Robust but weak winter atmospheric circulation response to future Arctic sea ice loss.

The possibility that Arctic sea ice loss weakens mid-latitude westerlies, promoting more severe cold winters, has sparked more than a decade of scientific debate, with apparent support from observations but inconclusive modelling evidence. Here we show that sixteen models contributing to the Polar Amplification Model Intercomparison Project simulate a weakening of mid-latitude westerlies in response to projected Arctic sea ice loss. We develop an emergent constraint based on eddy feedback, which is 1.2 to 3 times too weak in the models, suggesting that the real-world weakening lies towards the higher end of the model simulations. Still, the modelled response to Arctic sea ice loss is weak: the North Atlantic Oscillation response is similar in magnitude and offsets the projected response to increased greenhouse gases, but would only account for around 10% of variations in individual years. We further find that relationships between Arctic sea ice and atmospheric circulation have weakened recently in observations and are no longer inconsistent with those in models.

Paraneoplastic rheumatic disorders: a narrative review.

Paraneoplastic syndromes (PS) are a heterogeneous group of diseases related to a neoplasm, indirectly dependent on it. Diagnosis and the treatment are often a challenge for clinicians, not least because the pathogenetic mechanisms are highly complex and not entirely known. Nonetheless, in most cases, PS precede the diagnosis of malignancies, thus their identification is particularly important in addressing physicians' diagnostic work-up with regard to early cancer diagnosis. Among paraneoplastic syndromes, those of rheumatologic interest represent a large component. In this paper, we review the main rheumatic PS.

Estimating Subseasonal Variability and Trends in Global Atmosphere Using Reanalysis Data.

A new measure of subseasonal variability is introduced that provides a scale-dependent estimation of vertically and meridionally integrated atmospheric variability in terms of the normal modes of linearized primitive equations. Applied to the ERA-Interim data, the new measure shows that subseasonal variability decreases for larger zonal wave numbers. Most of variability is due to balanced (Rossby mode) dynamics but the portion associated with the inertio-gravity (IG) modes increases as the scale reduces. Time series of globally integrated variability anomalies in ERA-Interim show an increase in variability after year 2000. In recent years the anomalies have been about 2% above the 1981-2010 average. The relative increase in variability projecting on the IG modes is larger and more persistent than for the Rossby modes. Although the IG part is a small component of the subseasonal variability, it is an important effect likely reflecting the observed increase in the tropical precipitation variability.

The pathogenesis of the anaemia of chronic disorders.

Anemia of chronic disorders is a typical condition of infective, immunological and neoplastic diseases. Hepcidin and proinflammatory cytokines play a leading role in its pathogenesis. Hepcidin is a hormone produced by the liver that controls iron metabolism. It ensures that iron is retained by enterocytes (where the metal is absorbed) and by macrophages (that store the iron that results from the physiological breakdown of erythrocytes). Cytokines play a role in hepcidin synthesis, and in the proliferation and the maturation of the erythroid components within bone marrow. This paper discusses the pathogenetic mechanisms of anemia in chronic disorders.

Long-lasting regulation of galanin, opioid, and other peptides in dorsal root ganglia and spinal cord during experimental polyarthritis.

Mechanisms involved in transition from acute to chronic pain are still not well understood and our means to therapeutically influence this transition are limited. Moreover, very little is known about long-lasting consequences of prolonged exposure to painful stimuli with regard to phenotypic changes and pain experience. In this study we have analyzed long term behavioral and neurochemical effects of intradermal tail injection of heat-killed mycobacterium butyricum suspended in complete Freund's adjuvant. Calcitonin gene-related peptide (CGRP) and galanin mRNA levels were investigated in dorsal root ganglia of polyarthritic rats during the acute (21-) and the remission stage (79 days postinjection), and opioid peptide mRNAs and receptors were studied in the spinal cord. Most of the increases in peptide mRNA levels observed during the acute stage of arthritis were still present in the remission stages. Thus, CGRP and galanin mRNAs in DRGs, and opioid peptide mRNAs and opioid receptors in the spinal cord were still strongly up-regulated, when animals do not exhibit spontaneous pain behavior and inflammation. Hot-plate test in the presence of naloxone, performed in the remission stage, indicated that opiates participate in pain threshold regulation after prolonged painful condition. Finally, X-ray examination revealed a complete destruction of joint structure, thus suggesting a parallel lesion of peripheral nerve endings. These results suggest that in the remission stage of chronic joint inflammation several types of mechanisms are activated aiming at counteracting both inflammatory and neuropathic pain. Thus, opioid systems in the dorsal horn as well as galanin in DRG neurons are upregulated, both alternating pain.

