Heat-induced Damage Research Articles

Dodatek nano selena zmanjšuje od vročine povzročene oksidativne poškodbe v sejankah dateljeve palme s spremembami v rastlinskih hormonih in antioksidativni obrambi

Crops are destroyed by extreme heat, which also limits their growth and yield. The present study sought to determine whether selenium (0, 15, or 30 mg l-1) impacted ‘Barhee’ date palm seedling’s development under heat stress (in the field and canopy temperature). The growth parameters, chlorophyll and relative water content, ascorbic acid, catalase activity, and phytohormones in seedlings were reduced under heat stress. At the same time, ascorbate peroxidase activity, proline, phenols, malondialdehyde, hydrogen peroxide, and abscisic acid in seedlings increased. Enhancing growth features, chlorophyll content, relative water content, ascorbic acid, catalase activity, plant hormones, proline, phenols, and ascorbate peroxidase activity with exogenous nano-Selenium (15 mg l-1) reduced the negative impacts of heat stress. Date palm seedlings can be protected from high temperatures by using nano-selenium. Selenium reverses heat-induced oxidative damage by enhancing the antioxidative mechanism, improving reactive oxygen species scavenging, lowering lipid peroxidation, and modulating plant hormone levels.

Synergistic protective effects of 3,4-dihydroxyphenylglycol and hydroxytyrosol in male rats against induced heat stress-induced reproduction damage

Testicular heat stress disrupts spermiogenesis and damages testicular tissue. The study aims to assess 3,4-dihydroxyphenylglycol (DHPG) and hydroxytyrosol (HT) from olive oil as antioxidants to reduce heat-induced testicular damage. Seven groups of 35 male rats were used. Group I got normal saline. Group 2 had HS (43 °C for 20 min/day) and normal saline for 60 days. Groups 3–7 had HS and DHPG/HT doses (0.5 mg/kg DHPG, 1 mg/kg DHPG, 5 mg/kg HT, 0.5 mg/kg DHPG + 5 mg/kg HT, and 1 mg/kg DHPG + 5 mg/kg HT). The evaluation included tests on testicular tissue, sperm quality, oxidative status, gene activity, and fertility after 60 days. After DHPG and HT treatment, sperm motility, viability, and plasma membrane functionality, as well as levels of total antioxidant capacity (TAC), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT), and Bcl-2 gene expression, and in vivo fertility indexes increased. Meanwhile, abnormal morphology and DNA damage decreased, along with levels of glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA), and Bax, caspase-3, and caspase-9 gene expression, compared to the HS group. The study found that DHPG and HT have a more substantial synergistic effect when used together, improving reproductive health.

Pulsed Photothermal Therapy of Solid Tumors as a Precondition for Immunotherapy.

Photothermal therapy (PTT) refers to the use of plasmonic nanoparticles to convert electromagnetic radiation in the near infrared region to heat and kill tumor cells. Continuous wave lasers have been used clinically to induce PTT, but the treatment is associated with heat-induced tissue damage that limits usability. Here, the engineering and validation of a novel long-pulsed laser device able to induce selective and localized mild hyperthermia in tumors while reducing the heat affected zone and unwanted damage to surrounding tissue are reported. Long-pulsed PTT induces acute necrotic cell death in heat affected areas and the release of tumor associated antigens. This antigen release triggers maturation and stimulation of CD80/CD86 in dendritic cells in vivo that primes a cytotoxic T cell response. Accordingly, long-pulsed PTT enhances the therapeutic effects of immune checkpoint inhibition and increases survival of mice with bladder cancer. Combined, the data promote long-pulsed PTT as a safe and effective strategy for enhancing therapeutic responses to immune checkpoint inhibitors while minimizing unwanted tissue damage.

Exogenous 24-epibrassinolide (EBL) facilitates cell growth of Chlorella pyrenoidosa under high temperatures by enhancing the photosynthetic energy utilization and alleviating oxidative damage.

