to both inflammation and altered metabolic parameters. Anti TNF-α treatment markedly improves the rheological profile by mostly decreasing inflammation.

Vascular malformation of the glans penis successfully treated with Nd:YAG laser.

Penile venous malformations are uncommon and those located on the glans are even rarer. Treatment of venous malformations of the glans is currently controversial. Neodynium (Nd):YAG laser treatment may be a useful option.

Erosive pustular dermatosis of the scalp after photodynamic therapy.

Erosive pustular dermatosis of the scalp is a rare condition that tends to occur mainly in elderly patients. Clinically it is characterized by the presence of pustules, chronic crusted erosions with progressive scarring alopecia, and skin atrophy. Although etiology remains unclear, it seems to be triggered by local trauma such as surgical procedures, skin graft, ultraviolet light exposure, cryotherapy, craniotomy, or radiotherapy. To our knowledge, erosive pustular dermatosis of the scalp after photodynamic therapy has been seldom reported. We described a 81-year-old woman presenting with erosive pustular dermatosis of the scalp after photodynamic therapy for actinic keratosis.

Temporary alopecia after embolization of an arteriovenous malformation.

Alopecia after head and neck radiotherapy has been extensively reported in the literature. However, alopecia after endovascular procedures is seldom reported in the dermatological literature. Prolonged fluoroscopic imaging during these procedures may cause serious radiation injuries to the skin, such as dermatitis or alopecia. Radiation-induced temporary alopecia is a peculiar form of radiodermitis that occurs over the areas of the scalp that receive the highest doses of radiation. Although repopulation of alopecic patches occurs spontaneously without treatment, it is important to recognize this disorder to establish a correct diagnosis and inform patients about this transient side effect. We report a 44-year-old woman presenting with temporary alopecia after embolization of an arteriovenous malformation.

Posterior ocular involvement in Behçet's disease and thrombophilic mutations.

It is not well established whether there is an association among common inherited gene defects, Factor V (FV) Leiden, the prothrombin (PT) G20210A mutation, C677T methylene tetrahydrofolate reductase (MTHFR) and ocular Behçet's disease (BD). We aimed to evaluate the association of these mutations with posterior ocular involvement in 89 BD patients from eastern Spain (48 men and 41 women) of whom 23 had posterior ocular involvement and 66 did not. None of the 23 BD patients with posterior ocular involvement was a carrier of either FV Leiden or the PTG20210A mutation. Only 1 patient was a carrier of the 677TT MTHFR mutation, whereas 4 patients carried FV Leiden, 3 the PTG20210A mutation and 10 the 677TT MTHFR mutation in the group without posterior ocular involvement (p = 0.227, p = 0.556, p = 0.144), respectively. In our geographical area, the commonest thrombophilic mutations do not seem to be related with posterior ocular involvement in BD patients.

Rheological alterations and thrombotic events in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterised by increased venous and arterial thrombotic risk. Nevertheless, how hemorheological alterations contribute to thrombotic risk remains a question of debate. We aimed to determine the rheological profile in 105 patients with SLE (24 with a thrombotic event) and 105 healthy controls. We determined blood viscosity and erythrocyte aggregation along with plasma lipids and fibrinogen. Although SLE patients showed lower blood viscosity at 230 s(-1) at a native hematocrit when compared with controls (p < 0.001), differences disappeared after adjusting the hematocrit to 45% (p = 0.095). When comparing SLE patients with and without thrombotic events, no differences in any rheological parameter were found (p > 0.05), except in fibrinogen which was higher in patients with thrombosis (p = 0.013). No differences in the rheological parameters were observed when venous and arterial thrombotic events were compared, although a tendency for higher fibrinogen was observed in patients with venous thrombosis (p = 0.053). Only hematocrit, fibrinogen and triglycerides were independent predictors of native blood viscosity in the multivariate regression analysis, even after adjusting for continuous variables and for tobacco and hypertension: beta coefficient: 0.727 p < 0.001; beta coefficient: 0.152 p = 0.003 and beta coefficient: 0.133 p = 0.015, respectively. The logistic regression analysis revealed that neither increased native blood viscosity (BVn > 4.33) nor increased erythrocyte aggregation (EA1 > 7.85) increased thrombotic risk: OR 0.636, CI 0.313-3.12, p = 0.578 and OR 2.01, CI 0.77-5.20, p = 0.152, respectively. However, hyperfibrinogenemia (Fbg > 342 mg/dL) increased thrombotic risk by around three times: OR 3.44 CI 1.32-8.96, p = 0.011. Our results suggest that the role of blood viscosity and erythrocyte aggregation in thrombotic risk in SLE patients fails to demonstrate any association.