A histochemical study of the rheumatoid synovium: focus on nitric oxide, nerve growth factor high affinity receptor, and innervation.

OBJECTIVE: The synovium of patients with rheumatoid arthritis (RA) is characterized by massive cell proliferation, neoangiogenesis, and apoptosis. The nature of potential repressors/inducers of these phenomena is still largely unknown. We investigate if nitric oxide (NO) and nerve growth factor (NGF) can be considered potential mediators in these phenomena in RA. METHODS: Synovium of 15 patients with RA in active phase and synovium of 14 patients without synovial inflammation were processed for histochemical (NADPH-diaphorase) and immunohistochemical visualization of different isoforms for the NO synthesis enzyme NO synthase (NOS) and for NGF high affinity receptor trkA. RESULTS: Inducible NOS (iNOS) immunoreactivity and NADPH-diaphorase positivity were found in synoviocytes, fibroblast-like synoviocytes, fibroblasts, and inflammatory cells in the rheumatoid synovium. In the same areas and in the same cell types, although not in the same cells, we also found positivity for the NGF high affinity receptor trkA. CONCLUSION: We suggest that all elements involved in the transduction pathway that is activated by NGF and that proceeds through NO and tumor suppressor p53 are present in the synovium during RA, controlling cell cycle arrest, cell differentiation, and apoptosis.

Is neuronal nitric oxide involved in adjuvant-induced joint inflammation?

Several reports have described a role of macrophagic, endothelial and synoviocytal nitric oxide (NO) in inflammation, immunity and sensory processes in joint diseases. In view of the role of the peripheral nervous system in arthritis and owing to the presence of NO-producing neurons in primary sensory neurons, we have investigated the possible role of neuronal NO during adjuvant-induced joint inflammation in rats. Neural nitric oxide synthase production in sensory ganglia and the spinal cord was investigated by in situ hybridization and immunocytochemistry. Neuronal NO synthase mRNA expression and neuronal NO synthase immunoreactivity increased in lumbar dorsal root ganglia in arthritic rats compared to those of normal rats, whereas neuronal NO synthase mRNA expression decreased in lamina X and lamina I-II of the lumbar spinal cord. The administration of the selective neuronal NO synthase inhibitor 7-nitro indazole, reduced the joint inflammation, whereas the administration of the inducible NO synthase selective inhibitor, aminoguanidine, had no effect on inflammation when administered daily from the third day after adjuvant. These findings could indicate a role for neural NO in adjuvant arthritis.

Quality of life assessment during six months of NSAID treatment [Gonarthrosis and Quality of Life (GOAL) Study].

OBJECTIVE: To identify the time point of the greatest degree of improvement in daily living activities, pain and depression in patients with osteoarthritis (OA) of the knee during 6 months of treatment with NSAIDs, in order to define compliance and drop-out rate. METHODS: 107 patients were recruited into a multicentre, prospective, randomized, controlled trial comparing two treatments, piroxicam-beta-cyclodextrin (PBCD) and slow release diclofenac (DCL). RESULTS: The greatest improvement in quality of life occurred in both groups after 3 months, with a slight further gain observed by the end of treatment. The Stanford Health Assessment Questionnaire score improved (p < 0.05 vs baseline) at 3 and 6 months with PBCD and at 6 months with DCL. The Arthritis Impact Measurement Scale score improved (p < 0.05 vs baseline) after 6 months in both groups. Significant (p < 0.05 vs baseline) improvement in other psychological and pain scores were recorded in both groups after 3 and 6 months. Compliance with treatment at 3 months was 73% for PBCD and 72% for DCL, and was 60% in both groups at 6 months. CONCLUSIONS: The results of this study indicate that the optimal length of time for an NSAID trial in OA patients is 3 months, when assessment of daily living activities is considered as the main outcome criterion.

Peptide plasticity in primary sensory neurons and spinal cord during adjuvant-induced arthritis in the rat: an immunocytochemical and in situ hybridization study.