The microalga Chlorella pyrenoidosa is cultivated extensively for its constituents, which are of significant economic worth. Large-scale growth of C. pyrenoidosa in outdoor environments is subject to various stressors such as elevated temperature. The purpose of this study was to assess the protective effects of exogenous 24-epibrassinolide (EBL) on C. pyrenoidosa under high-temperature conditions. Compared to a temperature of 30°C, increasing the temperature to 43°C reduced the enzymatic capacity for carbon assimilation and resulted in the buildup of reactive oxygen species (ROS), thus reducing photosynthesis and proliferation. It was observed that exogenous EBL protected C. pyrenoidosa cells against high temperatures, with an optimal EBL concentration of 100 nM, resulting in enhanced capacity for photosynthetic carbon assimilation with a notable reduction in the imbalance between the absorption of light and energy used under high-temperature conditions. The addition of 100 nM EBL resulted in a 25.4% increase in cell density when exposed to elevated temperatures for 7 days. In addition, exogenous EBL reduced ROS production and increased the activities of critical antioxidant enzymes. This, in turn, mitigated heat-induced oxidative damage, resulting in advantageous outcomes in terms of cellular development and maintenance.

Treatment of Acute Wound Infections by Degradable Polymer Nanoparticle with a Synergistic Photothermal and Chemodynamic Strategy.

Mild-heat photothermal antibacterial therapy avoids heat-induced damage to normal tissues but causes bacterial tolerance. The use of photothermal therapy in synergy with chemodynamic therapy is expected to address this issue. Herein, two pseudo-conjugated polymers PM123 with photothermal units and PFc with ferrocene (Fc) units are designed to co-assemble with DSPE-mPEG2000 into nanoparticle NPM123/Fc. NPM123/Fc under 1064nm laser irradiation (NPM123/Fc+NIR-II) generates mild heat and additionally more toxic ∙OH from endogenous H2O2, displaying a strong synergistic photothermal and chemodynamic effect. NPM123/Fc+NIR-II gives >90% inhibition rates against MDR ESKAPE pathogens in vitro. Metabolomics analysis unveils that NPM123/Fc+NIR-II induces bacterial metabolic dysregulation including inhibited nucleic acid synthesis, disordered energy metabolism, enhanced oxidative stress, and elevated DNA damage. Further, NPM123/Fc+NIR-II possesses >90% bacteriostatic rates at infected wounds in mice, resulting in almost full recovery of infected wounds. Immunodetection and transcriptomics assays disclose that the therapeutic effect is mainly dependent on the inhibition of inflammatory reactions and the promotion of wound healing. What is more, thioketal bonds in NPM123/Fc are susceptible to ROS, making it degradable with highly favorable biosafety in vitro and in vivo. NPM123/Fc+NIR-II with a unique synergistic antibacterial strategy would be much less prone to select bacterial resistance and represent a promising antibiotics-alternative anti-infective measure.

Morin hydrate ameliorates heat-induced testicular impairment in a mouse model.

Heat stress is known to adversely affect testicular activity and manifest the pathogenesis of spermatogenesis. Morin hydrate is a plant-derived compound, which contains a wide range of biological activities. Thus, it is hypothesized that morin hydrate might have an ameliorative effect on heat-induced testicular impairment. There has not been any research on the impact of morin hydrate on heat-induced testicular damage. The experimental mice were divided into four groups, groups1 as the normal control group (CN), and the second which underwent heat stress (HS) by immersing the lower body for 15min in a thermostatically controlled water bath kept at 43°C (HS), and third and fourth heat-stressed followed by two different dosages of morin hydrate 10mg/kg (HSM10) and 100mg/kg (HSM100) for 14days. Morin hydrate treatment at 10mg/kg improved, circulating testosterone levels (increases 3βHSD), and oxidative stress along with improvement in the testis and caput and corpus epididymis histoarchitecture, however, both doses of morin hydrate improved sperm parameters. Morin hydrate treatment significantly increases germ cell proliferation, (GCNA, BrdU staining), expression of Bcl2 and decreases expression of active caspase 3. Heat stress also decreased the expression of AR, ER- α, and ER-β, and Morin hydrate treatment increased the expression of these markers in the 10mg/kg treatment group. Morin hydrate ameliorates heat-induced testicular impairment modulating testosterone synthesis, germ cell proliferation, and oxidative stress. These effects could be manifested by regulating androgen and estrogen receptors. However, the two doses showed differential effects of some parameters, which requires further investigations.

Multivariate Analysis Compares and Evaluates Heat Tolerance of Potato Germplasm.

