Total ice content and lipid saturation determine adipose tissue cryolipolysis by injection of ice-slurry.

OBJECTIVES: Cryolipolysis uses tissue cooling to solidify lipids, preferentially damaging lipid-rich cells. Topical cooling is popular for the reduction of local subcutaneous fat. Injection of biocompatible ice-slurry is a recently introduced alternative. We developed and verified a quantitative model that simulates the heat exchange and phase changes involved, offering insights into ice-slurry injection for treating subcutaneous fat. METHODS: Finite element method was used to model the spatial and temporal progression of heat transfer between adipose tissue and injected ice-slurry, estimating dose-response relationships between properties of the slurry and size of tissue affected by cryolipolysis. Phase changes of both slurry and adipose tissue lipids were considered. An in vivo swine model was used to validate the numerical solutions. Oils with different lipid compositions were exposed to ice-slurry in vitro to evaluate the effects of lipid freezing temperature. Microscopy and nuclear magnetic resonance (NMR) were performed to detect lipid phase changes. RESULTS: A ball of granular ice was deposited at the injection site in subcutaneous fat. Total injected ice content determines both the effective cooling region of tissue, and the duration of tissue cooling. Water's high latent heat of fusion enables tissue cooling long after slurry injection. Slurry temperature affects the rate of tissue cooling. In swine, when 30 ml slurry injection at -3.5°C was compared to 15 ml slurry injection at -4.8°C (both with the same total ice content), the latter led to almost twice faster tissue cooling. NMR showed a large decrease in diffusion upon lipid crystallization; saturated lipids with higher freezing temperatures were more susceptible to solidification after ice-slurry injection. CONCLUSIONS: Total injected ice content determines both the volume of tissue treated by cryolipolysis and the cooling duration after slurry injection, while slurry temperature affects the cooling rate. Lipid saturation, which varies with diet and anatomic location, also has an important influence.

Injectable ice slurry for reducing pericardial adipose tissue.

OBJECTIVES: Excess pericardial adipose tissue (PAT) is associated with a higher risk of cardiovascular diseases. Currently, available methods for reducing PAT volume include weight loss through diet and exercise, weight loss with medications, and bariatric surgery. However, these methods are all limited by low patient compliance to maintain the results. We have developed an injectable ice slurry that could selectively target and reduce subcutaneous adipose tissue volume. The aim of this study was to investigate the feasibility and safety of using injectable slurry to selectively reduce PAT volume in a preclinical large animal model. METHODS: PAT in Yucatan swine was injected with slurry or room temperature control solution. All animals were imaged with baseline chest computed tomography (CT) before slurry injection and at 2 months after injection to quantify PAT volume. Specimens from injected and noninjected PAT were harvested for histology. RESULTS: Slurry treatment of PAT was well tolerated in all animals. Slurry-induced selective cryolipolysis in treated PAT. CT imaging showed decrease in PAT volume in treated area at 8 weeks posttreatment compared to baseline, that was significantly different from control solution treated group (median [range]: -29.66 [-35.07 to -27.92]% vs. -1.50 [-11.69 to 8.69]% in control animals respectively, p < 0.05). CONCLUSIONS: This study demonstrated that slurry injection into PAT is feasible in a large animal model. Slurry injection was safe and effective in inducing selective cryolipolysis in PAT and reducing PAT volume. Slurry reduction of PAT could potentially serve as a novel treatment for cardiovascular diseases.

IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation.

Chronic inflammation's tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD. Mice lacking IL-33 were protected from chronic ACD and its skin cancer sequela compared with wild-type controls (P = 0.0002). IL-33's direct signaling onto Tregs was required for the development of the tumor-promoting immune environment in the skin. IL-33-Treg signaling was also required for chronic colitis and its associated colorectal cancer development in a colitis model (P < 0.0001). Significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases. Our findings elucidate the role of the IL-33/Treg axis in creating a tumor-promoting immune environment in chronic inflammatory diseases and suggest therapeutic targets for cancer prevention and treatment in high-risk patients.

Neural Selective Cryoneurolysis with Ice Slurry Injection in a Rat Model.

