Arterial and venous involvement in Behçet’s syndrome: a narrative review

Behçet syndrome (BS) is a unique type of vasculitis that affects veins and arteries of all sizes, leading to recurrent vascular events, mostly venous thrombosis. The prevalence of venous thromboembolism in BS patients ranges between 15 and 40%. Thrombosis is usually an early manifestation leading to diagnosis of BS in up to 40% of patients. BS is per se a model of inflammation-induced thrombosis. The primary autoimmune response activates lymphocytes that in turn produce a cytokine cascade that activates neutrophils, which modify the secondary structure of fibrinogen making it less susceptible to plasmin-induced lysis. This leads to endothelial dysfunction, platelet activation and overexpression of tissue factor leading to inflammatory thrombi, usually attached to the wall. The pathogenesis of thrombosis is especially relevant to direct the specific treatment, that is based on immunosuppression rather than anticoagulation. Superficial vein thrombosis (SVT) and deep vein thrombosis (DVT) are the most common form of thrombosis in BS, but thrombosis in atypical sites (cava vein, suprahepatic veins, intracardiac thrombus) and arterial involvement can also occur. We assessed the latest update of the European League Against Rheumatism recommendations for the management of BS. Vascular Behçet treatment is usually based of immunosuppressants, and the role of anticoagulation remains controversial. The use of interventional and surgical procedures should be carefully evaluated, due to the risk of triggering a vascular pathergy phenomenon.

     

Dissociation between contraction and relaxation: The possible role of phospholamban phosphorylation

Summary The relationship between myocardial relaxation and phosphorylation of phospholamban, an intrinsic protein of sarcoplasmic reticulum (SR), was studied in perfused rat hearts beating at constant rate and perfused at constant coronary flow. The positive inotropic effect (increase in developed tension, T, and maximal rate of rise of tension, + ) of 3×10^–9 and 3×10^–8M isoproterenol (ISO) occurred together, with a proportionately greater increase in maximal velocity of relaxation, – . Thus, the + /– ratio decreased 0.23±0.04 and 0.41±0.05 respectively. Time to half-relaxation (t_1/2) and the time constant of relaxation (Tau) were also significantly decreased by ISO. Phospholamban phosphorylation (in pmol³²Pi/mg SR protein) increased from 23±3.3 (control) to 42±2.3 (3×10^–9M ISO) and to 186±19.3 (3×10^–8M ISO). When the negative inotropic action of nifedipine was just offset by either Ca²⁺ (N–Ca²⁺) or ISO (N–I), relaxation was faster when ISO was present. Perfusion with N–I significantly decreased + /– 0.18±0.05, t_1/2 14±3 ms and Tau 1.4±0.2 ms. Phospholamban phosphorylation significantly increased from 23±3.3 to 40±4.9 pmol 32 Pi/mg SR protein. N–Ca²⁺ did not elicit any significant change in these parameters nor in phospholamban phosphorylation. Thus, phospholamban phosphorylation appears closely related to myocardial relaxation and may be one of the important mechanisms by which contractility and relaxation are dissociated in vivo.This work was supported by grants # 3-106600/85 from CONICET and # 2109-1239/85 from CIC.     

The minor components of the rat asialoglycoprotein receptor are apically located in neonatal enterocytes