High temperature is the most important environmental factor limiting potato (Solanum tuberosum L.) yield. The tuber yield has been used to evaluate the heat tolerance of some potato cultivars, but potato yield was closely correlated with the maturation period. Therefore, it is necessary to employ different parameters to comprehensively analyze and evaluate potato tolerance to heat stress. This study aimed to investigate physiologic changes during growth and development, and develop accurate heat tolerance evaluation methods of potato cultivars under heat stress. About 93 cultivars (including foreign elite lines, local landraces and cultivars) were screened using an in vitro tuber-inducing system (continuous darkness and 8% sucrose in the culture medium) under heat stress (30 °C) and normal (22 °C) conditions for 30 days. The tuber yield and number decreased significantly under heat stress compared to the control. A total of 42 cultivars were initially selected depending on tuber formation, after in vitro screening, further testing of selected cultivars was conducted in ex vitro conditions. The screened cultivars were further exposed to heat stress (35 °C/28 °C, day/night) for 60 days. Heat stress led to an increase in the plant height growth rate, fourth internode growth rate, and membrane damage, and due to heat-induced damage to chloroplasts, decrease in chlorophyll biosynthesis and photosynthetic efficiency. Three principal components were extracted by principal component analysis. Correlation and regression analysis showed that heat tolerance is positively correlated with the plant height growth rate, fourth internode growth rate, the content of chlorophyll b, photosynthetic rate, stomatal conductance, transpiration rate, tuber number, and tuber yield, and negatively correlated with the cell membrane injury level. The nine traits are accurate and representative indicators for evaluating potato tolerance to heat stress and could determine a relatively high mean forecast accuracy of 100.0% for the comprehensive evaluation value. Through cluster analysis and screening, cultivar FA, D73, and C132 had the highest heat comprehensive evaluation value, which could be further selected as heat-resistant varieties. This study provides insights into the different physiological mechanisms and accurate evaluation methods of potato cultivars under heat stress, which could be valuable for further research and breeding.

Investigation of heat-dissipation structures in resonant tunneling diodes and their characteristics on terahertz oscillators

This study investigates the heat dissipation structures for resonant tunneling diodes (RTDs). The n+-InGaAs conductive layer beneath the RTD double-barrier layer, which possesses low thermal conductivity and disrupting heat dissipation, has been replaced with n+-InP, which has high thermal conductivity. We manufactured simple RTD mesa structures with varying areas to analyze the impact of heat dissipation. Additionally, we conducted a study to explore the relationship between mesa area and power consumption at the RTD mesa under current–voltage measurements. The results clearly indicate that the proposed structure, incorporating an n+-InP layer, can function over an area twice as large without experiencing heat-induced destruction. By integrating this proposed structure, we successfully fabricated terahertz oscillators equipped with rectangular-cavity resonators. These oscillators achieved relatively high output power, approximately 0.2 mW was achieved at a frequency of 0.53 THz, all without any heat-induced damage, even within a large-area RTD device.

Mitigating Heat-Induced Sperm Damage and Testicular Tissue Abnormalities: The Protective Role of Radiofrequency Radiation from Wi-Fi Routers in Rodent Models

Mitigating Heat-Induced Sperm Damage and Testicular Tissue Abnormalities: The Protective Role of Radiofrequency Radiation from Wi-Fi Routers in Rodent Models

Heat-shock proteins, oxidative stress, and antioxidants in one-humped camels.

One-humped camels (Camelus dromedarius) exhibit remarkable adaptability to harsh desert environments through various physiological adaptations. This study aimed to assess variations and reference values of Heat-shock proteins (HSPs), physiological parameters, mineral concentrations, total antioxidant capacity (TAC), and malondialdehyde (MDA) in 90 healthy female one-humped camels from Zabol's outskirts in Iran. The objective was to understand how these camels adapt to heat stress. Blood samples were collected from camels located at five geographical regions and analyzed using standard kits and methods. Reference intervals for heat-shock protein 30 (HSP30), heat-shock protein 40 (HSP40), heat-shock protein 70 (HSP70), and heat-shock protein 90 (HSP90) were determined using the reference value advisor (RVA). The study found significant differences among different regions for HSPs (P < 0.05), MDA (P = 0.021), and TAC (P = 0.042) levels, indicating variations in adaptation mechanisms. However, no notable differences were observed for other measured parameters between these regions. There were no significant differences observed in the evaluated parameters between the age categories of > 36 months and < 36 months. The positive correlation between HSPs and MDA levels (ranging from 0.754 to 0.884) suggests that the synthesis of HSPs is triggered as a response to oxidative stress caused by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses. This oxidative stress, in turn, is a consequence of thermal stress. Additionally, the study reveals a negative association between TAC and HSP levels (ranging from - 0.660 to - 0.820), emphasizing the role of antioxidants in mitigating heat stress. The findings of this research offer compelling support for the critical role that HSPs play in protecting cells from heat-induced damage. Additionally, the presence of higher levels of HSPs in regions with more severe climate conditions serves as evidence of camels' adaptation to heat stress. These findings emphasize the substantial impact of environmental factors on HSP production and further reinforce the crucial role of HSPs in bolstering the resilience of camels. Further research is needed to explore HSP expression and mechanisms to effectively manage and enhance camel resilience in extreme temperatures.

