Cold urticaria: case series and literature review

Cold urticaria is one of the five most common causes of chronic urticaria and is grouped as a physical urticaria. It can occur after exposure to cold, either through solid objects, air or liquids. Patients may have symptoms of urticaria, angioedema, respiratory distress and even anaphylaxis when the skin is exposed to a cold environment, such as handling refrigerated objects, swimming in cold water or entering an air-conditioned room. Five cases of cold urticaria are presented, followed by a brief literature review.     

Chronic urticaria.

Urticaria affects 15% to 20% of the population once or more during a lifetime. Chronic urticaria is a frequent recurrent eruption over a period greater than 6 weeks; the cause remains a mystery in more than 75% of cases. Urticaria and angioedema may be produced by immunologic or nonimmunologic means. Urticarial vasculitis, contact urticaria, mastocytosis, physical urticarias, dermatographism, cholinergic urticaria, localized heat urticaria, cold urticaria, aquagenic urticaria, and vibratory angioedema all require specific evaluation and treatment. Chronic idiopathic urticaria is usually controlled by antihistamines; depending on the circadian rhythm of the eruption, sedative or nonsedative antihistamines are prescribed. Some patients will require a combination of H1 and H2 antagonists, or even parenteral corticosteroids.     

Increased concentration of platelet-derived chemokines in serum of patients with delayed pressure urticaria

BACKGROUND: Delayed pressure urticaria (DPU) is a distinct form of urticaria, characterized by marked dermal swelling, deep inflammatory infiltrate and systemic symptoms. Little is known about inflammatory mediators involved in this disease. OBJECTIVE: To investigate secretion of platelet-specific chemokines, platelet factor 4 (PF-4) and beta-thromboglobulin (beta-TG) during the course of DPU. METHODS AND MATERIAL: Plasma concentrations of PF-4 and beta-TG were measured in eight adult DPU patients and in 15, age- and sex-matched, healthy controls. RESULTS: Plasma PF-4 and beta-TG concentration scores were significantly higher in the DPU group as compared with the control subjects. CONCLUSION: The present study, as well as an earlier contribution, suggest that distinct platelet activity may be identified in different types of urticaria. In contrast to chronic idiopathic urticaria, chronic urticaria with a positive response to autologous serum skin testing, and acute urticaria, delayed pressure urticaria may be associated with increased secretion of platelet chemokines, similar to that observed in cold urticaria.     

Examination of the role of TRPM8 in human mast cell activation and its relevance to the etiology of cold-induced urticaria

Mast cells are considered the primary initiators of allergic diseases as a consequence of the release of multiple inflammatory mediators on activation. Although predominately activated through antigen-mediated aggregation of IgE-occupied-Fc?RI, they can also be induced to release mediators by other receptors and environmental stimuli. Based on studies conducted in the RBL 2H3 rodent mast cell line, the transient receptor potential melastatin 8 (TRPM8) cation channel has been implicated in the activation of mast cells in response to cold and, by inference, the development of urticaria. Here we investigated the expression and role of TRPM8 receptor, in both human and mouse non-transformed cells, with the aim of exploring the potential link between TRPM8 and the pathology of cold urticaria in humans. Although expressed in mouse mast cells, we found no evidence of TRPM8 expression in human mast cells or functional mutations in TRPM8 in cold urticaria patients. Furthermore, neither mouse nor human primary cultured mast cells degranulated in response to cold challenge or TRPM8 agonists and mast cell reactivity was unaffected in Trpm8^−/− mice. From these data, we conclude that TRPM8 is unlikely to directly regulate mast cell activation in cold urticaria. Thus, alternative mechanisms likely exist for the pathogenesis of this disease.     

Regulation of cryopyrin/Pypaf1 signaling by pyrin,the familial Mediterranean fever gene product

Cryopyrin, a member of the Nod protein family mutated in familial cold urticaria and Muckle-Wells syndrome, has been recently implicated in inflammation. However, the mechanism of activation and regulation of the cryopyrin signaling pathway remains poorly understood. We report here that co-expression of cryopyrin with its binding partner, ASC, induced both apoptosis and NF-kappaB activation. This signaling was mimicked by oligomerization of ASC, suggesting that cryopyrin activates downstream targets as reported for other Nod family members. Notably, pyrin, the product of the familial Mediterranean fever gene, inhibited cryopyrin-mediated apoptosis and NF-kappaB activation by disrupting the cryopyrin-ASC interaction. These results provide evidence for a cryopyrin signaling pathway activated through the induced proximity of ASC, which is negatively regulated by pyrin.     