Because specific uptake of the asialoglycoprotein haptocorrin has been reported in suckling distal intestine, evidence of the asialoglycoprotein receptor in rat ileum was sought. On Western blot, two different polyclonal antisera against purified rat holoreceptor recognized only proteins of the size of the minor receptor components (51 and 55 kilodaltons) in both suckling and adult rat intestine. Messenger RNA encoding the minor component (RHL-2/3) was detected in total RNA extracted from rat ileum. Calcium-specific binding of porcine or rat haptocorrin-[57Co]cobalamin complexes was detected in the brush border membranes of distal suckling rat and porcine small intestine. This binding was almost completely blocked by another asialoglycoprotein, asialofetuin. The pH optimum for binding was 6-9, with a Ka of 0.25 nmol/L and a capacity of 4.6 fmol/mg protein. These properties, with the exception of the low capacity, are all consistent with those of the intact receptor on hepatocytes. The intestinal receptor was localized not to the basolateral membrane, as in the liver, but to the apical brush border, as suggested by the binding data. Furthermore, immunoperoxidase stains of paraffin-embedded tissue detected strong binding to the brush border and apical phagolysosome of mid and distal suckling rat intestine. These data show that, contrary to expectations, the minor components of the asialoglycoprotein receptor are functional and expressed in the apical membrane of the suckling intestine. The abundance of the protein by Western blot suggests possible roles for it in the neonatal gut other than haptocorrin binding.     

Men suffer vertebral fractures with similar spinal T-scores to women

OBJECTIVE: To evaluate the applicability of the WHO densitometric criteria for the diagnosis of spinal osteoporosis in men and to compare it with women with vertebral fractures, as well as to analyze the role of vertebral dimensions in the development of spinal fractures. METHODS: For these purposes we analyzed, using DXA, vertebral projected area and lumbar bone mineral density (BMD), as well as T and Z-scores in lumbar spine in a cohort of 66946 individuals; 2556 of these subjects had one or more atraumatic vertebral fracture (396 men and 2160 postmenopausal women). RESULTS: Men and women with fractures showed significantly lower mean BMD, T-score and Z-score values than individuals without fractures while vertebral dimensions were similar in both groups of patients. When comparing men and women with vertebral fractures, the former showed a significantly greater projected area (46.89+/-5.5 vs. 39.13+/-4.6 cm(2) p<0.001) and lumbar BMD (0.991+/- 0.21 vs. 0.938+/- t0.19 g/cm(2) p<0.001). However, the median lumbar T-score values were similar for both sexes (-2.3 in women vs. -2.2 in men; p: NS). In addition, a similar percentage of men and women with vertebral fractures showed T-score values <-2.5 in the lumbar spine (44% vs. 46%, p=NS). CONCLUSION: We conclude that although men with vertebral fractures have greater vertebral dimensions and BMD than women, the lumbar T-scores are similar. Therefore, it seems reasonable to adopt the same T-score values for the diagnosis of osteoporosis in men and women.     

Response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C due to genotype 4

SUMMARY: Hepatitis C virus (HCV) genotypes 1 and 4 respond less well to pegylated interferon (pegIFN) plus ribavirin (RBV) therapy. For this reason most studies merge these two genotypes when assessing virological response. However, in most trials the HCV genotype 4 population is rather small, and conclusions are mainly derived from what occurs in HCV-1 patients. All HCV-4 patients coinfected with HIV who received pegIFN plus RBV in two different multicentre studies, PRESCO and ROMANCE, conducted respectively in Spain and Italy, were retrospectively analyzed. Baseline plasma HCV-RNA, proportion of patients with HCV-RNA <10 IU / mL at week 4 (rapid virological response), and HCV-RNA declines >2 logs at week 12 (early virological response, EVR) were all assessed as predictors of sustained virological response (SVR). Overall, 75 patients (60 men) were evaluated. Median age was 40 years and median CD4 count 598 cells / mm(3); 49% had plasma HIV-RNA <50 copies / mL; 71% had elevated liver enzymes and 31% had advanced liver fibrosis (Metavir F3-F4). Median serum HCV-RNA was 5.7 log IU / mL. Rapid virological response was attained by 10 (20%) patients and EVR by 26 (42%). Using intention-to-treat and on-treatment (OT) analyses, SVR was achieved by 21 / 75 (28%) and 21 / 62 (34%) of HCV-4 patients, respectively. In the multivariate analysis (OT), baseline HCV-RNA (OR 0.09 for every log increment; 95% CI: 0.01-0.7) and EVR (OR: 7.08; 95% CI: 1.8-27.2) were significantly and independently associated with SVR. This is the largest series of HIV-infected patients with chronic hepatitis C due to HCV-4 treated with pegIFN plus RBV examined so far and the results show that HCV-4 behaves similarly to HCV-1. Therefore, these patients should be considered as difficult to treat population. Baseline serum HCV-RNA and EVR are the best predictors of SVR in HCV-4 / HIV-coinfected patients.     