BACKGROUND: Postoperative pain caused by trauma to nerves and tissue around the surgical site is a major problem. Perioperative steps to reduce postoperative pain include local anesthetics and opioids, the latter of which are addictive and have contributed to the opioid epidemic. Cryoneurolysis is a nonopioid and long-lasting treatment for reducing postoperative pain. However, current methods of cryoneurolysis are invasive, technically demanding, and are not tissue-selective. This project aims to determine whether ice slurry can be used as a novel, injectable, drug-free, and tissue-selective method of cryoneurolysis and resulting analgesia. METHODS: The authors developed an injectable and selective method of cryoneurolysis using biocompatible ice slurry, using rat sciatic nerve to investigate the effect of slurry injection on the structure and function of the nerve. Sixty-two naïve, male Sprague-Dawley rats were used in this study. Advanced Coherent anti-Stokes Raman Scattering microscopy, light, and fluorescent microscopy imaging were used at baseline and at various time points after treatment for evaluation and quantification of myelin sheath and axon structural integrity. Validated motor and sensory testing were used for evaluating the sciatic nerve function in response to ice slurry treatment. RESULTS: Ice slurry injection can selectively target the rat sciatic nerve. Being injectable, it can infiltrate around the nerve. The authors demonstrate that a single injection is safe and selective for reversibly disrupting the myelin sheaths and axon density, with complete structural recovery by day 112. This leads to decreased nocifensive function for up to 60 days, with complete recovery by day 112. There was up to median [interquartile range]: 68% [60 to 94%] reduction in mechanical pain response after treatment. CONCLUSIONS: Ice slurry injection selectively targets the rat sciatic nerve, causing no damage to surrounding tissue. Injection of ice slurry around the rat sciatic nerve induced decreased nociceptive response from the baseline through neural selective cryoneurolysis.

Injectable slurry for selective destruction of neck adipose tissue in New Zealand obese mouse model.

PURPOSE: Increased neck circumference is a major risk factor for obstructive sleep apnea (OSA). New data suggest that increased adipose tissue in the neck may be a contributory cause of OSA. The aim of this study was to investigate safety and efficacy of a recently developed injectable ice slurry in selective reduction of neck adipose tissue in a mouse model. METHODS: We used the New Zealand obese mice that have increased volume of anterior neck fat, and are commonly used in OSA studies. MRI imaging was used to measure changes in fat tissue volume. RESULTS: Thirty animals were used in this study. Volumetric measurements in MRI images showed thatchanges in anterior neck adipose tissue volume from baseline in treated mice was significantly different in comparison with the control group (-1.09/kg ± 0.33/kg vs 0.68/kg ± 0.37/kg; p < 0.01 by two-tailed Student's t test). Histological analysis of samples from the treated area of the neck did not show scarring or damage to the surrounding tissues. CONCLUSIONS: Injection of ice slurry safely, effectively, and selectively reduces upper airway fat in New Zealand obese mice without scarring or damage to surrounding tissue. Our results suggest that slurry injection may be a novel and minimally invasive method of removing neck adipose tissue. This intervention should be further investigated to determine its suitability for treatment of OSA.

Assessment of rosacea severity: A review of evaluation methods used in clinical trials.

BACKGROUND: Novel rosacea treatments are needed. Assessment methodologies for clinical trials of rosacea treatments are not standardized and are relatively inadequate. To determine the efficacy of new treatments, a valid and reliable assessment methodology is needed. OBJECTIVE: We sought to determine the assessment methodologies used in clinical trials for rosacea treatments, to demonstrate the need for a valid and reliable assessment tool, and to describe the relevant properties of such a tool. METHODS: PubMed and MEDLINE were searched for clinical trials of rosacea treatments since January 1, 1985. RESULTS: In all, 32 clinical trials met inclusion criteria. Assessment methodologies were highly variable, and standardized assessment methodologies were used in only 3 studies. The various manifestations of rosacea were assessed inconsistently. LIMITATIONS: Eighteen articles could not be included as a result of lack of access to the full text. CONCLUSIONS: The diverse methodologies make the assessment of novel treatments and comparison of treatments difficult. A valid and reliable assessment tool is needed to properly assess novel treatments to improve the management of rosacea.

Sunscreens: Misconceptions and Misinformation.

Over the past 70 years, sunscreens have evolved from beach products designed to prevent sunburn to more cosmetically elegant skincare products intended to protect against multiple long-term adverse consequences of characteristically low-intensity daily UV and visible light exposure. Sunscreen testing and labeling intended to quantify such protection are unfortunately often misunderstood by users and have also led to illegal misleading and potentially dangerous industry practices. Changes in regulatory requirements, better policing, and more informative sunscreen labeling would benefit users and their physician advisors.

Cryoneurolysis with Injectable Ice Slurry Modulates Mechanical Skin Pain.

