Anti-SSA/Ro and anti-SSB/La antibodies. What's new?

Anti-SSA/Ro and anti-SSB/La autoantibodies recognize different epitopes on polypeptides associated with small RNAs called scYRNA situated mostly in the cytoplasmic compartment (70%) and few in the nuclear compartment (30%). These hYRNPs (h=human) can be found on the cytoplasmic membrane or in small blebs during apoptosis after various stimuli such as UVB, 17-beta-estradiol, viral infection, TNF alpha and other cellular apoptosis inducing molecules. At least two major different proteins are called SSA/Ro: a 52 kDa Ro (with two subtypes alpha and beta) and a 60 kDa Ro. There is only one SSB/La protein of 48 kDa. In some circumstances, other proteins such as calreticuline (MW 57 kDa) join Ro/SSA proteins on some YRNAs. Anti-SSA/Ro antibodies are detected in the sera of 30% of patients with SLE, even during preclinical setting; anti-Ro/SSA are strongly associated (90%) with some subtypes of SLE such as old-onset (>50 y) SLE, subacute lupus erythematosus, drug-induced subacute lupus erythematosus and in patients with hereditary C2 or C4 or C1q deficiency with lupus or lupus-like disease. Anti-SSA/Ro are also associated with primary Sj?gren syndrome (50% to 60%) and with undifferenciated connective tissue disease (UCTD). Anti-SSA/Ro antibodies are almost always present in sera of mothers with babies with neonatal lupus syndrome (NNL) and with complete congenital heart block (CCHB). This last event is very unusual in pregnant patients with anti-Ro/SSA antibodies (1% to 2% of primigeste women). Some good evidences such as experimental models in vitro or ex-vivo, argue for the responsibility of maternal anti-Ro/SSA 52 kDa and/or anti-La/SSB antibodies (or associated IgG antibodies) as major etiologic factor of CCHB and NNL. IgG anti-Ro 52 beta kDa has been shown able to interrupt the atrioventricular conduction as well as the L calcium channel influx of fetal cardiocytes. Other factors must be taken into account to explain discordant twins (with and without CCHB). More recently anti-Ro/SSA antibodies were associated with QT interval prolongation in newborns without CCHB.     

Nailfold capillaroscopic findings in primary Sjögren’s syndrome with and without Raynaud’s phenomenon and/or positive anti-SSA/Ro and anti-SSB/La antibodies

The aim of this study was to assess nailfold capillaroscopic (NC) findings in patients with primary Sjögren’s syndrome (PSS) with and without Raynaud’s phenomenon (RP) as well as in the presence of positive anti-SSA/Ro and anti-SSB/La antibodies. Videocapillaroscopy was performed in 150 patients with PSS. Data collected included demographics, presence of RP, PSS symptoms, antinuclear antibodies, rheumatoid factor, anti-Ro, anti-La, anti-CCP, salivary scintigraphy, labial biopsy, and NC findings. RP was present in 32 % of PSS, keratoconjunctivitis sicca in 91 %, oral xerosis in 93 %, and skin or genital xerosis in 53 %. In patients with positive anti-SSA/Ro (75 %) and positive anti-SSB/La (40 %), NC showed normal findings in 53 % of cases and non-specific in 36 %. In patients with PSS, NC was normal in 51 % of cases and non-specific in 34 %. Scleroderma pattern was found in 14 patients. RP associated with PSS had non-specific capillaroscopy in 40 % of cases (p = 0.1). Pericapillary haemorrhages (p = 0.06) and capillary thrombosis (p = 0.2) were not increased, but more dilated capillaries were detected in 48 % of cases. Patients with positive anti-Ro and/or anti-La have not a distinct NC profile. Patients with RP associated with PSS had more dilated capillaries, but neither pericapillary haemorrhages nor capillary thrombosis was observed.     

Melanocortin 5 receptor signaling and internalization: Role of MAPK/ERK pathway and β-arrestins 1/2

The Melanocortin 5 receptor (MC5R) is a G-protein coupled receptor (GPCR) that exhibits high affinity for α-MSH. Here we present evidence for MC5R-GFP internalization and subsequent recycling to cell surface, in α-MSH-stimulated HeLa cells. This melanocortin induces a biphasic activation of ERK1/2 with an early peak at 15min, a G(i)-protein driven, β-arrestins 1/2 independent process, and a late sustained activation that is regulated by β-arrestins 1/2. ERK1/2 lead to downstream phosphorylation of 90-kDa ribosomal S6 kinases (p90RSK) and mitogen- and stress-activated protein kinase 1 (MSK1). Only a small fraction (10%) of phosphorylated p90RSK and ERK1/2 translocates to the nucleus inducing c-Fos expression. α-MSH also activates CREB through cAMP/PKA pathway. In 3T3-L1 adipocytes, where MC5R is endogenously expressed, α-MSH also induces phosphorylation and cytosolic retention of the same signaling molecules. These findings provide new evidence on the signaling mechanisms underlying MC5R biological response to α-MSH.     

