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Background and Purpose: The chemotherapy agent oxaliplatin can give rise to oxaliplatin‐induced peripheral neuropathy (OIPN). Here, we investigated whether T‐type calcium channels (Cav3) contribute to OIPN. Experimental Approach: We chronically treated mice with oxaliplatin and assessed pain responses and changes in expression of Cav3.2 calcium channels. We also tested the effects of T‐type channel blockers on cold sensitivity in wild‐type and Cav3.2 null mice. Key Results: Oxaliplatin treatment led to mechanical and cold hypersensitivity in male and female mice. Mechanical hypersensitivity persisted in Cav3.2 null mice of both sexes. Intraperitoneal or intrathecal delivery of pan T‐type channel inhibitors attenuated mechanical hypersensitivity in wild‐type but not Cav3.2 null mice. Remarkably cold hypersensitivity occurred in female but not male Cav3.2 null mice even without oxaliplatin treatment. Unexpectedly, intrathecal, intraplantar or intraperitoneal delivery of T‐type channel inhibitors Z944 or TTA‐P2 transiently induced cold hypersensitivity in both male and female wild‐type mice. Acute knockdown of specific Cav3 isoforms revealed that the depletion of Cav3.1 in males and depletion of either Cav3.1 or Cav3.2 in females triggered cold hypersensitivity. Finally, reducing Cav3.2 expression by disrupting the interactions between Cav3.2 and the deubiquitinase USP5 with the small organic molecule II‐2 reversed oxaliplatin‐induced mechanical and cold hypersensitivity and importantly did not trigger cold allodynia. Conclusion and Implications: Altogether, our data indicate that T‐type channels differentially contribute to the regulation of cold and mechanical hypersensitivity, and raise the possibility that T‐type channel blockers could promote cold allodynia. [ABSTRACT FROM AUTHOR]

About half of young Japanese women have a cold constitution, which heightens susceptibility to cold syndrome. In recent years, new findings on the physiological features of a cold constitution have increased. A cold constitution lowers the quality of daily life, so coldness and the related complaints need to be alleviated. Single dynamic exercise transiently relieves coldness via the warm-up effect. Exercise training decreases sensitivity to cold under normal temperature conditions and enhances peripheral cutaneous vasodilatory responses in young women with a cold constitution. This review provides an overview of the physiological characteristics of women’s cold constitution and the acute and chronic effects of physical exercise as a countermeasure.

One of the most common issues caused by antineoplastic agents is chemotherapy-induced peripheral neuropathy (CIPN). In patients, CIPN is a sensory neuropathy accompanied by various motor and autonomic changes. With a high prevalence of cancer patients, CIPN is becoming a major problem for both cancer patients and for their health care providers. Nonetheless, there are lacking effective interventions preventing CIPN and treating the CIPN symptoms. A number of studies have demonstrated the cellular and molecular signaling pathways leading to CIPN using experimental models and the beneficial effects of some interventions on the CIPN symptoms related to those potential mechanisms. This review will summarize results obtained from recent human and animal studies, which include the abnormalities in mechanical and temperature sensory responses following chemotherapy such as representative bortezomib, oxaliplatin and paclitaxel. The underlying mechanisms of CIPN at cellular and molecular levels will be also discussed for additional in-depth studies needed to be better explored. Overall, this paper reviews the basic picture of CIPN and the signaling mechanisms of the most common antineoplastic agents in the peripheral and central nerve systems. A better understanding of the risk factors and fundamental mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Extreme thermophiles Calditerricola satsumensis DD2 and D3 were isolated from mesothermal municipal sludge, a material used for hyperthermal composting. To understand the ecologically anomalous findings, their behavior at various temperatures, membrane fatty acid composition, and draft genome sequences were compared with those of C. satsumensis YMO81T and Calditerricola yamamurae YMO722T, already isolated from hyperthermal compost. All four strains grew between 56 and 83 °C. However, strains DD2 and D3 were stable for ≥48 h at a wide range of temperatures (20–75 °C), while strains YMO81T and YMO722T were highly labile at lower temperatures. The former strains maintained their colony-forming ability for >180 days at 20 °C, while the latter strains lost it within 1 d. All four strains showed similar composition of membrane fatty acid, which were not affected by 20 °C treatment. Comparative draft genome analyses showed that 13 candidate genes were present only in strains DD2 and D3, and the specific expression of six gene homologs was confirmed. A DNA chaperone, site-specific recombinase XerD homolog, had tetra adenine sequence at its upper gene region, and was up-regulated by 20 °C treatment in DD2 and D3, suggesting a possible role in the cold tolerance of sludge-derived strains. In addition, the lack of another possible DNA chaperone, a homolog of the ATP-dependent DNA helicase, in the compost-derived strains may accelerate their sensitivity to cold shock. In conclusion, we speculate that the specific phenotypic and genotypic characteristics of sludge-derived strains are responsible for their unusual ecological distribution at ambient temperatures. [ABSTRACT FROM AUTHOR]

Background: Glomus tumors are uncommon tumors and their occurrence in the foot is even less common. Glomus tumors of the toes are often missed, causing delays in diagnosis and treatment. We report an ambispective observational study of glomus tumors of the toes that were treated at our institution. Methods: We reviewed the records of all the patients who underwent excision of toe glomus tumors in our department from January 2010 to September 2022. The follow-up data were collected from the outpatient records and by telephonic interview. Single Assessment Numeric Evaluation (SANE) score, Foot and Ankle Outcome Score (FAOS), and the Foot Function Index (FFI) were collected. Results: Out of all the patients treated for glomus tumors, we found that 7 patients had glomus tumors of the toes. Of the 7 patients, 6 were women and 1 was a male. The mean follow-up of our patients was 66.4 months (range, 7-109 months). Of the 7 patients, 1 presented with recurrent glomus tumor 30 months following the primary operation, for which she underwent excision again, after which she was symptom free. Another patient who developed recurrent symptoms on telephonic interview refused any further treatment. Among the 6 patients who were symptom-free at follow-up (including the patient who underwent excision for the recurrent tumor), the median SANE score, and FFI were 99.5 (IQR, 96-100) and 0.5 (IQR, 0-2) respectively. The mean FAOS was 96 (SD, 3.3). Conclusion: Surgical excision of the subungual toe glomus tumors can be curative. Recurrence of toe glomus tumors was noted in 2 patients (29%), one of whom refused further surgery. Re-excision in the other patient resulted in complete resolution of symptoms. Level of Evidence: Level III, ambispective observational study. [ABSTRACT FROM AUTHOR]

Case: Glomus tumors of the hand are rare tumors that occur predominantly in the subungual region. Though multicentric glomus tumors have been reported in the subungual region involving the nailbed, monostotic multiple intraosseous glomus tumors have not been reported so far. We report a case of a 36 year-old woman who presented with a 5-year history of intermittent thumb pain, aggravated with exposure to cold or pressure. A glomus tumor of the thumb was excised, but symptoms returned 3 months later. She ultimately underwent curettage with bone grafting of a recurrent glomus tumor at the same site, and has been free of symptoms for 1.5 years. Conclusion: Intraosseous glomus tumors may present as multiple synchronous lesions. This, to the best of our knowledge, is the first case report of monostotic multiple intraosseous glomus tumors. [ABSTRACT FROM AUTHOR]