Erythrocyte deformability in naïve HIV-infected patients.

HIV-infected patients are at increased cardiovascular risk. Although several studies have analyzed the hemorheological profile in these patients, studies dealing with erythrocyte deformability are scarce. Moreover, studies have been performed in HIV patients on antiretroviral treatment which may influence this rheological parameter. We analyzed erythrocyte deformability (Elongation Index) at 12, 30 and 60 Pa by means of the Rheodyn SSD in 34 naïve HIV-infected patients (22 males and 12 females) and 34 HIV negative control subjects (24 males and 10 females). Erythrocyte indices (MCV, MCH, MCHC), reticulocytes, plasma lipids, iron, folic acid, vitamin B12 and hepatic enzymes were also determined. When compared with controls, naïve HIV-infected patients showed lower total cholesterol, iron, bilirubin and folic acid (p = 0.009, p = 0.003, p = 0.004, p = 0.004, respectively) and higher triglycerides (TG), aspartate aminotransferase (AST) and gamma glutamyl transferase (γGt) levels (p = 0.017, p = 0.042, p = 0.004, respectively). In the multivariate regression analysis, MCV, γGt and triglycerides were independent predictors of EI60. Neither erythrocyte indices nor reticulocyte count showed differences (p > 0.05). No differences in the Elongation Index at any of the shear stresses tested (12, 30, 60 Pa) were found (p > 0.05). The results of the present study indicate that naïve HIV-infected patients not on antiretroviral treatment do not present decreased erythrocyte deformability when compared with HIV negative control subjects.

Haplotypes of the endothelial protein C receptor gene and Behçet's disease.

INTRODUCTION: Behçet's disease is a vasculitis of unknown cause in which thrombosis occurs in about 25% of patients. Two haplotypes of the endothelial protein C receptor gene, H1 and H3, are associated with the risk of thrombosis. Thus, the objective of this study was to evaluate the influence of these haplotypes on the thrombosis risk in Behçet's disease. MATERIAL AND METHODS: We evaluated the H1 and H3 haplotypes in 87 patients with Behçet's disease, 19 with and 68 without a history of thrombosis, and in 260 healthy individuals. We also measured protein C, activated protein C, and soluble endothelial protein C receptor levels in all individuals. RESULTS: The presence of the H1 haplotype seemed to protect Behçet's patients against thrombosis (odds ratio 0.21; 95% CI 0.1-0.8; p=0.023), whereas the frequency of the H3 haplotype was lower in patients than in control individuals (0.19; 0.1-0.5; p=0.006). Furthermore, the H1 haplotype was associated with increased levels of activated protein C, whereas the H3 haplotype was associated with the highest soluble endothelial protein C levels. Moreover, activated protein C levels were lower in patients with than in patients without posterior uveitis (p<0.001). CONCLUSIONS: These findings indicate that the H1 haplotype protects Behçet's patients from thrombosis, likely via increased levels of activated protein C, whereas individuals carrying the H3 haplotype seem to be protected from the clinical manifestations associated with Behçet's disease, probably via increased soluble endothelial protein C levels.

Hemorheological profile in primary Sjögren's syndrome: a case-control study.