New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes

Mutations of CIAS1 have recently been shown to underlie familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS), in three families and one family, respectively. These rare autosomal dominant diseases are both characterized by recurrent inflammatory crises that start in childhood and that are generally associated with fever, arthralgia, and urticaria. The presence of sensorineural deafness that occurs later in life is characteristic of MWS. Amyloidosis of the amyloidosis-associated type is the main complication of MWS and is sometimes associated with FCU. In FCU, cold exposure is the triggering factor of the inflammatory crisis. We identified CIAS1 mutations, all located in exon 3, in nine unrelated families with MWS and in three unrelated families with FCU, originating from France, England, and Algeria. Five mutations--namely, R260W, D303N, T348M, A439T, and G569R--were novel. The R260W mutation was identified in two families with MWS and in two families with FCU, of different ethnic origins, thereby demonstrating that a single CIAS1 mutation may cause both syndromes. This result indicates that modifier genes are involved in determining either a MWS or a FCU phenotype. The finding of the G569R mutation in an asymptomatic individual further emphasizes the importance of such modifier a gene (or genes) in determining the disease phenotype. Identification of this gene (or these genes) is likely to have significant therapeutic implications for these severe diseases.     

Thermogenetic mechanisms involved in Man's fitness to resist cold exposure

People whose evolution has taken place in contrasting climates, appear to have an almost identical critical temperature (27–29°C). This does not exclude the existence of minor variations within and between populations with regard to individual fitness to resist cold exposure. The main factor by which Man's fitness to resist cold exposure can be varied, appears to be thermogenesis. The biological variation of BMR, shivering, a possible non-shivering thermogenesis, and the maximal aerobic power is reviewed. BMR of an individual can vary with diet, general health, habitual physical activity, as well as various environmental conditions, conceivably including cold exposure. A definite inter- and intra-individual variation in shivering threshold exists. The underlying mechanism of these differences is poorly understood, however. Firm evidence in favour of a non-shivering thermogenesis in Man is lacking. Man's capability to raise his metabolism in muscular exercise is an important part of his fitness to resist cold exposure. This capability can be assessed by measurement of maximal oxygen uptake. Maximal oxygen uptake is influenced by age, sex, health, diet and habitual physical activity. It is questionable if evolution in contrasting climates brings about variation in maximal oxygen uptake.     

Adjustment of the peripheral circulation in human cold acclimatization: A critical review

The literature concerning the peripheral circulatory changes in human cold acclimatization is briefly reviewed. The warmer extremities in the cold earlier attributed to a “Metabolic acclimatization to cold” are possibly an effect of improved physical fitness, but the underlying mechanisms are still unclear. The evidence concerning a total body acclimatization to cold is equivocal. An increased hand vasoconstriction in the cold in subjects with an insulative type of acclimatization to cold may be of relatively little importance for the general thermal balance and accentuate the deteriorating effect of cold on hand functioning. There is good evidence for local manifestations of a cold acclimatization in Man: a quickened onset of an increased cold induced vasodilatation, markedly reduced or abolished cold pain and a lowered cold pressor response. The underlying mechanism is most probably a central nervous habituation to cold—possibly the main physiological mechanism in human cold acclimatization. The importance of an intact hand functioning for survival in the cold is stressed.     

Identification of a locus on chromosome 1q44 for familial cold urticaria

Familial cold urticaria (FCU) is a rare autosomal dominant inflammatory disorder characterized by intermittent episodes of rash with fever, arthralgias, conjunctivitis, and leukocytosis. These symptoms develop after generalized exposure to cold. Some individuals with FCU also develop late-onset reactive renal amyloidosis, which is consistent with Muckle-Wells syndrome. By analyzing individuals with FCU from five families, we identified linkage to chromosome 1q44. Two-point linkage analysis revealed a maximum LOD score (Zmax) of 8.13 (recombination fraction 0) for marker D1S2836; multipoint linkage analysis identified a Zmax of 10. 92 in the same region; and haplotype analysis defined a 10.5-cM region between markers D1S423 and D1S2682. Muckle-Wells syndrome was recently linked to chromosome 1q44, which suggests that the two disorders may be linked to the same locus.     

Mechanisms of cold pain

Avoidance of cold pain is an important survival mechanism. Intriguingly, whilst cooling can cause numbness, damage sensing mechanisms still seem to operate at low temperatures, and pain can be perceived from cooled damaged tissue. Recent studies have identified two cold-activated transient receptor potential (TRP) channels present in sensory neurons as transducers of cold stimuli. TRPM8 seems to mediate responses to cooling whilst TRPA1 is activated, possibly indirectly, by more extreme cold conditions. The existence of cold-responsive neurons that do not express these channels suggests that other transducers of cold stimuli remain to be discovered. Subsequent action potential electrogenesis and probably propagation from sensory neurons innervating cold tissues depends upon the presence of Na(v)1.8, the sole voltage-gated sodium channel that fails to inactivate at low temperatures. This may explain the remarkable specificity of Na(v)1.8 expression in nociceptive neurons, where it plays an important role in pain pathways.     

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

Disruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild‐type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS‐14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging.     

甜菜碱提高植物抗寒性的机理及其应用

甜菜碱是植物重要的渗透调节物质,在低温等逆境条件下,许多植物细胞中迅速积累甜菜碱以维持细胞的渗透平衡.对近几年来甜菜碱提高植物抗寒性的机理研究及其应用,包括甜菜碱的生物合成途径、低温胁迫下甜菜碱对植物的保护机理、甜菜碱合成酶基因的转化及外源甜菜碱在植物抗寒中的应用进行了综述.     