Change of EPO treatment from subcutaneous epoetin to intravenous epoetin or darbepoetin alpha

This prospective, two-arm, clinical trial assesses the effectiveness in maintaining the levels of haemoglobin (Hb) between 11 and 13 g/d1 and the safety of changing the administration route (from subcutaneous to intravenous) of epoetin (rHuEPO) alpha at equidose versus a changeover to darbepoetin alpha, taking the exact equivalence in peptide mass between the two as referent in patients with chronic renal insufficiency (CRI) in haemodialysis. A total of 112 patients previously treated with epoetin and no dose modification during the 8 weeks prior to the study and stable levels of Hb were included. Of these, 92.1% finished the follow-up period (24 weeks). After changing the administration route of rHuEPO, a significant increase in the resistance index (REI, weekly dose per kilogram of weight/levels of hemoglobin) was observed with mean values of 2.73 (p < 0.018) and 4.37 (p < 0.001) after 16 and 24 weeks respectively, requiring an increase of the dose greater than 15% over the baseline in 6 1.1% of the patients. The changeover to, darbepoetin alpha, independently of the administration route, was accompanied by a decrease in REI starting in the 8th week (mean levels of 0.012, 0.018 and 0.023 after 8, 16 and 24 weeks respectively), significant (p < 0.001) at the 3 cutoff points of the study. The conversion factor increased significantly up to 1:260 in week 24. Both erythropoietic stimulating factors (EST) were well tolerated and no unexpected side effects were observed. In conclusion, treatment of anaemia with darbepoetin alpha in patients with CRI in haemodialysis previously treated with rHuEPO proved to be more effective than the use of epoetin intravenously, significantly improving the resistance index. In addition, the treatment with darbepoetin alpha was well tolerated in these patients.     

Do patient-related blood donors represent a threat to the safety of the blood supply?

BACKGROUND AND OBJECTIVES: Patient-related blood donors contribute to a significant proportion of the blood units collected in hospital-based blood banks. However, there is some concern on the safety of this kind of donation because of the possible existence of incentives for the donor to conceal deferrable risk factors, thus increasing the risk of donation within the window-period of transfusion-transmitted infections. We tested the hypothesis that if patient-related blood donors are less safe than community ones, the former would display both a higher prevalence of viral markers and a predominance of undisclosed risk-factors with low social acceptability. DESIGN AND METHODS: Comparison of virus reactivity rates against hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV), and the associated risk-factors, between patient-related and community donors who donated whole blood in our center during a five-year period. RESULTS: During the period under study 72,226 donors gave 149,944 whole blood units, of which 22,888 (15.3%) were provided by patient-related donors. There were 273 confirmed virus-reactive donations (15 anti-HIV, 148 anti-HCV and 110 HBsAg). The adjusted prevalence of virus reactivity was 19 (95% CI: 11-35) times higher in first-time donors than in repeat donors, 3.5 (95% CI: 2.3-4.1) times higher in donors > or = 30 years old than in younger ones, and 2.5 (95% CI: 1.9-3.2) times higher in patient-related donors than in community donors. With regard to deferrable risk-factors not disclosed at the time of donation, there was no significant difference between patient-related and community donors in the frequency of people who denied any risk-factor or who admitted intravenous drug use or high-risk sex. Past household contact with individuals having liver disease was significantly more frequent in patient-related donors than in community ones. INTERPRETATION AND CONCLUSIONS: Our results do not support the hypothesis that patient-related donors represent an increased risk of window-period donation because they conceal deferrable risk factors more frequently than community donors.