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel that is activated by a variety of stimuli and acts as a nociceptor. Mouse and human TRPA1 exhibit different reactivity to some stimuli, including chemicals such as menthol as well as cold stimuli. The cold sensitivity of TRPA1 in mammalian species is controversial. Here, we analyzed the reactivity of heterologously expressed canine TRPA1 as well as the mouse and human orthologs to menthol or cold stimulation in Ca2+-imaging experiments. Canine and human TRPA1 exhibited a similar response to menthol, that is, activation in a concentration-dependent manner, even at the high concentration range in contrast to the mouse ortholog, which did not respond to high concentration of menthol. In addition, the response during the removal of menthol was different; mouse TRPA1-expressing cells exhibited a typical response with a rapid and clear increase in [Ca2+]i (“off-response”), whereas [Ca2+]i in human TRPA1-expressing cells was dramatically decreased by the washout of menthol and [Ca2+]i in canine TRPA1-expressing cells was slightly decreased. Finally, canine TRPA1 as well as mouse and human TRPA1 were activated by cold stimulation (below 19–20°C). The sensitivity to cold stimulation differed between these species, that is, human TRPA1 activated at higher temperatures compared with the canine and mouse orthologs. All of the above responses were suppressed by the selective TRPA1 inhibitor HC-030031. Because the concentration-dependency and “off-response” of menthol as well as the cold sensitivity were not uniform among these species, studies of canine TRPA1 might be useful for understanding the species-specific functional properties of mammalian TRPA1. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer mediates entry into host cells by binding receptors, CD4 and CCR5/CXCR4, and fusing the viral and cell membranes. In infected cells, cleavage of the gp160 Env precursor yields the mature Env trimer, with gp120 exterior and gp41 transmembrane Env subunits. Env cleavage stabilizes the State-1 conformation, which is the major target for broadly neutralizing antibodies, and decreases the spontaneous sampling of more open Env conformations that expose epitopes for poorly neutralizing antibodies. During HIV-1 entry into cells, CD4 binding drives the metastable Env from a pretriggered (State-1) conformation into more "open," lower-energy states. Here, we report that changes in two dissimilar elements of the HIV-1 Env trimer, namely particular gp120 glycans and the gp41 fusion peptide-proximal region (FPPR), can independently modulate the stability of State 1. Individual deletion of several gp120 glycans destabilized State 1, whereas removal of a V1 glycan resulted in phenotypes indicative of a more stable pretriggered Env conformation. Likewise, some alterations of the gp41 FPPR decreased the level of spontaneous shedding of gp120 from the Env trimer and stabilized the pretriggered State-1 Env conformation. State-1-stabilizing changes were additive and could suppress the phenotypes associated with State-1-destabilizing alterations in Env. Our results support a model in which multiple protein and carbohydrate elements of the HIV-1 Env trimer additively contribute to the stability of the pretriggered (State-1) conformation. The Env modifications identified in this study will assist efforts to characterize the structure and immunogenicity of the metastable State-1 conformation. IMPORTANCE: The elicitation of antibodies that neutralize multiple strains of HIV-1 is an elusive goal that has frustrated the development of an effective vaccine. The pretriggered shape of the HIV-1 envelope glycoprotein (Env) spike on the virus surface is the major target for such broadly neutralizing antibodies. The "closed" pretriggered Env shape resists the binding of most antibodies but is unstable and often assumes "open" shapes that elicit ineffective antibodies. We identified particular changes in both the protein and the sugar components of the Env trimer that stabilize the pretriggered shape. Combinations of these changes were even more effective at stabilizing the pretriggered Env than the individual changes. Stabilizing changes in Env could counteract the effect of Env changes that destabilize the pretriggered shape. Locking Env in its pretriggered shape will assist efforts to understand the Env spike on the virus and to incorporate this shape into vaccines. [ABSTRACT FROM AUTHOR]

• Cut lilies respond to ethylene in a tissue-specific manner. • Ethylene accelerates only flower senescence in cold-stored flowers. • Cold stress changes ethylene perception through changes at receptor level. • 1-MCP is effective in delaying flower senescence but not leaf senescence. Fresh cut lily flowers often have a long postharvest life and produce undetectable levels of ethylene. This changes after cold storage, when lilies produce a higher amount of ethylene with a very early leaf and then flower senescence. Such changes to postharvest physiology are likely ethylene-dependant, either due to a higher level of ethylene production or a change in ethylene sensitivity as a result of alteration in the expression of genes involved in the biosynthesis, perception and signalling of ethylene. Therefore, we investigated the transcriptional regulation of ethylene biosynthesis, perception, and signalling pathways in response to cold storage in the cut lily cultivar 'Marlon'. Cut lily stems were treated as follows: 1) control (no treatments), 2) 1-Methylcyclopropene (1-MCP; an ethylene action inhibitor) (10 nL L −1), 3) ethylene (10 μL L −1), and 4) 1-MCP (10 nL L −1) + ethylene (10 μL L −1) for 12 h, thereafter, half of each treated group were cold stored at 5 °C in 12 h light/dark condition for 7 days. We assessed quality characteristics, ethylene production, and the expression of its biosynthesis, perception, and signalling genes. Ethylene and 1-MCP treatments had no effects on non-cold-stored plants. Cold storage led to much earlier leaf yellowing (from 8 to 4 days), and flowers senesced and abscised 3 days earlier. In cold-stored plants, flower senescence and abscission were hastened by ethylene and delayed by 1-MCP. These findings indicate that ethylene does influence flower senescence following cold storage but leaf senescence is under the control of other factors. Our results suggest that treatments that focus on ethylene blockers to prolong postharvest life in lilies will be effective for flowers but not leaves. [ABSTRACT FROM AUTHOR]

The clinical evaluation of patients with neurosensory injury is based on quantitative sensory testing. Such tests require the patient's cooperation, which may sometimes hinder a correct diagnosis. Objective findings, e.g., with biomarkers, would therefore be valuable. We evaluated serum biomarkers of vascular and neural injury in 92 patients with vibration injuries and in 64 referents. Thrombomodulin (TM), a biomarker for endothelial damage, was elevated in HAVS patients with Raynaud's phenomenon (RP) compared to those without, as it also was in comparison to the referents. In the patients without RP, those with increased cold sensitivity showed somewhat higher--but not significantly different--values of TM (p = 0.4) than those without increased cold sensitivity, indicating an endothelial dysfunction or injury. [ABSTRACT FROM AUTHOR]

Single-tooth sandals under new development have special material and shape characteristics. Exercises with single-tooth sandals can increase pressing stimulus on the soles of the feet, thereby suppressing a decline in medial longitudinal arch and elevating sole surface temperature. This study thus aimed to examine the effects of exercise with single-tooth sandals on medial longitudinal arch and sole surface temperature. Sixteen young adults (23 ± 5 years) participated in 20 min of stepping exercise on the spot. They randomly put on a regular normal sandal (N conditions) or a single-tooth sandal (Z conditions) on each left and right side. Before and after exercise, medial longitudinal arch and sole surface temperature were assessed by digital caliper and straightedge and thermography, respectively. No significant differences in baseline parameters were observed between N and Z conditions. After exercise, arch height and arch height ratio significantly reduced in N conditions, but not in Z conditions. Central sole surface temperature in Z conditions also increased significantly, and the changes in surface temperature were significantly higher in Z conditions than in N conditions. Therefore, these findings suggest that exercise with single-tooth sandals has a positive effect on a suppressing decline in medial longitudinal arch and an elevation in sole surface temperature. [ABSTRACT FROM AUTHOR]