Overexpression of GmPIF4b affects morpho-physiological traits to reduce heat-induced grain loss in soybean

Heat waves associated with climate change seriously threaten crop productivity. Crop seed yield depends on the success of reproduction. However, reproductive development is most vulnerable to heat stress conditions. Perception of heat and its conversion into cellular signals is a complex process. The basic helix loop helix (bHLH) transcription factor, Phytochrome Interacting Factor 4 (PIF4), plays a significant role in this process. However, studies on PIF4- mediated impacts on crop grain yield at a higher temperature are lacking. We investigated the overexpression of GmPIF4b in soybean to alleviate heat-induced damage and yield using a transgenic approach. Our results showed that under high-temperature conditions (38°C/28°C), overexpressing soybeans plants had higher chlorophyll a and b, and lower proline accumulation compared to WT. Further, overexpression of GmPIF4b improved pollen viability under heat stress and reduced heat-induced structural abnormalities in the male and female reproductive organs. Consequently, the transgenic plants produced higher pods and seeds per plant at high temperatures. Quantitative RT-PCR analysis showed that the overexpressing GmPIF4b soybeans had higher transcripts of heat shock factor, GmHSF-34, and heat-shock protein, GmHSP90A2. Collectively, our results suggest that GmPIF4b regulates multiple morpho-physiological traits for better yield under warmer climatic conditions.

Effect of translucency and absorbance of composite on temperature change during photopolymerization.

This study investigated the effect of translucency and absorbance of conventional (FiltekTM-Z350-XT) and bulk-fill (Tetric®-N-Ceram) composites on temperature change during photopolymerization, using a non-contact infrared sensor. Three shades from each composite were selected to prepare disk-shaped specimens (n=3), which then photopolymerized with LED-light for 20 s. A second light exposure was performed on the photopolymerized specimens. The first peak temperature rise during composite photopolymerization (ΔTtotal), second peak temperature rise by the light (ΔTlight), and net peak temperature rise by composite curing heat (ΔTcomposite) were obtained from the temperature change vs. time curve. The changes in ΔTtotal and ΔTlight with varying the composite shade were greater than those in ΔTcomposite. The conventional composite showed higher ΔTtotal and ΔTlight than bulk-fill composite. ΔTtotal and ΔTlight increased as translucency parameter decreased, and absorbance increased. The potential risk for heat-induced pulpal damage should be considered when selecting a composite shade, especially for deep cavities.

Influence of different heat transfer models on therapeutic temperature prediction and heat-induced damage during magnetic hyperthermia

Magnetic hyperthermia regulates the therapeutic temperature within a specific range to damage malignant cells after exposing the magnetic nanoparticles inside tumor tissue to an alternating magnetic field. The therapeutic temperature of living tissues can be generally predicted using Pennes' bio-heat equation after ignoring both the inhomogeneity of biological structure and the microstructural responses. Although various of the bio-heat transfer models proposed in literature fix these shortages, there is still a lack of a comprehensive report on investigating the discrepancy for different models when applied in the magnetic hyperthermia context. This study compares four different bio-heat equations in terms of the therapeutic temperature distribution and the heat-induced damage situation for a proposed geometric model, which is established based on computed tomography images of a tumor bearing mouse. The therapeutic temperature is also used as an index to evaluate the effect of two key relaxation times for the phase lag behavior on bio-heat transfer. Moreover, this work evaluates the effects of two blood perfusion rates on both the treatment temperature and the cumulative equivalent heating minutes at 43 °C. Numerical analysis results reveal that relaxation times for phase-lag behavior as well as the porosity for living tissues directly affect the therapeutic temperature variation and ultimately the thermal damage for the malignant tissue during magnetic hyperthermia. The dual-phase-lag equation can be converted into Pennes’ equation and simple-phase-lag equation when relaxation times meet specific conditions during the process of heat transfer. In addition, different blood perfusion rates can result in an amplitude discrepancy for treatment temperature, but this parameter does not change the characteristics of thermal propagation during therapy.