HbHope/HbS and HbS/β-thal double compound heterozygosity in a Mauritanian family: clinical and biochemical studies

The hemoglobin Hope was discovered in a Mauritanian family that comes from Gorgol in the southwest of the country. The family belongs to the Soninké ethnic group, which is one of the black population groups in Mauritania. Along with this abnormal hemoglobin, HbS and beta-thalassemia were also found. This family, which we refer to as D, was encountered during a survey we conducted to study hemoglobinopathies in Mauritania. First the father was identified to carry an association of HbS and HbHope, then the study was extended to the entire family members: the wife who was found to have a beta-thalassemia trait and their three children who were found to carry HbS/beta-thalassemia mutations each. All together this family carries three different mutations that resulted in a double compound heterozygosity HbHope/HbS and HbS/beta-thal.     

An Association between Mycobacteriummalmoense and Coal Workers’ Pneumoconiosis

An association between Mycobacterium malmoense and underlying lung disease has been described. The purpose of this study was to further explore this relationship and in particular to identify any relationship between Coal Workers’ Pneumoconiosis (CWP) and M. malmoense infection. Patient charts were reviewed of all patients who had a positive sputum or bronchoalveolar lavage for M. malmoense from 1999 to 2006 in a large district general hospital in South Yorkshire, UK. We also performed a literature review in search of this association; one case report was found. Four patients had positive sputum cultures for M. malmoense but only three of these fulfilled the ATS 1997 criteria for diagnosis of disease. Of these three patients, all had clinical and radiologic evidence of CWP. This study strengthens the evidence of a link between nontuberculous mycobacteria and underlying lung disease but more importantly highlights an association between M. malmoense and CWP which has been rarely reported and is poorly understood.     

Differential effects of isoflurane and ketamine/inactin anesthesia on cAMP and cardiac function in FVB/N mice during basal state and β–adrenergic stimulation

We evaluated the effect of the inhalant anesthetic isoflurane and the injectable combination of anesthetics ketamine/inactin on cardiac function by measuring left ventricular (LV) pressure in situ during control conditions and during -adrenergic stimulation with isoproterenol (ISO). The control heart rate (HR) and the maximal rate of contraction were significantly higher in the isoflurane group, but there was no difference in the rate of relaxation. During the ISO (0.32 ng · g body wt^–1· min^–1) stimulation the developed pressure (DP) increased 9.8 ± 1.8% (n = 11) in the ketamine/inactin group and was unchanged in the isoflurane group. The HR increased 28.4 ± 4.8% (n = 11) in the ketamine/inactin group and only 3.4 ± 0.6% (n = 11) in the isoflurane group. The rate of contraction increased 103.2 ± 9.3% (n = 11) and 13.6 ± 4.6% (n = 11) in the ketamine/inactin and isoflurane groups, respectively. At this dose of ISO the rate of relaxation did not change significantly. In control conditions there was no difference in levels of cAMP between the groups (2.29 ± 0.25 pmol/mg protein (n = 5) in the ketamine/inactin group and 2.79 ± 0.35 pmol/mg protein (n = 6) in the isoflurane group). However, during the ISO stimulation the cAMP level increased only in the ketamine/ inactin group of animals (3.50 ± 0.30 pmol/mg protein; n = 5). This level was significantly higher than the level in the isoflurane group stimulated with ISO (2.22 ± 0.30 pmol/mg protein; n = 6). In summary, our results indicate that the anesthetics differ significantly in the extent of depression of the basal and -adrenergic stimulated state with the second messenger cAMP playing a prominent role.     

What does the Tpeak-Tend interval reflect? An experimental and model study

Background

It is unclear whether the T_peak-T_end interval is an index of the transmural or the total dispersion of repolarization.

Methods

We examined the T_peak-T_end interval using a computer model of the rabbit heart ventricles based on experimentally measured transmural, apicobasal, and interventricular gradients of action potential duration.

Results

Experimentally measured activation-recovery intervals increased from apex to base, from the left ventricle to the right ventricle, and in the apical portion of the left ventricle from epicardium to endocardium and from the right side of septum to the left side. The simulated T_peak corresponded to the earliest end of repolarization, whereas the T_end corresponded to the latest end of repolarization. The different components of the global repolarization dispersion were discerned by simulation.

Conclusions

The T_peak-T_end interval corresponds to the global dispersion of repolarization with distinct contributions of the apicobasal and transmural action potential duration gradients and apicobasal difference in activation times.     

Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir ± Ribavirin for HCV in Brazilian Adults with Advanced Fibrosis

Introduction and aim. Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an open-label multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection.Material and methods. All patients received coformulated OBV/ PTV/r daily + DSV twice daily (3-DAA). GTIa-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/ RBV nonresponders with cirrhosis who were treated for 24 weeks. GTIb-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA < 15 IU/mL) at post-treatment Week 12 (SVR₁₂).Results. The study enrolled 222 patients, 214 achieved an SVR₁₂ (96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR₁₂ was achieved in 111/ 112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event.Discussion. The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).     

A unified and universal explanation for Lévy laws and 1/f noises

Lévy laws and 1/f noises are shown to emerge uniquely and universally from a general model of systems which superimpose the transmissions of many independent stochastic signals. The signals are considered to follow, statistically, a common—yet arbitrary—generic signal pattern which may be either stationary or dissipative. Each signal is considered to have its own random transmission amplitude and frequency. We characterize the amplitude-frequency randomizations which render the system output''s stationary law and power-spectrum universal—i.e., independent of the underlying generic signal pattern. The classes of universal stationary laws and power spectra are shown to coincide, respectively, with the classes of Lévy laws and 1/f noises—thus providing a unified and universal explanation for the ubiquity of these classes of “anomalous statistics” in various fields of science and engineering.     

Nampt/PBEF/Visfatin: A regulator of mammalian health and longevity?

Eukaryotes have evolved elaborate mechanisms to survive periods of adversity. By manipulating genes that control these mechanisms, researchers have found they can generate more stress resistant, longer-lived organisms. One of these is the PNC1 gene of Saccharomyces cerevisiae, a master "longevity regulatory gene" that translates a variety of environmental stresses into lifespan extension by activating the sirtuin family of longevity deacetylases. Master longevity genes such as PNC1 are highly adaptive because they allow organisms to respond in a concerted way to adversity and to rapidly evolve life strategies to compensate for a changing environment. Hence, they should be well conserved. We propose that there is a functional equivalent of PNC1 in mammals called Nampt (a.k.a. PBEF/Visfatin), a stress-responsive gene that would coordinately regulate metabolism, cell defenses, and resistance to diseases of aging.     

Is circulating osteocalcin related to adipokines and overweight/obesity in children and adolescents?

Osteocalcin (OC) has recently been described to be involved in the regulation of glucose and energy metabolism. We aimed to evaluate whether or not OC serum levels were related to parameters of overweight and serum adipokine levels of healthy children and adolescents in dependence on gender and pubertal stage.In a cross sectional study (Leipzig Schoolchildren Project) 497 healthy, caucasian children and adolescents of all pubertal stages were included. We measured anthropometric data height, weight, fat mass, waist-to-hip ratio, pubertal development and performed biochemical analyses of osteocalcin, leptin, adiponectin and resistin serum levels by immunoassay.OC serum levels were associated with pubertal development achieving peak values at Tanner stage 3. There was no significant association of OC serum levels with overweight and obesity as measured by BMI and WHR. In addition, OC demonstrated no significant association with serum levels of leptin and adiponectin but a negative association with resistin in both genders independent of pubertal stages (r= - 0.329, p<0.0001).We conclude that there is no major relationship between OC and metabolism, but we can not exclude minor relations between OC and metabolism. The negative relationship with serum resistin levels might rather point to a link between OC and inflammatory states.     

Effects of meal size and composition on incretin, α-cell, and β-cell responses

The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate postprandial insulin release from the β-cells. We investigated the effects of 3 standardized meals with different caloric and nutritional content in terms of postprandial glucose, insulin, glucagon, and incretin responses. In a randomized crossover study, 18 subjects with type 2 diabetes mellitus and 6 healthy volunteers underwent three 4-hour meal tolerance tests (small carbohydrate [CH]-rich meal, large CH-rich meal, and fat-rich meal). Non-model-based and model-based estimates of β-cell function and incremental areas under the curve of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP were calculated. Mixed models and Friedman tests were used to test for differences in meal responses. The large CH-rich meal and fat-rich meal resulted in a slightly larger insulin response as compared with the small CH-rich meal and led to a slightly shorter period of hyperglycemia, but only in healthy subjects. Model-based insulin secretion estimates did not show pronounced differences between meals. Both in healthy individuals and in those with diabetes, more CH resulted in higher GLP-1 release. In contrast with the other meals, GIP release was still rising 2 hours after the fat-rich meal. The initial glucagon response was stimulated by the large CH-rich meal, whereas the fat-rich meal induced a late glucagon response. Fat preferentially stimulates GIP secretion, whereas CH stimulates GLP-1 secretion. Differences in meal size and composition led to differences in insulin and incretin responses but not to differences in postprandial glucose levels of the well-controlled patients with diabetes.