'Huangguan' pear (Pyrus bretschneideri Rehd) fruit is susceptible to cold, characterized by developing peel browning spots (PBS) during cold storage. Additionally, ethylene pretreatment reduces chilling injury (CI) and inhibits PBS occurrence, but the mechanism of CI remains unclear. Here, we deciphered the dynamic transcriptional changes during the PBS occurrence with and without ethylene pretreatment via time-series transcriptome. We found that ethylene suppressed the cold-signaling gene expression, thereby decreasing the cold sensitivity of the 'Huangguan' fruit. Moreover, the "Yellow" module closely correlated with PBS occurrence was identified via weighted gene co-expression network analysis (WGCNA), and this module was related to plant defense via Gene Ontology (GO) enrichment analysis. Local motif enrichment analysis suggested that the "Yellow" module genes were regulated by ERF and WRKY transcription factors. Functional studies demonstrated that PbWRKY31 has a conserved WRKY domain, lacks transactivation activity, and localizes in the nucleus. PbWRKY31-overexpressed Arabidopsis were hypersensitive to cold, with higher expression levels of cold signaling and defense genes, suggesting that PbWRKY31 participates in regulating plant cold sensitivity. Collectively, our findings provide a comprehensive transcriptional overview of PBS occurrence and elucidate the molecular mechanism by which ethylene reduces the cold sensitivity of 'Huangguan' fruit as well as the potential role of PbWRKY31 in this process. [ABSTRACT FROM AUTHOR]

The effects during healthy aging of the tetrodotoxin-resistant voltage-gated sodium channel 1.8 (Nav1.8), the acid-sensing ion channel-3 (ASIC3), the purinergic-receptor 2X3 (P2X3) and transient receptor potential of melastatin-8 (TRPM8) on responses to non-noxious stimuli are poorly understood. These effects will influence the transferability to geriatric subjects of findings obtained using young animals. To evaluate the involvement of these functional markers in mechanical and cold sensitivity to non-noxious stimuli and their underlying mechanisms, we used a combination of immunohistochemistry and quantitation of immunostaining in sub-populations of neurons of the dorsal root ganglia (DRG), behavioral tests, pharmacological interventions and Western-blot in healthy male Wistar rats from 3 to 24 months of age. We found significantly decreased sensitivity to mechanical and cold stimuli in geriatric rats. These behavioural alterations occurred simultaneously with differing changes in the expression of Nav1.8, ASIC3, P2X3 and TRPM8 in the DRG at different ages. Using pharmacological blockade in vivo we demonstrated the involvement of ASIC3 and P2X3 in normal mechanosensation and of Nav1.8 and ASIC3 in cold sensitivity. Geriatric rats also exhibited reductions in the number of A-like large neurons and in the proportion of peptidergic to non-peptidergic neurons. The changes in normal sensory physiology in geriatric rats we report here strongly support the inclusion of aged rodents as an important group in the design of pre-clinical studies evaluating pain treatments. [ABSTRACT FROM AUTHOR]

Mohammad Mustafa,1 Hadeel Alsulaimani,2 Abdulrahman Alhaddad,3 Sara Almujil,2 Zainab Albar,4 Yasser Bawazir,5 Roaa Alsolaimani,5 Mohammed A Omair6 1Department of Medicine, Rheumatology Unit, University of Jeddah, Jeddah, Saudi Arabia; 2Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 3Faculty of Medicine, King Saud Bin Abdulaziz University for Health and Science, Jeddah, Saudi Arabia; 4School of Medicine, Umm Al Qura University, Makkah, Saudi Arabia; 5Rheumatology Unit, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 6Division of Rheumatology, Department of Medicine, King Saud University, Riyadh, Saudi ArabiaCorrespondence: Mohammad Mustafa, Department of Medicine, University of Jeddah, Jeddah, Saudi Arabia, Tel +966 541318900, Email Mamustafa@uj.edu.saPurpose: Raynaud’s phenomenon (RP) is defined as frequent ischaemic attacks in the fingers and toes due to vascular vasospasm. Studies have been conducted in many countries worldwide to determine the prevalence of RP. The aim of the current study was to assess the prevalence of RP in the Saudi Arabian population.Patients and Methods: An online survey based on international consensus criteria used to diagnose RP was conducted to collect data from individuals from the Saudi population. Participants were considered positive if they had triphasic or biphasic colours of the extremities with cold-related sensitivity. Awareness of RP was also assessed.Results: A total of 1025 responses were collected and included in the final analysis. The prevalence of RP was 4.29%, including 22% men and 77% women. The most common age group among women was 26– 40 years (36.3%). Familiarity with RP was low, with 56.82% of participants lacking adequate awareness regarding RP. Only 32% of patients with RP reported attending doctor visits regarding symptoms of the disease.Conclusion: The RP prevalence in Saudi Arabia is comparable to that reported in the international literature. Public awareness activities should be conducted to increase knowledge about RP.Trial Registration: Not applicable.Keywords: Raynaud’s phenomenon, cold sensitivity, awareness

Cold-inducible RNA-binding-protein (CIRP) is a cold shock protein that plays a protective role in genotoxic stress response. CIRP modulates inflammation in human diseases, inhibits cell proliferation, and protects cells from genotoxic damage during cellular stress. The mild cold responsive element and specificity protein 1 (SP1) play a role in Cirp expression at low temperatures. Although previous studies have provided insights into the immune functions of SP1 or CIRP, the mechanisms by which CIRP and SP1 me diate inflammatory responses remain largely unknown. Therefore, in the current study, we examined whether Cirp expression is affected by genetic factors related to temperature sensitivity as well as under low temperature. We performed a genome-wide association study on cold sensitivity in 2,000 participants. Fifty-six genome-wide significant trait-locus pairs were identified (p<1×10-5, false discovery rate < 0.05). Among these variants, rs1117050 and rs11170510 had a strong linkage disequilibrium (r² > 0.8) relationship and expression quantitative trait locus-associated signals with the nearest Sp1 gene. We confirmed that the minor alleles of rs11170510 and rs58123204 were associated with increased Sp1 expression. Additionally, Sp1 overexpression led to CIRP translocation from the nucleus to the cytoplasm. CIRP protein levels increased in serum samples that had minor alleles of rs11170510 and rs58123204. Levels of various pro-inflammatory cytokines were also significantly increased in human peripheral blood mononuclear cells with minor alleles of rs11170510 and rs58123204. These results suggest that genetic factors related to cold sensitivity regulate CIRP expression and function and provide valuable insights into prediction of potential diseases through analysis of inherent genetic factors in humans. [ABSTRACT FROM AUTHOR]

Although cancer and diabetes are common diseases, the relationship between diabetes, neuropathy and the risk of developing peripheral sensory neuropathy while or after receiving chemotherapy is uncertain. In this review, we highlight the effects of chemotherapy on the onset or progression of neuropathy in diabetic patients. We searched the literature in Medline and Scopus, covering all entries until 31 January 2021. The inclusion and exclusion criteria were: (1) original article (2) full text published in English or Spanish; (3) neuropathy was specifically assessed (4) the authors separately analyzed the outcomes in diabetic patients. A total of 259 papers were retrieved. Finally, eight articles fulfilled the criteria, and four more articles were retrieved from the references of the selected articles. The analysis of the studies covered the information about neuropathy recorded in 768 cancer patients with diabetes and 5247 control cases (non-diabetic patients). The drugs investigated are chemotherapy drugs with high potential to induce neuropathy, such as platinum derivatives and taxanes, which are currently the mainstay of treatment of various cancers. The predisposing effect of co-morbid diabetes on chemotherapy-induced peripheral neuropathy depends on the type of symptoms and drug used, but manifest at any drug regimen dosage, although greater neuropathic signs are also observed at higher dosages in diabetic patients. The deleterious effects of chemotherapy on diabetic patients seem to last longer, since peripheral neuropathy persisted in a higher proportion of diabetic patients than non-diabetic patients for up to two years after treatment. Future studies investigating the risk of developing peripheral neuropathy in cancer patients with comorbid diabetes need to consider the duration of diabetes, cancer-induced neuropathic effects per se (prior chemotherapy administration), and the effects of previous cancer management strategies such as radiotherapy and surgery.