Cutaneous pain is a common symptom of skin disease, and available therapies are inadequate. We developed a neural selective and injectable method of cryoneurolysis with ice slurry, which leads to a long-lasting decrease in mechanical pain. The aim of this study is to determine whether slurry injection reduces cutaneous pain without inducing the side effects associated with conventional cryoneurolysis. Using the rat sciatic nerve, we examined the effects of slurry on nerve structure and function in comparison with the effects of a Food and Drug Administration‒approved cryoneurolysis device (Iovera). Coherent anti-Stokes Raman scattering microscopy and immunofluorescence staining were used to investigate histological effects on the sciatic nerve and on downstream cutaneous nerve fibers. Complete Freund's Adjuvant model of cutaneous pain was used to study the effect of the slurry on reducing pain. Structural changes in myelin induced by slurry were comparable with those induced by Iovera, which uses much colder temperatures. Compared with that of Iovera, the decrease in mechanical pain due to slurry was less profound but lasted longer without signs of dysesthesia. Slurry did not cause a reduction of epidermal nerve fibers or a change in thermal pain sensitivity. Slurry-treated rats showed reduced cutaneous mechanical pain in response to Complete Freund's Adjuvant. Slurry injection can be used to successfully reduce cutaneous pain without causing dysesthesia.

Selective reduction of visceral adipose tissue with injectable ice slurry.

Reduction in visceral adipose tissue (VAT) mass reduces body weight and metabolic disease risk in obese patients. However surgical removal of VAT is highly invasive and thus not clinically feasible. We developed an injectable ice slurry for selective reduction of adipose tissue through cryolipolysis. The aim of this study was to investigate safety, feasibility and mechanism of ice slurry-induced cryolipolysis of VAT. Perigonadal VAT in diet-induced obese mice and rats was subjected to slurry or sham treatment. Body weight and blood chemistry were monitored for 56 days post-treatment. Histological analysis and molecular studies were performed to elucidate mechanisms of fat reduction. Treatment of VAT was well tolerated in all animals. Slurry induced adipocyte cell death via selective cryolipolysis; significant weight loss was noted at day 21 post-treatment. RNA sequencing from treated VAT samples showed increased expression of genes involved in inflammation, immune response, collagen biosynthesis and wound healing, and decreased expression of adipokines. This study demonstrates that slurry treatment is safe and effective in inducing cryolipolysis of VAT and subsequent weight loss in mice. Ice slurry is promising as a minimally-invasive treatment to reduce visceral adipose tissue.

Fast-acting and injectable cryoneurolysis device.

Cryoneurolysis is an opioid-sparing therapy for long-lasting and reversible reduction of pain. We developed a nerve-selective method for cryoneurolysis by local injection of ice-slurry (- 5 to - 6 °C) that induced decrease in nocifensive response starting from about a week after treatment and lasting up to 8 weeks. In this study, we test the hypothesis that injection of colder slurry leads to faster onset of analgesia. Colder slurry (- 9ºC) was injected around the rat sciatic nerve to induce cryoneurolysis. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on surrounding tissues. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths. Functional tests were used to assess changes in sensory and motor function in the treated hind paw. No inflammation or scarring was detected in surrounding skin and muscle tissues at day 7 post slurry injection. Functional tests showed rapid onset reduction in mechanical pain sensitivity starting from day 1 and lasting up to day 98. CARS imaging demonstrated disintegration of myelin sheaths post treatment followed by complete recovery of nerve structure by day 140. In this study we showed that colder slurry (- 9 °C) produces more rapid onset and longer duration of analgesia, while remaining nerve-selective.

Full Recovery after Multiple Treatments with Injectable Ice Slurry.

Background: Cryoneurolysis uses tissue cooling as an opioid-sparing, long-lasting treatment for peripheral nerve pain. A nerve-selective method for cryoneurolysis by local injection of ice-slurry was developed to allow cryoneurolysis to be performed with a standard needle and syringe, similar to peripheral nerve blocks. Since the treatment of patients with chronic pain may require repeated injections, we investigated the safety and tolerance of repeated treatments in a rat model. Methods: Three repeated ice-slurry treatments, given 6 weeks apart were performed around the rat sciatic nerve. Nerve and surrounding tissues were collected up to 4 months after the third treatment for analysis. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths and axon structure. Immunofluorescence (IF) staining was used to study effects on axon density. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on sciatic nerve and surrounding tissue. Results: Histologic and CARS image analysis of nerve tissue collected months after three injections demonstrated recovery of nerve structure, myelin organization and axon density to baseline levels, without any residual inflammation, scarring or neuroma formation. No inflammation or scarring was detected in surrounding skin and muscle tissues. Conclusion: Repeated ice-slurry injections cause temporary, nerve-selective and reversible changes in the peripheral nerve. There was no histologic damage to surrounding skin and muscle tissues. Repeated treatments with injectable ice-slurry for cryoneurolysis appear to be safe and well tolerated. Clinical studies for patients with chronic pain are warranted.