Participation of the prostacyclin-thromboxane system in the mechanisms of prevention of arrhythmia caused by occlusion of the coronary artery in adapted rats]

It was found, that adaptation of rats to cold and physical exercise prevented ventricular fibrillation, caused by the occlusion of the left anterior coronary artery. An adaptation to cold only or to physical exercise do not prevent ventricular arrhythmias. An significant increase of prostacyclin/thromboxane index in plasma and heats was estimated in rats adapted to cold and physical exercise in relation to control non-adapted group in condition of functional rest or acute myocardial ischemia. It was assumed that an increase of prostacyclin/thromboxane ratio has a significant role in antiarrhythmic action of adaptation.     

Diaspore ecology of Mertensia maritima: effects of physical treatments and their relative timing on dispersal and germination

This paper reports an experimental study of water dispersal potential and germination of the shingle beach plant Mertensia maritima in which we consider the effects of physical factors (cold treatment, mechanical wear of the pericarp and salt-water exposure) on the diaspores. Our approach also includes testing effects of different orders of the treatments, in contrast to most earlier studies of diaspore ecology. A cold period was necessary to break seed dormancy, and prolonged cold treatment (stratification at 2°C) enhanced germination. Mechanical wear of the pericarp before cold treatment did not affect germination, whereas mechanical wear after cold treatment increased germination significantly. Seeds exposed to 6 weeks of cold treatment before floating in salt water for 6 weeks did not germinate. In contrast, for seeds given the same cold treatment after floating, the germination was more than 50%. Most undamaged and slightly damaged nutlets stayed afloat throughout the dispersal experiment (9 weeks) in 3% salt water, whereas seeds that fell out of damaged nutlets sunk immediately. Thus, the results suggest that the potential for long-distance dispersal is high unless the diaspores (nutlets) are severely damaged, but the order of cold treatment and water dispersal seems to be of great importance for germination: seeds dispersed in autumn (before cold periods) have a much higher probability of germinating than seeds dispersed in winter or early spring (after a cold period). Similar effects of the relative timing of physical processes have hitherto only been reported for two other water-dispersed beach plants. Future studies in diaspore ecology should consider such timing effects as they may be important determinants of the distribution and abundance of plants.     

Effect of aspirin on pruritus.

The effect of 900 mg aspirin on persistent itch from chronic dermatoses other than urticaria (eight patients) and other causes (five patients) was measured subjectively using a 10 cm line and objectively as nocturnal scratch using limb meters. There was no change in itch or scratch and it is concluded that aspirin neither affects itch centrally by a pain related mechanism nor affects itch physiologically by cyclo-oxygenase inhibition in the skin.     

Spermidine acetylation in response to a variety of stresses in Escherichia coli

Heat shock, cold shock, ethanol, and alkaline shift, but not hydrogen peroxide, stimulate the accumulation of monoacetylspermidine in Escherichia coli. Acetylation occurs with nearly equal frequencies at both the N1 and N8 positions of this ubiquitous polycation. Spermidine acetylation does not appear to be associated with known stress regulons, such as htpR, oxyR, and SOS. E. coli, capable of acetylating spermidine, constitutively express a spermidine acetyltransferase activity during all phases of growth, and this activity is unaffected by cold shock. A mutant strain, incapable of acetylating spermidine, does not express this enzyme activity but grows at an identical rate as the parent strain at 37 degrees C. These results demonstrate that the monoacetylation of spermidine in E. coli is regulated by some mechanism other than a stress-inducible acetyltransferase and is not essential for growth of these cells. They suggest that polyamine acetylation is involved in the responses of these organisms to a variety of chemical and physical stresses.     

Evening rather than morning increased physical activity alters the microbiota in mice and is associated with increased body temperature and sympathetic nervous system activation

Voluntary training and food modulate the fecal microbiota in humans and mice. Although there are some reports of the timing effects of voluntary training and feeding on metabolism, the timing effects of these factors on microbiota have not been investigated. Therefore, we investigated the effects of the timing of voluntary training and feeding on the gut microbiota.The ICR mice were housed under conditions with an early (in the morning) or late (evening) active phase of increased physical activity. Furthermore, to investigate why voluntary training affects the gut microbiota, mice were housed in a cold environment and received propranolol administration with increased physical activity. After that, we collected cecal contents and feces and measured cecal pH. Short-chain fatty acids (SCFA) were measured from cecal contents. Microbiota was determined using sequencing of the V3-V4 region of the 16S rDNA gene.This study found that increased evening physical activity rather than morning activity decreases cecal pH, increases SCFA, and changes the microbiota. It is especially important that increased evening physical activity is induced under the post-prandial voluntary training condition. Also, we found that cold room housing, sympathetic blockade, or both suppressed the increased physical activity-induced changes in cecal pH, SCFA, and microbiota. Allobaculum responded to increased physical activity through body temperature increases and sympathetic activation.Post-prandial increased physical activity, rather than pre-prandial increased physical activity by evening voluntary wheel training, altered the microbiota composition, which may be related to the increase in body temperature and sympathetic nervous system activation.