The clinical evaluation of patients with neurosensory injury is based on quantitative sensory testing. Such tests require the patient’s cooperation, which may sometimes hinder a correct diagnosis. Objective findings, e.g., with biomarkers, would therefore be valuable. We evaluated serum biomarkers of vascular and neural injury in 92 patients with vibration injuries and in 64 referents. Thrombomodulin (TM), a biomarker for endothelial damage, was elevated in HAVS patients with Raynaud’s phenomenon (RP) compared to those without, as it also was in comparison to the referents. In the patients without RP, those with increased cold sensitivity showed somewhat higher—but not significantly different—values of TM (p = 0.4) than those without increased cold sensitivity, indicating an endothelial dysfunction or injury.

To cope with temperature fluctuations, molecular thermosensors in animals play a pivotal role in accurately sensing ambient temperature. Transient receptor potential melastatin 8 (TRPM8) is the most established cold sensor. In order to understand how the evolutionary forces bestowed TRPM8 with cold sensitivity, insights into both emergence of cold sensing during evolution and the thermodynamic basis of cold activation are needed. Here, we show that the trpm8 gene evolved by forming and regulating two domains (MHR1-3 and pore domains), thus determining distinct cold-sensitive properties among vertebrate TRPM8 orthologs. The young trpm8 gene without function can be observed in the closest living relatives of tetrapods (lobe-finned fishes), while the mature MHR1-3 domain with independent cold sensitivity has formed in TRPM8s of amphibians and reptiles to enable channel activation by cold. Furthermore, positive selection in the TRPM8 pore domain that tuned the efficacy of cold activation appeared late among more advanced terrestrial tetrapods. Interestingly, the mature MHR1-3 domain is necessary for the regulatory mechanism of the pore domain in TRPM8 cold activation. Our results reveal the domain-based evolution for TRPM8 functions and suggest that the acquisition of cold sensitivity in TRPM8 facilitated terrestrial adaptation during the water-to-land transition. [ABSTRACT FROM AUTHOR]

The mid-elevation forest of California's Sierra Nevada poses a bioclimatic paradox. Mid-elevation trees experience a montane Mediterranean climate, with near-freezing winter days and rain-free summers. The asynchrony between warmth and water input suggests low primary production, limited by photosynthetic dormancy in winter cold, and again in summer and early autumn with drought, yet this forest is characterized by tall trees and high biomass. We used eddy covariance in a mid-elevation Sierra stand to understand how winter cold and summer drought limit canopy photosynthesis and production. The trees exhibited canopy photosynthesis year-round. Trees avoided winter dormancy, and daytime CO2uptake continued despite a deep snowpack and near-freezing temperatures. Photosynthesis on sunny days continued at half of maximum rates when air temperature was 0 °C. Likewise, the vegetation avoided summer drought dormancy, and high rates of daytime CO2uptake and transpiration continued despite a 5-month period with only negligible water input. We attribute this drought avoidance to deep rooting and availability of deep soil water. Year-round photosynthesis helps explain the large biomass observed in the Sierra Nevada, and implies adaptive strategies that may contribute to the resiliency or vulnerability of Sierran vegetation to climate change.

Objectives . This study aimed to evaluate the influence of individual characteristics (sex, age, body mass index [BMI] and smoking habits) on the tolerance time, pain ratings and rewarming time of hand cold stress testing (CST). Methods . We included 153 subjects (63% men) working in a Swedish open-pit mine (participation rate 41%). The right hand was immersed in 3 °C circulating water for up to 45 s. Pain ratings were registered every fifth second using a visual analog scale. Results . The tolerance time (mean ± standard deviation) was 35 ± 12 s for men and 29 ± 14 s for women ( p  = 0.007). The youngest age group (18-29 years) had the longest tolerance time, while the oldest group (54-65 years) had the shortest ( p  = 0.005). Women had significantly higher pain ratings than men after 5, 10 and 25 s. The group with the highest BMI had the shortest rewarming time ( p  < 0.001). Conclusions . Age and sex influenced the tolerance time of hand CST, while only sex affected the pain ratings and BMI the rewarming time. When performing CST in future studies, these parameters should be considered.

RNase R (encoded by the rnr gene) is a highly processive 3' → 5' exoribonuclease essential for the growth of the psychrotrophic bacterium Pseudomonas syringae Lz4W at low temperature. The cell death of a rnr deletion mutant at low temperature has been previously attributed to processing defects in 16S rRNA, defective ribosomal assembly, and inefficient protein synthesis. We recently showed that RNase R is required to protect P. syringae Lz4W from DNA damage and oxidative stress, independent of its exoribonuclease activity. Here, we show that the processing defect in 16S rRNA does not cause cell death of the rnr mutant of P. syringae at low temperature. Our results demonstrate that the rnr mutant of P. syringae Lz4W, complemented with a RNase R deficient in exoribonuclease function (RNase R D284A ), is defective in 16S rRNA processing but can grow at 4 °C. This suggested that the processing defect in ribosomal RNAs is not a cause of the cold sensitivity of the rnr mutant. We further show that the rnr mutant accumulates copies of the indigenous plasmid pLz4W that bears a type II toxin-antitoxin (TA) system (P. syringae antitoxin-P. syringae toxin). This phenotype was rescued by overexpressing antitoxin psA in the rnr mutant, suggesting that activation of the type II TA system leads to cold sensitivity of the rnr mutant of P. syringae Lz4W. Here, we report a previously unknown functional relationship between the cold sensitivity of the rnr mutant and a type II TA system in P. syringae Lz4W., Competing Interests: Conflict of interest The authors have no conflict of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Although cancer and diabetes are common diseases, the relationship between diabetes, neuropathy and the risk of developing peripheral sensory neuropathy while or after receiving chemotherapy is uncertain. In this review, we highlight the effects of chemotherapy on the onset or progression of neuropathy in diabetic patients. We searched the literature in Medline and Scopus, covering all entries until 31 January 2021. The inclusion and exclusion criteria were: (1) original article (2) full text published in English or Spanish; (3) neuropathy was specifically assessed (4) the authors separately analyzed the outcomes in diabetic patients. A total of 259 papers were retrieved. Finally, eight articles fulfilled the criteria, and four more articles were retrieved from the references of the selected articles. The analysis of the studies covered the information about neuropathy recorded in 768 cancer patients with diabetes and 5247 control cases (non-diabetic patients). The drugs investigated are chemotherapy drugs with high potential to induce neuropathy, such as platinum derivatives and taxanes, which are currently the mainstay of treatment of various cancers. The predisposing effect of co-morbid diabetes on chemotherapy-induced peripheral neuropathy depends on the type of symptoms and drug used, but manifest at any drug regimen dosage, although greater neuropathic signs are also observed at higher dosages in diabetic patients. The deleterious effects of chemotherapy on diabetic patients seem to last longer, since peripheral neuropathy persisted in a higher proportion of diabetic patients than non-diabetic patients for up to two years after treatment. Future studies investigating the risk of developing peripheral neuropathy in cancer patients with comorbid diabetes need to consider the duration of diabetes, cancer-induced neuropathic effects per se (prior chemotherapy administration), and the effects of previous cancer management strategies such as radiotherapy and surgery. [ABSTRACT FROM AUTHOR]