Subcutaneous Fat Reduction with Injected Ice Slurry.

BACKGROUND: Cryolipolysis is a noninvasive method for removal of subcutaneous fat for body contouring. Conventional cryolipolysis with topical cooling requires extracting heat from subcutaneous fat by conduction across the skin, thus limiting the amount and the location of the fat removed. The authors hypothesized that local injection of a physiological ice slurry directly into target adipose tissue would lead to more efficient and effective cryolipolysis. METHODS: Injectable slurries containing 20 percent and 40 percent ice content were made using common parenteral agents (normal saline and glycerol), then locally injected into the subcutaneous fat of swine. Ultrasound imaging, photography, histological, and gross tissue responses were monitored before and periodically up to 8 weeks after injection. RESULTS: Fat loss occurred gradually over several weeks following a single ice slurry injection. There was an obvious and significant 55 ± 6 percent reduction in adipose tissue thickness compared with control sites injected with the same volume of melted slurry (p < 0.001, t test). The amount of fat loss correlated with the total volume of ice injected. There was no scarring or damage to surrounding tissue. CONCLUSION: Physiological ice slurry injection is a promising new strategy for selective and nonsurgical fat removal.

Chronic Inflammation Promotes Skin Carcinogenesis in Cancer-Prone Discoid Lupus Erythematosus.

High-risk skin cancer is a rare, but severe, complication associated with discoid lupus erythematosus (DLE). Chronic scar, inflammation, UVR, and immunosuppressive medications are proposed explanations for this heightened skin cancer risk; however, the exact mechanism driving skin carcinogenesis in DLE is unknown. The distinct co-localization of multiple independent skin cancers with areas of active inflammation in two DLE patients followed over 8 years strongly suggested that lupus inflammation promotes skin carcinogenesis in DLE. To investigate this clinical observation, we subjected lupus-prone MRL/lpr and control (MRL/n) mice to a skin carcinogenesis protocol. Skin tumors developed preferentially within the cutaneous lupus inflammation without scarring in MRL/lpr mice (P < 0.01). The inflammation in MRL/lpr skin was characterized by the accumulation of regulatory T cells, mast cells, M2 macrophages, and markedly elevated transforming growth factor-ß1 and IL-6 levels, which have been linked to tumor promotion. Tacrolimus treatment reduced skin inflammation and blocked cancer development in MRL/lpr mice (P = 0.0195). A similar tumor-promoting immune environment was detected in SCCs and the perilesional skin of cancer-prone DLE patients. Therefore, discoid lupus inflammation promotes skin cancer in high-risk DLE patients, and blocking the inflammation may be critical for preventing this life-threatening complication of DLE.

Validity and Reliability of a Rosacea Self-Assessment Tool.

The lack of validated rosacea assessment tools is a hurdle in assessing rosacea severity. This article discusses a valid and reliable rosacea severity self-assessment tool (RSAT) to measure rosacea severity. To determine test-retest validity, participants completed the self-assessment twice. A blinded physician graded the participant's disease severity with the Investigator Global Severity (IGS) score. Pearson correlations were used to assess the relationship between the self-assessment measure and the IGS. Test-retest RSAT measurements were correlated. The RSAT represents a valid and reliable tool. This tool may facilitate determination of rosacea severity in survey research studies.

New developments in the treatment of rosacea - role of once-daily ivermectin cream.

Rosacea is a chronic dermatological disorder with a variety of clinical manifestations localized largely to the central face. The unclear etiology of rosacea fosters therapeutic difficulty; however, subtle clinical improvement with pharmacologic treatments of various drug categories suggests a multifactorial etiology of the disease. Factors that may contribute to disease pathogenesis include immune abnormality, vascular abnormality, neurogenic dysregulation, presence of cutaneous microorganisms, UV damage, and skin barrier dysfunction. The role of ivermectin in the treatment of rosacea may be as an anti-inflammatory and anti-parasitic agent targeting Demodex mites. In comparing topical ivermectin and metronidazole, ivermectin was more effective; this treatment modality boasted more improved quality of life, reduced lesion counts, and more favorable participant and physician assessment of disease severity. Patients who received ivermectin 1% cream had an acceptable safety profile. Ivermectin is efficacious in decreasing inflammatory lesion counts and erythema.

Interventions to increase adherence to acne treatment.

