Long-term follow-up in primary Sjögren’s syndrome reveals differences in clinical presentation between female and male patients

Background

Despite men being less prone to develop autoimmune diseases, male sex has been associated with a more severe disease course in several systemic autoimmune diseases. In the present study, we aimed to investigate differences in the clinical presentation of primary Sjögren’s syndrome (pSS) between the sexes and establish whether male sex is associated with a more severe form of long-term pSS.

Methods

Our study population included 967 patients with pSS (899 females and 68 males) from Scandinavian clinical centers. The mean follow-up time (years) was 8.8 ± 7.6 for women and 8.5 ± 6.2 for men (ns). Clinical data including serological and hematological parameters and glandular and extraglandular manifestations were compared between men and women.

Results

Male patient serology was characterized by more frequent positivity for anti-Ro/SSA and anti-La/SSB (p = 0.02), and ANA (p = 0.02). Further, men with pSS were more frequently diagnosed with interstitial lung disease (p = 0.008), lymphadenopathy (p = 0.04) and lymphoma (p = 0.007). Conversely, concomitant hypothyroidism was more common among female patients (p = 0.009).

Conclusions

We observe enhanced serological responses and higher frequencies of lymphoma-related extraglandular manifestations in men with pSS. Notably, lymphoma itself was also significantly more common in men. These observations may reflect an aggravated immune activation and a more severe pathophysiological state in male patients with pSS and indicate a personalized managing of the disease due to the influence of the sex of patients with pSS.

     

Adjuvant Effects Elicited by Novel Oligosaccharide Variants of Detoxified Meningococcal Lipopolysaccharides on Neisseria meningitidis Recombinant PorA Protein: A Comparison in Mice

Neisseria meningitidis lipopolysaccharide (LPS) has adjuvant properties that can be exploited to assist vaccine immunogenicity. The modified penta-acylated LPS retains the adjuvant properties of hexa-acylated LPS but has a reduced toxicity profile. In this study we investigated whether two modified glycoform structures (LgtE and IcsB) of detoxified penta-acylated LPS exhibited differential adjuvant properties when formulated as native outer membrane vesicles (nOMVs) as compared to the previously described LgtB variant. Detoxified penta-acylated LPS was obtained by disruption of the lpxL1 gene (LpxL1 LPS), and three different glycoforms were obtained by disruption of the lgtB, lgtE or icsB genes respectively. Mice (mus musculus) were immunized with a recombinant PorA P1.7-2,4 (rPorA) protein co-administered with different nOMVs (containing a different PorA serosubtype P1.7,16), each of which expressed one of the three penta-acylated LPS glycoforms. All nOMVs induced IgG responses against the rPorA, but the nOMVs containing the penta-acylated LgtB-LpxL1 LPS glycoform induced significantly greater bactericidal activity compared to the other nOMVs or when the adjuvant was Alhydrogel. Compared to LgtE or IcsB LPS glycoforms, these data support the use of nOMVs containing detoxified, modified LgtB-LpxL1 LPS as a potential adjuvant for future meningococcal protein vaccines.     

Different bioavailability in humans of wheat and fish selenium as measured by blood platelet response to increased dietary Se

The bioavailabilities of selenium (Se) from Se-rich fish species and Se-rich wheat were compared in a study involving 32 healthy volunteers. Initial serum Se values were 109±16 μg/L (mean±SD). For 6 wk, one group (n=11) included Se-rich bread in their diet, bringing daily average intake of Se up to 135±25 μg/d. Another group (n=11) consumed Se-rich fish daily (average Se intake: 115±31 μg/d), whereas the control group (n=10) ate their normal diet, providing 77±25 μg Se/d. Serum Se increased by 17% (P<0.01), and platelet Se increased by 30% (P<0.01) in the wheat group. Although platelet Se decreased by 11% in the fish group, no changes in serum and platelet Se in the fish or control group reached statistical significance. Glutathione peroxidase (EC 1.11.1.9; GSH-Px) activity in serum and platelets did not change during the study, nor did platelet mercury (Hg) content. Since the dietary intake of Hg, arsenium (As), and fatty acids could not satisfactorily explain the lack of response in the fish group, the results are indicative of low bioavailability of fish Se in humans. At present, wheat Se seems to be the most important factor contributing to the body stores of Se in this study population. Dr. Norheim died on January 9, 1991.     