Summary: Organismal stressors such as cold exposure require a systemic response to maintain body temperature. Brown adipose tissue (BAT) is a key thermogenic tissue in mammals that protects against hypothermia in response to cold exposure. Defining the complex interplay of multiple organ systems in this response is fundamental to our understanding of adipose tissue thermogenesis. In this study, we identify a role for hepatic insulin signaling via AKT in the adaptive response to cold stress and show that liver AKT is an essential cell-nonautonomous regulator of adipocyte lipolysis and BAT function. Mechanistically, inhibition of forkhead box O1 (FOXO1) by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue (WAT) and increasing circulating fibroblast growth factor 21 (FGF21). Our data identify a role for hepatic insulin signaling via the AKT-FOXO1 axis in regulating WAT lipolysis, promoting BAT thermogenic capacity, and ensuring a proper thermogenic response to acute cold exposure.

A unique trait, i.e. yellowing of apical/young leaves in response to low temperature and high relative humidity was identified in a chickpea genotype, ICCX110069. To determine inheritance pattern of this trait, ICCX110069 was crossed to four other genotypes, GL14050, GL14049, GL14059 and SAGL152117, that exhibited normal green apical leaves under similar environmental conditions. The F1, F2, F3, BC1F1 and BC1F2 generations were generated. A ratio of 13 normal green leaf: three yellow leaf was found to be the best fit, indicated digenic gene action with suppressor effect of normal green leaf over the expression of yellowing of apical/young leaf trait. The chlorophyll content was significantly lower, while guaiacol peroxidase activity was significantly higher in yellow leaves of ICCX110069 as compared to green leaves of the same genotype and of GL14049, indicating the competence of antioxidative defence mechanism involved with the expression of this trait. [ABSTRACT FROM AUTHOR]

To study the effect of intradiscal injection of simvastatin on discogenic pain in rats and its possible mechanism, 30 adult female rats were used in this experiment. Twenty rats were randomly divided into sham operation group (Control group), intervertebral disk degeneration group (DDD group), intervertebral disk degeneration + hydrogel group (DDD + GEL group), and intervertebral disk degeneration + simvastatin group (DDD + SIM group). The mechanical pain threshold and cold sensation in rats were measured. The contents of NF-kappa B1, RelA, GAP43, SP, CGRP, TRPM 8, IL-1β, and TNF-α in the intervertebral disk (IVD), the corresponding contents of dorsal root ganglion (DRG) and plantar skin GAP43 and TRPM 8 were quantitatively detected by PCR. The corresponding IVDs were stained to detect their degeneration. There was no significant difference in the mechanical pain threshold between the groups at each time point. From the first day to the 8th week after surgery, the cold-sensing response of the DDD group was significantly higher than that of the Control group (P < 0.05). At 7 and 8 weeks postoperatively, the cold-sensing response of the DDD + SIM group was significantly lower than that of the DDD + GEL group (P < 0.05). The levels of NF-κB1, RelA, GAP43, SP, CGRP, TRPM8, IL-1β, and TNF-α in the IVD of DDD + SIM group were significantly lower than those in DDD group (P < 0.05). The content of GAP43 and TRPM8 in rat plantar skin decreased significantly and TRPM8 in DRG decreased significantly (P < 0.05).

To study the effect of intradiscal injection of simvastatin on discogenic pain in rats and its possible mechanism, 30 adult female rats were used in this experiment. Twenty rats were randomly divided into sham operation group (Control group), intervertebral disk degeneration group (DDD group), intervertebral disk degeneration + hydrogel group (DDD + GEL group), and intervertebral disk degeneration + simvastatin group (DDD + SIM group). The mechanical pain threshold and cold sensation in rats were measured. The contents of NF-kappa B1, RelA, GAP43, SP, CGRP, TRPM 8, IL-1β, and TNF-α in the intervertebral disk (IVD), the corresponding contents of dorsal root ganglion (DRG) and plantar skin GAP43 and TRPM 8 were quantitatively detected by PCR. The corresponding IVDs were stained to detect their degeneration. There was no significant difference in the mechanical pain threshold between the groups at each time point. From the first day to the 8th week after surgery, the cold-sensing response of the DDD group was significantly higher than that of the Control group (P < 0.05). At 7 and 8 weeks postoperatively, the cold-sensing response of the DDD + SIM group was significantly lower than that of the DDD + GEL group (P < 0.05). The levels of NF-κB1, RelA, GAP43, SP, CGRP, TRPM8, IL-1β, and TNF-α in the IVD of DDD + SIM group were significantly lower than those in DDD group (P < 0.05). The content of GAP43 and TRPM8 in rat plantar skin decreased significantly and TRPM8 in DRG decreased significantly (P < 0.05). [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Does recreational cold exposure result in cold sensitivity and is this associated with endothelial dysfunction and impaired sensory thermal thresholds?What is the main finding and its importance?Previous cold exposure was correlated with cold sensitivity of the foot, which might indicate the development of a subclinical non‐freezing cold injury. Endothelial function and thermal detection were not impaired in cold‐sensitive individuals; therefore, further research is required to understand the pathophysiology of subclinical and clinical forms of non‐freezing cold injury. In this study, we investigated whether cold‐sensitive (CS) individuals, who rewarm more slowly after a mild cold challenge, have impaired endothelial function and sensory thermal thresholds (STTs) and whether this is related to reported cold exposure. Twenty‐seven participants with varying previous cold exposure undertook three tests: an STT test, i.e. determination of warm and cold STTs of the fingers and dorsal foot; an endothelial function test, i.e. measurement of cutaneous vascular conductance (CVC) during iontophoresis of ACh on the forearm, finger and foot; and a CS test, involving immersion of a foot for 2 min in water at 15°C followed by 10 min of rewarming in air at 30°C. Toe skin temperature (Tsk) measured during the CS test was used to form a CS group (<32°C before and 5 min after immersion) and an otherwise closely matched control group [Tsk >32°C; n = 9 (four women) for both groups]. A moderate relationship was found between cold exposure ranking and Tsk rewarming (r = 0.408, P = 0.035, n = 27) but not STT or endothelial function. The Tsk and blood flow were lower in CS compared with control subjects before and after foot immersion [Tsk, mean (SD): 30.3 (0.9) versus 34.8 (0.8) and 27.9 (0.8) versus 34.3 (0.8)°C, P < 0.001; and CVC: 1.08 (0.79) versus 3.82 (1.21) and 0.79 (0.52) versus 3.45 (1.07) flux mmHg−1, n = 9, P < 0.001, respectively]. However, no physiologically significant differences were observed between groups for endothelial function or STT. A moderate correlation between previous cold exposure and toe Tsk rewarming after foot immersion was observed; however, CS was not associated with impaired endothelial function or reduced thermal detection. [ABSTRACT FROM AUTHOR]