Chronic polyarthritis due to complete Freund's adjuvant injection is characterized by severe inflammation and pain. In the present immunocytochemical and in situ hybridization study on the rat, we quantitatively investigated peptide and peptide messenger RNA expression in the sensory circuit at the spinal level, i.e. sensory neurons in the dorsal root ganglia and in nerve endings and local neurons in the dorsal horn of the spinal cord. The immunocytochemical experiments were carried out five, 13 and 21 days after complete Freund's adjuvant injection, whereas in situ hybridization study was performed after 21 days from complete Freund's adjuvant injection. The main results in the present study are the following: (i) a decrease in substance P-, calcitonin gene-related peptide- and galanin-like immunoreactivities in dorsal root ganglia is observed five days after complete Freund's adjuvant injection, with recovery (calcitonin gene-related peptide and galanin) or even an increase (substance P) after 21 days; (ii) calcitonin gene-related peptide, substance P and galanin peptide levels are increased in dorsal root ganglia after 21 days; (iii) opioid peptide (enkephalin and dynorphin), substance P and galanin messenger RNAs are strongly up-regulated in dorsal horn neurons after 21 days; (iv) neuropeptide Y content increases in dorsal root fibres and neuropeptide Y messenger RNA levels decrease in spinal neurons after 21 days; and (v) a dramatic decrease in calcitonin gene-related peptide and cholecystokinin messenger RNA levels is found in motoneurons in the ventral horn after 21 days. These data indicate that peptide expression in dorsal root ganglia and the spinal cord is markedly influenced by severe inflammation with distinct and individual temporal patterns, which are also related to the severe rearrangement of joint structure during polyarthritis. The increase in galanin levels in dorsal root ganglia 21 days after complete Freund's adjuvant injection can be related to the structural damage of nerve fibres. Thus, there may be a transition from inflammatory to neuropathic pain, which could have consequences for treatment of patients with rheumatoid arthritis.

Connective tissue in skin biopsies from patients suffering systemic sclerosis.

Little information is available on elastin during systemic sclerosis since biochemical and morphological data have primarily focused on collagen and glycosaminoglycan alterations of connective tissues in this pathological process. We performed ultrastructural, morphometric, biochemical and in situ hybridisation analyses on skin biopsies from patients affected by scleroderma and from site and age-matched control subjects. Affected skin revealed alterations in the distribution and organisation of collagen bundles and fibrils together with zonal increase of the microfibrillar component. Elastic fibres were significantly more numerous than in control skin, were more frequently vacuolated and characterised by electron-dense inclusions; moreover, morphometric analysis provided evidence for a significant increase of the percentage of both collagen bundles and elastin fibres in the measured tissue, compared to normal skin. Biochemical analysis seemed to confirm the increased elastin content per unit of dried weight tissue in sclerodermic skin. Differences observed among patients were only partially associated with disease duration and/or to severity of clinical manifestations. The abnormal amount of elastic fibres observed in skin biopsies from patients, and data from in situ hybridisation suggest the presence of a deregulation of the whole extracellular matrix that might be related to the role of cytokines such as TGF-beta, which has already been suggested to be involved in systemic sclerosis and in enhanced collagen and elastin production.

Enhancement of BALB/c 3T3 cells transformation by 1,2-dibromoethane promoting effect.

Two of the most representative halogenated aliphatic hydrocarbons, 1,2-dibromoethane and 1,1,2,2-tetrachloroethane, were tested in the two-stage cell transformation model for analysing the promoting ability. Both of these compounds had previously been found to exert genotoxic effects, probably acting as moderate initiators. BALB/c 3T3 cells were initiated with subtransforming doses of N-methyl-N-nitro-N-nitrosoguanidine or 3-methylcholanthrene and then exposed to a chronic treatment with different non-transforming dosages of the two haloalkanes. 1,1,2,2-Tetrachloroethane did not exert any promoting activity in that system. By contrast, significant promoting effects by 1,2-dibromoethane were observed both in cells treated with N-methyl-N-nitro-N-nitrosoguanidine and in cells treated with 3-methylcholanthrene. Promotion of the transformation process initiated with 3-methylcholanthrene was detectable when confluent cells in the chemical-treated plates were replated in the level-II amplification test. This experimental procedure allowed cells to perform further rounds of replications and transformed foci to became detectable. Results gave evidence for a promoting role of 1,2-dibromoethane in multistep carcinogenesis, probably responsible for the higher oncogenic ability of this compound with respect to 1,1,2,2-tetrachloroethane.