Rheological blood behavior in primary Sjögren's syndrome (SS) has been scarcely investigated. We evaluated the rheological profile (blood viscosity, plasma viscosity, erythrocyte deformability, erythrocyte aggregation, erythrocyte aggregation time and erythrocyte disaggregation threshold) along with fibrinogen, high-sensitive C reactive protein, plasma lipids, immunoglobulins, total proteins and erythrocyte sedimentation rate in 22 patients with primary SS (2 males, 20 females, aged 58 ± 9 years) and in 22 healthy volunteers (3 males, 19 females, aged 57 ± 5 years). Patients showed statistically higher plasma viscosity, erythrocyte sedimentation rate and G immunoglobulin (IgG) levels and lower total cholesterol than controls (p = 0.006, p = 0.023, p = 0.034, p = 0.036, respectively). Three patients with extraglandular involvement showed the highest plasma viscosity values: 1.98 cP, 1.70 cP and 1.65 cP, respectively. No differences were observed for the other rheological parameters analyzed. In a multivariate regression analysis, only fibrinogen, triglycerides and IgG were independent determinants for plasma viscosity values (beta coefficient: 0.335; p = 0.001; beta coefficient: 0.242; p = 0.019; beta coefficient: 0.660; p < 0.001, respectively). Our results indicate that patients with primary SS show increased plasma viscosity, mostly related with IgG levels without other alterations in the rheological profile. Further research with a larger sample size achieved by multicenter studies would be desirable.

Thrombotic events in systemic lupus erythematosus. Its association with acquired and inherited thrombophilic defects.

Systemic lupus erythematosus (SLE) is characterised by increased venous and arterial thrombotic risk. Although antiphospholipid antibodies (APAs) have been shown to be related with thrombotic tendency in these patients, in more than 40% of them, thrombosis occurs without the presence of such antibodies. We analysed the association of venous and arterial thrombotic events with acquired (anticardiolipin antibodies (ACAs) and lupus anticoagulant (LA)) and inherited (antithrombin (AT), protein C (PC), protein S (PS) deficiencies, factor V Leiden and the prothrombin G20210A mutation), thrombophilic risk factors in 86 SLE patients and 89 healthy controls. Patients showed a higher significant percentage of ACAs titres IgG>41 GPL u/ml and LA than controls (P=0.009; P<0.001, respectively), although no differences in AT, PC, PS deficiencies, factor V Leiden and prothrombin G20210A mutation was observed (P>0.05). When patients with and without thrombosis were compared, those with thrombosis showed a statistically higher percentage of ACAs IgG>41 GPL u/ml and LA (P=0.048; P=0.001, respectively), OR 4.33; 95% CI 1.01-18.50 and OR 11.57; 95% CI 3.28-40.75, respectively. When venous and arterial thrombotic events were considered separately, the presence of LA constituted a risk factor for arterial thrombosis (P=0.010), OR 11.33; 95% CI 1.86-68.89, as well as for venous thrombosis (P=0.005), OR 10.15; 95% CI 2.12-48.64, while ACAs IgG>41 GPL u/ml on their own, were not associated with arterial or venous thrombosis (P=0.142, P=0.233, respectively). In addition inherited thrombophilic risk factors AT, PC, PS deficiencies, factor V Leiden and PT G20210A mutation do not seem to increase thrombotic risk in SLE patients.

Haemorheological profile in patients with systemic sclerosis.

The relationship between rheological alterations and systemic sclerosis (SSc) is not well established. We have determined in 27 patients with SSc (4 male, 21 female ) aged 59 +/- 14 years and in a well matched control group the whole rheological profile, i.e. blood viscosity (BV), plasma viscosity (PV), erythrocyte aggregation (EA), erythrocyte deformability (ED) along with fibrinogen (Fbg), C-reactive protein (CRP), lipids, and erythrocyte indices. Patients show higher Fbg, PV and EA (P<0.01) and lower ED (P<0.01). A negative significant correlation was found between ED and inflammation markers, both CRP (P<0.05) and Fbg (P<0.01), indicating that decreased ED seems to be related to inflammatory changes at microcirculatory levels. In addition, patients with anticentromere antibodies show significantly lower ED than those without (P<0.05). The clinical significance of this observation needs to be clarified, deserving further research.

Fibrinolytic inhibitor levels and polymorphisms in Behçet disease and their association with thrombosis.

This study aimed to assess the fibrinolytic inhibitors and their association with thrombosis in Behçet disease. Thrombin activatable fibrinolysis inhibitor (TAFI) (P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) levels (P = 0.022) were significantly higher in 79 patients than in 84 controls. No significant differences were observed in CPB2 (TAFI) Thr325Ile and SERPINE1 (PAI1) 4G/5G polymorphism distribution between patients and controls. TAFI activity levels were significantly higher in patients with thrombosis than in those without thrombosis (P = 0.024). In conclusion, the increased TAFI levels in Behçet disease could contribute to the increased risk of thrombosis observed in these patients.