The outer membrane of Gram-negative bacteria is a barrier to chemical and physical stress. Phospholipid transport between the inner and outer membranes has been an area of intense investigation and, in E. coli K-12, it has recently been shown to be mediated by YhdP, TamB, and YdbH, which are suggested to provide hydrophobic channels for phospholipid diffusion, with YhdP and TamB playing the major roles. However, YhdP and TamB have different phenotypes suggesting distinct functions. We investigated these functions using synthetic cold sensitivity (at 30 °C) caused by deletion of yhdP and fadR , a transcriptional regulator controlling fatty acid degradation and unsaturated fatty acid production, but not by Δ tamB Δ fadR or Δ ydbH Δ fadR ,. Deletion of tamB suppresses the Δ yhdP Δ fadR cold sensitivity suggesting this phenotype is related to phospholipid transport. The Δ yhdP Δ fadR strain shows a greater increase in cardiolipin upon transfer to the non-permissive temperature and genetically lowering cardiolipin levels can suppress cold sensitivity. These data also reveal a qualitative difference between cardiolipin synthases in E. coli , as deletion of clsA and clsC suppresses cold sensitivity but deletion of clsB does not despite lower cardiolipin levels. In addition to increased cardiolipin, increased fatty acid saturation is necessary for cold sensitivity and lowering this level genetically or through supplementation of oleic acid suppresses the cold sensitivity of the Δ yhdP Δ fadR strain. Although indirect effects are possible, we favor the parsimonious hypothesis that YhdP and TamB have differential substrate transport preferences, most likely with YhdP preferentially transporting more saturated phospholipids and TamB preferentially transporting more unsaturated phospholipids. We envision cardiolipin contributing to this transport preference by sterically clogging TamB-mediated transport of saturated phospholipids. Thus, our data provide a potential mechanism for independent control of the phospholipid composition of the inner and outer membranes in response to changing conditions.

Most mammals maintain their body temperature around 37°C, whereas in hibernators it can approach 0°C without triggering a thermogenic response. The remarkable plasticity of the thermoregulatory system allowed mammals to thrive in variable environmental conditions and occupy a wide range of geographical habitats, but the molecular basis of thermoregulation remains poorly understood. Here we leverage the thermoregulatory differences between mice and hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus) to investigate the mechanism of cold sensitivity in the preoptic area (POA) of the hypothalamus, a critical thermoregulatory region. We report that, in comparison to squirrels, mice have a larger proportion of cold-sensitive neurons in the POA. We further show that mouse cold-sensitive neurons express the cyclic nucleotide-gated ion channel CNGA3, and that mouse, but not squirrel, CNGA3 is potentiated by cold. Our data reveal CNGA3 as a hypothalamic cold sensor and a molecular marker to interrogate the neuronal circuitry underlying thermoregulation.

Abstract Background Chemical intolerance is a widespread public health problem characterized by symptoms that reportedly result from low-level exposure to chemicals. Although several studies have reported factors related to chemical intolerance in adults, the impact of family members has not been reported. In the present study, we investigated the background factors related to chemical intolerance in family members and parent–child relationships. Methods We distributed a self-reported questionnaire to 4325 mothers who were invited to visit the Kishiwada Health Center in Kishiwada City, Osaka, between January 2006 and December 2007 for the regular health checkup of their three-and-a-half-year-old children. Results The prevalence of chemical intolerance in the 3-year-old children was almost one eighteenth of that reported by their mothers. Multiple logistic regression analyses revealed that cold sensitivity [odds ratio (OR), 1.89; 95% confidence interval (CI), 1.04–3.44], past bronchial asthma (OR, 2.84; 95% CI, 1.46–5.53), and any past allergies (OR, 2.21; 95% CI, 1.36–3.60) were significantly associated with chemical intolerance in the mother. The presence of indoor cat during childhood (OR, 1.99; 95% CI, 1.08–3.69) was significantly associated with chemical intolerance in the mother; however, the association was weak compared with cold sensitivity and past asthma and allergies. The current chemical intolerance of the mother was significantly associated with allergic rhinitis (OR, 2.32; 95% CI, 1.19–4.53), bronchial asthma (OR, 3.66; 95% CI, 2.00–6.69), and chronic bronchitis (OR, 3.69; 95% CI, 1.04–13.03) in her 3-year-old child. Conclusions The results suggest that inherent physical constitution and childhood housing environment are associated with a risk of acquiring chemical intolerance. Children of mothers with chemical intolerance have a possible risk of respiratory hypersensitivity or inflammation. Further investigation is recommended to determine the inherent physical constitution and background environmental factors associated with the risk of acquiring chemical intolerance. The impact of having mothers with chemical intolerance on the health of children also requires further study.

Climate warming is facilitating the expansion of many cold‐sensitive woody species in woodland–grassland ecotones worldwide. Recent research has demonstrated that this range expansion can be further enhanced by positive vegetation–microclimate feedbacks whereby woody canopies induce local nocturnal warming, which reduces freeze‐induced damage and favors the establishment of woody plants. However, this local positive feedback can be counteracted by biotic drivers such as browsing and the associated consumption of shrub biomass. The joint effects of large‐scale climate warming and local‐scale microclimate feedbacks on woody vegetation dynamics in these ecotones remain poorly understood. Here, we used a combination of experimental and modeling approaches to investigate the effects of woody cover on microclimate and the consequent implications on ecological stability in North American coastal ecosystems. We found greater browsing pressure and significant warming (~2°C) beneath shrub canopies compared to adjacent grasslands, which reduces shrub seedlings' exposure to cold damage. Cold sensitivity is evidenced by the significant decline in xylem hydraulic conductivity in shrub seedlings when temperatures dropped below −2°C. Despite the negative browsing–vegetation feedback, a small increase in minimum temperature can induce critical transitions from grass to woody plant dominance. Our framework also predicts the threshold temperature of −7°C for mangrove–salt marsh ecotones on the Atlantic coast of Florida. Above this reference temperature a critical transition may occur from salt marsh to mangrove vegetation, in agreement with empirical studies. Thus, the interaction between ongoing global warming trends and microclimate feedbacks may significantly alter woody vegetation dynamics and ecological stability in coastal ecosystems where woody plant expansion is primarily constrained by extreme low temperature events. [ABSTRACT FROM AUTHOR]