Heat-induced leaf epidermal cell damage triggers autophagy-mediated mesophyll cell expansion in Arabidopsis

Heat-induced leaf epidermal cell damage triggers autophagy-mediated mesophyll cell expansion in Arabidopsis

Endotherms trade body temperature regulation for the stress response.

Responding to perceived threats is energetically expensive and can require animals to curtail somatic repair, immunity, and even reproduction to balance energy ledgers. In birds and mammals, energetic demands of thermoregulation are often immense, yet whether homeostatic body temperatures are also compromised to aid the stress response is not known. Using data sourced from over 60 years of literature and 24 endotherm species, we show that exposure to non-thermal challenges (e.g. human interaction, social threats) caused body temperatures to decrease in the cold and increase in the warmth, but particularly when species-specific costs of thermoregulation were high and surplus energy low. Biophysical models revealed that allowing body temperature to change in this way liberated up to 24% (mean = 5%) of resting energy expenditure for use towards coping. While useful to avoid energetic overload, these responses nevertheless heighten risks of cold- or heat-induced damage, particularly when coincident with cold- or heatwaves.

Chlorogenic acid ameliorates the heat stress-induced impairment of porcine Sertoli cells by suppressing oxidative stress and apoptosis

Sertoli cells are an important type of somatic cell in the testis that are in direct contact with spermatogonia in vivo and play an important role in the process of spermatogenesis. Chlorogenic acid (CGA) plays a pivotal role in the regulation of the mammalian cell heat stress response. For example, CGA treatment protects porcine oocytes from heat stress-induced apoptosis and prevents reduced embryo quality. However, the role of CGA treatment in protecting porcine testicular Sertoli cells against heat-induced damage has rarely been studied. This study aimed to identify the protective effects of CGA on oxidative stress and apoptosis in Sertoli cells under heat stress. The present results demonstrated that the addition of CGA significantly inhibited the accumulation of reactive oxygen species (ROS) and apoptosis in Sertoli cells induced by heat stress and decreased the expression of CASP3 protein and the BAX/BCL-2 protein ratio. CGA pretreatment also prevented the heat stress-induced reductions in the mitochondrial membrane potential, PCNA protein expression, and SOD and CAT activities. Moreover, CGA treatment reversed S phase cell cycle arrest and increased the HSP70 protein expression levels. Overall, these results suggest that oxidative damage participates in the inhibition of the proliferation of Sertoli cells and the increase in their apoptosis induced by heat stress, and the protective effects of CGA treatment on Sertoli cells under heat stress provide a theoretical basis for preventing heat stress injury in animals.

Systematic thermal analysis of the Arabidopsis proteome: Thermal tolerance, organization, and evolution.

Understanding the thermal stability of the plant proteome in the context of the native cellular environment would aid the design of crops with high thermal tolerance, but only limited such data are available. Here, we applied quantitative mass spectrometry to profile the thermal stability of the Arabidopsis proteome and identify thermo-sensitive and thermo-resilient protein networks in Arabidopsis, providing a basis for understanding heat-induced damage. We also show that the similarities of the protein-melting curves can be used as a proxy to evaluate system-wide protein-protein interactions in non-engineered plants and enable the identification of transient interactions exhibited by metabolons in the context of the cellular environment. Finally, we report a systematic comparison of the thermal stability of paralogs in Arabidopsis to aid the investigation and understanding of gene duplication and protein evolution. Taken together, our results could have broad implications for the fields of plant thermal tolerance, plant protein assemblies, and evolution.

Effect of testicular degeneration on expression of sperm protein at 22kDa in stallions.