1,2-Dibromoethane as an initiating agent for cell transformation.

The two-stage transformation assay increases the sensitivity of cells to chemicals and permits detection of carcinogens acting as initiating agents. 1,2-Dibromoethane, a representative halogenated aliphatic, has been tested in the two-stage BALB/c 3T3 cells transformation test at dosage from 16 microM to 128 microM. This dose range is much lower than those previously found efficient in transforming BALB/c 3T3 cells. Apart from the lowest dose, which induced borderline effects, all the other assayed dosages appeared to induce heritable changes in the target cells. The initiated cells were revealed as fully transformed foci both in the combination with a chronic promoting treatment and also by allowing cells to perform more rounds of cell replication. The results clearly show that 1,2-dibromoethane can act as an initiator of cell transformation.

Dermal elastin and collagen in systemic sclerosis. Effect of D-penicillamine treatment.

Skin biopsies from 4 systemic sclerosis (SSc) patients, 6 SSc patients treated with D-penicillamine (from 8 to 60 months) and 4 normal subjects were analyzed by light and electron microscopy. By light microscopy, collagen bundles of SSc dermis were thicker and more compact than in age-matched controls; D-penicillamine treatment did not significantly modify their organization. On the contrary, a stereological analysis showed that the elastin volume density was higher in patients than in controls, and increased again after D-penicillamine treatment: moreover, the number of elastin fibers per unit area was significantly higher in the dermis of patients compared to controls, and became even higher after D-penicillamine treatment. The phenomena were evident in all strata of the dermis; however, the most significant increase of elastin in SSc patients compared to controls was in the superficial dermis, whereas after D-penicillamine treatment, all the strata of the dermis showed a significant increase in the percentage of elastin and in the number of elastin fibers per unit area compared to untreated patients and to controls. There were no relationships between elastin increase and time from the onset of SSc or time and dose of D-penicillamine treatment. At the ultrastructural level, collagen fibrils had rather heterogeneous diameters and formed more compact fibers, especially in the reticular and in the deep dermis of SSc patients compared to controls. After D-penicillamine, collagen fibril diameters in three of 5 patients examined were statistically wider and more heterogeneous than in controls and in untreated patients, whereas in the other 2 subjects both the mean diameter and the distribution of the class diameter were similar to both controls and untreated patients. This could suggest a specific individual reaction to the drug. Elastin fibers were smaller, more numerous and polymorphous in all patients compared to controls. After D-penicillamine, elastin fibers became even more numerous and smaller than in untreated patients. There was no correlation between the number and size of the elastin fibers and the time or dose of D-penicillamine. The internal organization of the elastin fibers was normal. These data indicate that the amount and distribution of collagen and elastin are altered in the dermis of SSc patients, and that D-penicillamine interferes with the deposition of both fibrous proteins in the dermal extracellular space.

[Histochemical identification of lymphocytic infiltration in the rheumatoid nodule]. / Identification histochimique de l'infiltration lymphocytaire dans le nodule rhumatoide.

The authors have used histochemical techniques to identify lymphocytic infiltrations in the rheumatoid nodule. They used the technique of alpha-naphtyl-acetate esterase (ANAE) for macrophages, ANAE plus Sodium Fluoride (NaF) for T-lymphocytes and 5-nucleotidase for B-lymphocytes. The results of this study reveal that the lymphocytic component of the rheumatoid nodule is mostly B-lymphocytes.

[Changes in the atlanto-odontoid articulation in rheumatoid arthritis. Radiologic observations in 86 cases]. / Le alterazioni dell'articolazione atlo-odontoidea nell'artrite reumatoide. Osservazioni radiologiche in 86 casi.

The authors describe the alterations of atlanto-axial joint observed in patients with rheumatoid arthritis: 16 of 86 patients = 18.6% (15 females and 1 male) showed the presence of joint luxation. The authors suggest that a "dynamic" tomographic study in lateral orthostatic projection, with indifferent position and head flexed, is essential for demonstrating the changes of this joint and that examination should be performed in all patients with rheumatoid arthritis, even if they are asymptomatic.