SUMMARY: The overly zinc sensitive Arabidopsis thaliana mutant ozs3 shows reduced growth of the primary root, which is exacerbated by an excess specifically of Zn ions. In addition, ozs3 plants display various subtle developmental phenotypes, such as longer petioles and early flowering. Also, ozs3 seedlings are completely but reversibly growth‐arrested when shifted to 4°C. The causal mutation was mapped to a gene encoding a putative substrate‐recognition receptor of cullin4 E3 ligases. OZS3 orthologous genes can be found in almost all eukaryotic genomes. Most species from Schizosaccharomyces pombe to Homo sapiens, and including A. thaliana, possess one ortholog. No functional data are available for these genes in any of the multicellular model systems. CRISPR‐Cas9‐mediated knockout demonstrated that a complete loss of OZS3 function is embryo‐lethal, indicating essentiality of OZS3 and its orthologs. The OZS3 protein interacts with the adaptor protein DAMAGED DNA BINDING1 (DDB1) in the nucleus. Thus, it is indeed a member of the large yet poorly characterized family of DDB1‐cullin4 associated factors in plants. Mutant phenotypes of ozs3 plants are apparently caused by the weakened DDB1–OZS3 interaction as a result of the exchange of a conserved amino acid near the conserved WDxR motif. Significance Statement: Analysis of a Zn hypersensitive Arabidopsis thaliana mutant has identified an essential cullin4 E3 ligase substrate‐recognition receptor gene with uncharacterized orthologs in most eukaryotic model systems. Mutant phenotypes, which include inhibition of primary root elongation, growth arrest in the cold and UV‐C hypersensitivity, are hypothesized to be caused by a compromised DNA damage response. [ABSTRACT FROM AUTHOR]

Glycosylphosphatidylinositol (GPI) is synthesized in the endoplasmic reticulum (ER) and added onto proteins to form GPI‐anchored proteins. Among the many proteins involved in this process, ACAT‐related enzyme‐2 required for viability 1 (Arv1) is a candidate, functioning as a flippase that translocates GPI intermediates from the cytoplasmic side into the luminal side of the ER membranes. Here, we show that the deletion of the ARV1 gene in yeast leads to cold‐sensitive defects in cell growth and GPI anchor synthesis. Furthermore, complementation assays show that the overexpression of a missense human ARV1‐G189R mutant does not completely restore the cold‐sensitive phenotypes of the yeast arv1 mutant. Our results support the proposed role of Arv1 in GPI anchor synthesis and suggest that ARV1‐linked human diseases result from defective GPI anchor synthesis. [ABSTRACT FROM AUTHOR]

Cold stress is a major abiotic stress, restricting plant growth and development. Therefore, gene expression in response to cold stress and during cold acclimation has been studied intensively, including the ICE–CBF–COR pathway, as well as the modulation of this cascade by secondary messengers, for instance mitogen-activated protein kinase (MAPK) cascades. In contrast, the early events of cold perception and cold adaption have received far less attention. This is partially due to the fact that cold is a physical signal, which requires the conceptual framework to be adjusted. In this review, we address the role of microtubules in cold sensing, and propose a model whereby microtubules, while not being part of signalling itself, act as modulators of cold sensitivity. The purpose of this model is to derive implications for future experiments that will help to provide a more complete understanding of cold adaptation. [ABSTRACT FROM AUTHOR]

• The BoPQL2 gene exhibits 4 amino acid substitutions between white-green variegated leaf and white leaf ornamental kale. • Three BoPQL2 -deficient mutants were generated using CRISPR/Cas9 technology. • The BoPQL2 -deficient mutants showed increased sensitivity to low temperature. • Inner leaves of BoPQL2 -deficient mutants were free of green margins at low temperatures below 16 °C. Leaf color is an important ornamental trait for ornamental kale. In our previous study, the BoPQL2 gene was identified to exhibit significant differential expression between white and green leaf tissues of ornamental kale. In this study, the gene BoPQL2 was cloned from 'D11′ with white-green variegated inner leaves and '1631′ with fully white inner leaves. Five SNPs were identified between the two above materials, of which four lead to four amino acid substitutions. To elucidate the function of the BoPQL2 gene in ornamental kale, the CRISPR- BoPQL2 vector was constructed and transformed into the 'D11′. Three BoPQL2 -deficient mutants were generated, including two homozygous mutants and one double allelic mutant. Compared to the wildtype, the three mutants exhibited full white inner leaves without green margins under the same low temperature condition. These results indicate that the mutations in the BoPQL2 gene increased sensitivity to the low temperature of ornamental kale, thus affecting leaf margin coloration. This study lays the foundation for improving ornamental kale genotypes by editing the BoPQL2 gene. [ABSTRACT FROM AUTHOR]

Abstract Background Sex-related differences in human thermal and pain sensitivity are the subject of controversial discussion. The goal of this study in a large number of subjects was to investigate sex differences in thermal and thermal pain perception and the thermal grill illusion (TGI) as a phenomenon reflecting crosstalk between the thermoreceptive and nociceptive systems. The thermal grill illusion is a sensation of strong, but not necessarily painful, heat often preceded by transient cold upon skin contact with spatially interlaced innocuous warm and cool stimuli. Methods The TGI was studied in a group of 78 female and 58 male undergraduate students and was evoked by placing the palm of the right hand on the thermal grill (20/40 °C interleaved stimulus). Sex-related thermal perception was investigated by a retrospective analysis of thermal detection and thermal pain threshold data that had been measured in student laboratory courses over 5 years (776 female and 476 male undergraduate students) using the method of quantitative sensory testing (QST). To analyse correlations between thermal pain sensitivity and the TGI, thermal pain threshold and the TGI were determined in a group of 20 female and 20 male undergraduate students. Results The TGI was more pronounced in females than males. Females were more sensitive with respect to thermal detection and thermal pain thresholds. Independent of sex, thermal detection thresholds were dependent on the baseline temperature with a specific progression of an optimum curve for cold detection threshold versus baseline temperature. The distribution of cold pain thresholds was multi-modal and sex-dependent. The more pronounced TGI in females correlated with higher cold sensitivity and cold pain sensitivity in females than in males. Conclusions Our finding that thermal detection threshold not only differs between the sexes but is also dependent on the baseline temperature reveals a complex processing of “cold” and “warm” inputs in thermal perception. The results of the TGI experiment support the assumption that sex differences in cold-related thermoreception are responsible for sex differences in the TGI.

• Reserpine induces fibromyalgia-like pain symptoms via kinin B 1 and B 2 receptors. • Kinins and their receptors are involved in fibromyalgia-like pain symptoms. • Kinin receptors might represent a target for relieving fibromyalgia-like pain symptoms. Fibromyalgia is a disease characterised as generalised chronic primary pain that causes functional disability and a reduction in patients' quality of life, without specific pathophysiology or appropriate treatment. Previous studies have shown that kinins and their B 1 and B 2 receptors contribute to chronic painful conditions. Thus, we investigated the involvement of kinins and their B 1 and B 2 receptors in a fibromyalgia-like pain model induced by reserpine in mice. Nociceptive parameters (mechanical allodynia, cold sensitivity and overt nociception) and behaviours of burrowing, thigmotaxis, and forced swimming were evaluated after reserpine administration in mice. The role of kinin B 1 and B 2 receptors was investigated using knockout mice or pharmacological antagonism. The protein expression of kinin B 1 and B 2 receptors and the levels of bradykinin and monoamines were measured in the sciatic nerve, spinal cord and cerebral cortex of the animals. Knockout mice for the kinin B 1 and B 2 receptor reduced reserpine-induced mechanical allodynia. Antagonism of B 1 and B 2 receptors also reduced mechanical allodynia, cold sensitivity and overt nociception reserpine-induced. Reserpine altered thigmotaxis, forced swimming and burrowing behaviour in the animals; with the latter being reversed by antagonism of kinin B 1 receptor. Moreover, reserpine increased the protein expression of kinin B 1 and B 2 receptors and levels of kinin, as well as reduced the levels of monoamines in peripheral and central structures. Kinins and its B 1 and B 2 receptors are involved in fibromyalgia-like pain symptoms. B 1 or B 2 receptors might represent a potential target for the relief of fibromyalgia-like pain symptoms. [ABSTRACT FROM AUTHOR]