Sperm protein at 22kDa has been associated with fertility. The objectives of this study were to determine (1) the localization pattern of SP22 on ejaculated and caudal epididymal equine spermatozoa and in epididymal fluid, and to (2) characterize SP22 protein and mRNA expression in testicular and epididymal tissues in response to heat-induced testicular degeneration. Semen was collected before and after hemi-castration, as well as prior to and following insulation of the remaining testes, and tissue specimens were collected for analysis. Histopathology confirmed degeneration in insulated testes. Ejaculated and epididymal spermatozoa from samples collected prior to insulation of the testicles had a predominant staining pattern of SP22 over the equatorial region. However, the equatorial pattern in the pre-insulation epididymal semen samples was significantly lower than in the pre-insulation ejaculated semen samples (68±3, 81±2.6, respectively). Ejaculated and epididymal samples collected after insulation of the testicles showed a complete loss of staining as the predominant pattern. Western blot analysis verified the presence of SP22 on fresh ejaculated spermatozoa prior to and following heat-induced degeneration, on epididymal spermatozoa after testicular insulation, and in testicular and epididymal tissues. Heat insulation significantly reduced messenger RNA expression in the head of the epididymis and testicular tissues. Immunohistochemistry of the testicular and epididymal tissues pre-heating showed considerably weaker staining than the same tissues post-heating. It was concluded that heat-induced testicular damage causes both loss and relocation of SP22 on the sperm membrane. Future studies are warranted to determine the diagnostic value of these findings.

Whole genome transcriptomic reveals heat stroke molecular signatures in humans.

An evolutionary heat shock response (HSR) protects most living species, including humans, from heat-induced macromolecular damage. However, its role in the pathogenesis of heat stroke is unknown. We examined the whole genome transcriptome in peripheral blood mononuclear cells of a cohort of subjects exposed to the same high environmental heat conditions, who developed heat stroke (n=19) versus those who did not (n=19). Patients with heat stroke had a mean rectal temperature at admission of 41.7 ±0.8°C, and eight were in deep coma (Glasgow Coma Score=3). The transcriptome showed that genes involved in more than half of the entire chaperome were differentially expressed relative to heat stress control. These include the heat shock protein, cochaperone, and chaperonin genes, indicating a robust HSR. Differentially expressed genes also encoded proteins related to unfolded protein response, DNA repair, energy metabolism, oxidative stress, and immunity. The analysis predicted perturbations of the proteome network and energy production. Cooling therapy attenuated these alterations without complete restoration of homeostasis. We validated the significantly expressed genes by a real-time polymerase chain reaction. The findings reveal the molecular signature of heat stroke. They also suggested that a powerful HSR may not be sufficient to protect against heat injury. The overwhelming proteotoxicity and energy failure could play a pathogenic role. KEY POINTS: Most living species, including humans, have inherent heat stress response (HSR) that shields them against heat-induced macromolecular damage. The role of the HSR in subjects exposed to environmental heat who progressed to heat stroke versus those that did not is unknown. Our findings suggest that heat stroke induces a broad and robust HSR of nearly half of the total heat shock proteins, cochaperones, and chaperonin genes. Heat stroke patients exhibited inhibition of genes involved in energy production, including oxidative phosphorylation and ATP production. Significant enrichment of neurodegenerative pathways, including amyloid processing signalling, the Huntington's and Parkinson's disease signalling suggestive of brain proteotoxicity was noted. The data suggests that more than a powerful HSR may be required to protect against heat stroke. Overwhelming proteotoxicity and energy failure might contribute to its pathogenesis.

Erythema Ab Igne: A Clinical Review

Erythema ab igne (EAI) is a skin condition caused by chronic heat-induced damage. The rash usually progresses over weeks to months of repeated or prolonged exposure to subthreshold-intensity infrared radiation that is not hot enough to cause a burn. The diagnosis is clinical based on patient history and physical examination, but a biopsy can reveal dilated vasculature, interface dermatitis, and pigment incontinence. Erythema ab igne initially was described in association with patients cooking over wood-fire stoves but has been shown over the decades to have a variety of causes. Herein, we describe various etiologies of EAI, including new heat-producing technologies, cultural practices, psychiatric illnesses, and even iatrogenic causes. However, the cause most commonly is application of heat for treatment of chronic pain, which may be a diagnostic clue for an underlying chronic illness. Although there are no current US Food and Drug Administration-approved therapies for treatment of EAI hyperpigmentation, the prognosis is excellent because removal of the heat source often will result in spontaneous resolution over time. Finally, chronic EAI rarely has been reported to evolve into squamous cell carcinoma, poorly differentiated carcinoma, cutaneous marginal zone lymphoma, and even Merkel cell carcinoma.