Neuropeptide Y and sympathetic vascular control in man

A parallel increase in systemic plasma levels of neuropeptide Y (NPY)-like immunoreactivity (LI) and noradrenaline (NA) was found during thoracotomy and surgery involving cardiopulmonary bypass in man. Thus, plasma levels of NPY-LI increased from 29 +/- 4 pmol/l before anaesthesia to 59 +/- 10 after thoracotomy and to 87 +/- 8 pmol/l upon cardiopulmonary bypass. The corresponding NA levels increased from 1.3 +/- 0.1 nmol/l before anaesthesia to 3.0 +/- 0.6 and 4.2 +/- 5 nmol/l after thoracotomy and cardiopulmonary bypass, respectively. A significant correlation was found between plasma levels of NPY-LI and NA during the operation but not between NPY-LI and adrenaline. The NPY-LI in human plasma was found to be similar to synthetic porcine NPY on reversed phase high performance liquid chromatography. Human submandibular arteries contained high levels of NPY-LI (24 +/- 3 pmol/g). In in vitro experiments on isolated human submandibular arteries, NPY in low concentrations (1000 pmol/l) was found to potentiate the contractile effects of NA or transmural nerve stimulation and to exert vasoconstrictor activity per se in higher concentrations. The calcium-entry antagonist nifedipine abolished both the NPY-induced contractions and the enhancement of NA-evoked contractions. NPY depressed the nerve stimulation-evoked 3H-NA release from human submandibular arteries via a prejunctional mechanism which was resistant to nifedipine. NPY contracted human mesenteric veins and renal arteries, but not mesenteric arteries. In conclusion, NPY seems to be co-released with NA upon sympathetic activation in man. Furthermore, NPY exerts both pre- and postjunctional effects on sympathetic control of human blood vessels.     

Concentration of Selenium in Liver in Relation to Copper Level in Normal and Copper-Poisoned Sheep

Copper absorption, liver accumulation and development of copper toxicosis in sheep are influenced by a variety of other elements, in particular molybdenum, sulphur and zinc (Underwood 1977). In a previous study on liver concentrations of copper, molybdenum and zinc in normal and copper-poisoned sheep, no direct correlation was found between the concentrations of the three metals, but molybdenum was significantly lower in the livers from sheep dead from chronic copper poisoning than in normal animals (Frøslie & Norheim 1976).     

A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism

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Mapping out structural features in clinical care calling for ethical sensitivity: a theoretical approach to promote ethical competence in healthcare personnel and clinical ethical support services (CESS)

Clinical ethical support services (CESS) represent a multifaceted field of aims, consultancy models, and methodologies. Nevertheless, the overall aim of CESS can be summed up as contributing to healthcare of high ethical standards by improving ethically competent decision-making in clinical healthcare. In order to support clinical care adequately, CESS must pay systematic attention to all real-life ethical issues, including those which do not fall within the 'favourite' ethical issues of the day. In this paper we attempt to capture a comprehensive overview of categories of ethical tensions in clinical care. We present an analytical exposition of ethical structural features in judgement-based clinical care predicated on the assumption of the moral equality of human beings and the assessment of where healthcare contexts pose a challenge to achieving moral equality. The account and the emerging overview is worked out so that it can be easily contextualized with regards to national healthcare systems and specific branches of healthcare, as well as local healthcare institutions. By considering how the account and the overview can be applied to i) improve the ethical competence of healthcare personnel and consultants by broadening their sensitivity to ethical tensions, ii) identify neglected areas for ethical research, and iii) clarify the ethical responsibility of healthcare institutions' leadership, as well as specifying required institutionalized administration, we conclude that the proposed account should be considered useful for CESS.     

Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high‐fat/high‐sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.     

Interleukin-1 inhibition and fatigue in primary Sjögren's syndrome--a double blind, randomised clinical trial

Objectives

Fatigue is a major cause of disability in primary Sjögren''s syndrome (pSS). Fatigue has similarities with sickness behaviour in animals; the latter mediated by pro-inflammatory cytokines, in particular interleukin (IL)-1, acting on neuronal brain cells. We hypothesised that IL-1 inhibition might improve fatigue in pSS patients; thus, we examined the effects and safety of an IL-1 receptor antagonist (anakinra) on fatigue.

Methods

Twenty-six pSS patients participated in a double-blind, placebo-controlled parallel group study. Patients were randomised to receive either anakinra or a placebo for four weeks. Fatigue was evaluated by a fatigue visual analogue scale and the Fatigue Severity Scale. The primary outcome measure was a group-wise comparison of the fatigue scores at week 4, adjusted for baseline values. Secondary outcome measures included evaluation of laboratory results and safety. The proportion of patients in each group who experienced a 50% reduction in fatigue was regarded as a post-hoc outcome. All outcomes were measured at week 4.

Results

There was no significant difference between the groups in fatigue scores at week 4 compared to baseline after treatment with anakinra. However, six out of 12 patients on anakinra versus one out of 13 patients on the placebo reported a 50% reduction in fatigue VAS (p = 0.03). There were two serious adverse events in each group.

Conclusions

This randomised, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction in fatigue in pSS in its primary endpoint. A 50% reduction in fatigue was analysed post-hoc, and significantly more patients on the active drug than on placebo reached this endpoint. Although not supported by the primary endpoint, this may indicate that IL-1 inhibition influences fatigue in patients with pSS.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00683345","term_id":"NCT00683345"}}NCT00683345