This study aimed to explore and describe the impact on patients with oxaliplatin-induced cold sensitivity in the early stages. An inductive design was used for this qualitative study, which included open-ended, and in-depth interviews with 18 cancer patients. Throughout the study, the authors followed the COREQ checklist. The interviews were audiorecorded and listened to multiple times. Observation notes were also recorded following each interview. Thematic analysis developed six main themes and 13 subthemes. The first theme concerns changing habits, including changes in fluid intake and clothing choice, changes in bathing and eating habits, and changes in caregiver roles. The second theme includes changes in daily routine behaviors that are perceived as difficulties with changing routines. The third theme is avoiding triggers; the fourth theme is anxiety about self-care. The fifth theme includes a subtheme of difficulty in contact. The final theme includes adaptation to life, caring responsibilities, changes in sexual functions, the performance of religious activities, and social activities This study provides an overview of the lived experiences of oxaliplatin-induced cold sensitivity among cancer patients. Patients faced fewer adverse events by avoiding initiators from the first treatment. They changed their eating and drinking habits owing to difficulties. The findings of this study can be used to better understand oxaliplatin-induced cold sensitivity, identify patients needs based on their experience, and develop interventions to improve patient outcomes. [ABSTRACT FROM AUTHOR]

We evaluated the efficacy and tolerability of Hachimi-jio-gan (HJG; 八味地黃丸 bā wèi dì huáng wán) and Gosha-jinki-gan (GJG; 濟生腎氣丸 jì shēng shèn qì wán), two traditional Japanese medicines, in 60 patients with lower urinary tract symptoms (LUTS) having cold sensitivity unresponsive to α1-blockers or antimuscarinic drugs. All patients received a mixture of HJG or GJG for 12 weeks in addition to α1-blockers or antimuscarinic drugs as add-on therapy. International Prostate Symptom Score, International Prostate Symptom Score–Quality of Life, Benign Prostatic Hyperplasia Impact Index, and the number of nocturnal voids were statistically much improved. However, there was no change in maximal urinary flow rate and post-void residual urine. Urinary 8-hydroxy-2-deoxyguanosine was statistically greatly improved from baseline after treatment in the HJG group compared to the GJG group. Adverse reactions were observed in 8.3% of patients, but all reactions were mild. Both HJG and GJG mixtures can serve as safe and effective potential therapeutic alternatives in patients with LUTS and cold sensitivity unresponsive to α1-blockers or antimuscarinic drugs. Additionally, HJG mixture was found to have anti-oxidative activity, and therefore further long-term clinical investigations are needed to examine its anti-aging effects in addition to its effect on urinary symptoms.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel that is activated by a variety of stimuli and acts as a nociceptor. Mouse and human TRPA1 exhibit different reactivity to some stimuli, including chemicals such as menthol as well as cold stimuli. The cold sensitivity of TRPA1 in mammalian species is controversial. Here, we analyzed the reactivity of heterologously expressed canine TRPA1 as well as the mouse and human orthologs to menthol or cold stimulation in Ca 2+ -imaging experiments. Canine and human TRPA1 exhibited a similar response to menthol, that is, activation in a concentration-dependent manner, even at the high concentration range in contrast to the mouse ortholog, which did not respond to high concentration of menthol. In addition, the response during the removal of menthol was different; mouse TRPA1-expressing cells exhibited a typical response with a rapid and clear increase in [Ca 2+ ] i ("off-response"), whereas [Ca 2+ ] i in human TRPA1-expressing cells was dramatically decreased by the washout of menthol and [Ca 2+ ] i in canine TRPA1-expressing cells was slightly decreased. Finally, canine TRPA1 as well as mouse and human TRPA1 were activated by cold stimulation (below 19-20°C). The sensitivity to cold stimulation differed between these species, that is, human TRPA1 activated at higher temperatures compared with the canine and mouse orthologs. All of the above responses were suppressed by the selective TRPA1 inhibitor HC-030031. Because the concentration-dependency and "off-response" of menthol as well as the cold sensitivity were not uniform among these species, studies of canine TRPA1 might be useful for understanding the species-specific functional properties of mammalian TRPA1.

We studied changes in cold hypersensitivity from 3 to 7 years following severe hand injuries. Data was collected using postal questionnaires 7 years after injury in 71 patients who had participated in a 3-year follow-up from the time of injury. There was no change in cold sensitivity measured using the McCabe Cold Sensitivity Severity scale (CSS) from 3 to 7 years after injury. However, there was a trend toward decreased severity measured using a five-level scale of self-reported cold hypersensitivity. Compared to the 3-year follow-up, fewer respondents rated their condition as severe and two patients had recovered from their cold hypersensitivity at the 7-year follow-up. Furthermore, 21 (30%) of the respondents stated a decrease in cold hypersensitivity during the last 2 years. Limitations in cold associated activities and the importance of being less limited in leisure activities (NRS 0-10) did not change between the two follow-ups. In conclusion, the CSS-scores did not change from 3 to 7 years after injury. Several patients experienced improvements in cold hypersensitivity, but few recovered completely from the condition. [ABSTRACT FROM AUTHOR]

Purpose: To identify factors associated with the reporting of cold sensitivity, by comparing cases to controls with regard to anthropometry, previous illnesses and injuries, as well as external exposures such as hand-arm vibration (HAV) and ambient cold.Methods: Through a questionnaire responded to by the general population, ages 18-70, living in Northern Sweden (N = 12,627), cold sensitivity cases (N = 502) and matched controls (N = 1004) were identified, and asked to respond to a second questionnaire focusing on different aspects of cold sensitivity as well as individual and external exposure factors suggested to be related to the condition. Conditional logistic regression analyses were performed to determine statistical significance.Results: In total, 997 out of 1506 study subjects answered the second questionnaire, yielding a response rate of 81.7%. In the multiple conditional logistic regression model, identified associated factors among cold sensitive cases were: frostbite affecting the hands (OR 10.3, 95% CI 5.5-19.3); rheumatic disease (OR 3.1, 95% CI 1.7-5.7); upper extremity nerve injury (OR 2.0, 95% CI 1.3-3.0); migraines (OR 2.4, 95% CI 1.3-4.3); and vascular disease (OR 1.9, 95% CI 1.2-2.9). A body mass index ≥ 25 was inversely related to reporting of cold sensitivity (0.4, 95% CI 0.3-0.6).Conclusions: Cold sensitivity was associated with both individual and external exposure factors. Being overweight was associated with a lower occurrence of cold sensitivity; and among the acquired conditions, both cold injuries, rheumatic diseases, nerve injuries, migraines and vascular diseases were associated with the reporting of cold sensitivity. [ABSTRACT FROM AUTHOR]

Cold intolerance after nerve injury can be severe and has been associated with high levels of pain and disability. This article provides an overview of the assessment and nonoperative management of cold-induced symptoms after peripheral nerve injury. A comprehensive evaluation should include both objective measures such as skin temperatures and subjective tools to assess the patient's perspective and impact of the symptoms. Management of the patient with cold intolerance remains challenging and should include adaptive strategies, warming interventions, and desensitization conditioning programs to minimize cold-induced pain and hyperresponses. [ABSTRACT FROM AUTHOR]