BACKGROUND: Adherence to acne medication is poor and is a major reason why treatment plans are ineffective. Recognizing solutions to nonadherence is critical. OBJECTIVE: The purpose of this study is to describe the hurdles associated with acne nonadherence and to provide mechanisms on how to ameliorate them. METHODS: PubMed database was searched. Of the 419 search results, 29 articles were reviewed to identify hurdles to adherence and corresponding solutions. RESULTS: Hurdles to primary nonadherence where the medication is not even started, include lack of knowledge, confusion about usage, weak physician-patient relationship, fear of adverse reactions, and cost. Secondary nonadherence hurdles where the medication is started but is not taken as directed include lack of results, complex regimens, side effects, busy lifestyle, forgetfulness, inconvenience, and psychiatric comorbidity. Solutions to these hurdles include treatment simplification, technology, and dynamic education. LIMITATIONS: Adherence is affected by numerous factors, but available literature analyzing acne adherence and interventions to improve adherence to treatment is limited. CONCLUSION: There are several hurdles in adhering to acne treatment. Recognition of these hurdles and finding appropriate solutions may be as important to treatment outcomes as choosing the right medication to prescribe.

Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis.

Advances in the field of cancer immunology, including studies on tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs), have led to new immunotherapeutics with proven efficacy against late-stage cancers. However, the antitumor potential of the immune system in targeting early-stage cancers remains uncertain. Here, we demonstrated that both genetic and chemical induction of thymic stromal lymphopoietin (TSLP) at a distant site leads to robust antitumor immunity against spontaneous breast carcinogenesis in mice. Breast tumors exposed to high circulating levels of TSLP were arrested at an early adenoma-like stage and were prevented from advancing to late carcinoma and metastasis. Additionally, CD4+ Th2 cells mediated the antitumor effects of TSLP, challenging the notion that Th2 cells only promote cancer. We also discovered that TSLP is expressed by the breast tumor cells themselves and acts to block breast cancer promotion. Moreover, TSLP-induced immunity also blocked early stages of pancreatic cancer development. Together, our findings demonstrate that TSLP potently induces immunity directed against early stages of breast cancer development without causing inflammation in the normal breast tissue. Moreover, our results highlight a previously unappreciated function of the immune system in controlling the early development of cancer and establish a fundamental role for TSLP and Th2 cells in tumor immunity against early-stage cancers.

Rosacea patients seeking advice: Qualitative analysis of patients' posts on a rosacea support forum.

BACKGROUND: Social media have become outlets for patients to voice opinions and ask questions. Since suffering from rosacea is an isolating experience and the disease is poorly understood, patients use social media to expand their knowledge about the condition. OBJECTIVE: To understand rosacea patients' online health information seeking habits to obtain a better insight of their educational needs. METHODS: Ten percent of posts in online rosacea forum composed of 3350 members and 27 051 posts, discussing patient viewpoints and concern, selected by stratified random sampling. Three hundred and nine queries were directly categorized to patients "seeking advice" by two investigators and qualitatively analyzed. RESULTS: Patients primarily sought advice about treatments (n = 155, 50.1%), triggers (n = 53, 17.1%), diet (n = 48, 15.5%), skin care (n = 37, 11.9%) and special presentations of the disease (n = 22, 7.1%). Questions frequently pertained to adverse effects, efficacy and target of therapy (78, 49, 30 posts, respectively). CONCLUSION: Proactively providing reliable resources and comprehensive explanations on treatments, triggers, diet and skin care could be helpful in reducing patients' confusion about rosacea and enhancing rosacea patient-physician relationships.

Tolerability of Topical Retinoids: Are There Clinically Meaningful Differences Among Topical Retinoids?

BACKGROUND: Topical retinoids are first-line treatment options for acne vulgaris. These drugs, however, produce varying degree of cutaneous irritation within the first few weeks of treatment. OBJECTIVE: Our purpose was to examine differences in tolerability of topical retinoids and assess whether these differences would be clinically meaningful. METHODS: A PubMed search was performed for sources on topical retinoids in acne vulgaris treatment. Thirty-four clinical studies were analyzed. RESULTS: Thirteen studies had statistically significant results on tolerability of retinoid based on retinoid, vehicle, concentration, or skin type. All studies classified most of skin reactions as mild-moderate. Large differences in the number of dropouts due to irritation were not identified. CONCLUSION: Irritation studies did not show a high frequency of clinically significant irritation with topical retinoids. We anticipate that the large variation in patient use of topical retinoids would likely account for more variation in response than differences between drug formulations.

Acne vulgaris.

Acne vulgaris is a chronic inflammatory disease - rather than a natural part of the life cycle as colloquially viewed - of the pilosebaceous unit (comprising the hair follicle, hair shaft and sebaceous gland) and is among the most common dermatological conditions worldwide. Some of the key mechanisms involved in the development of acne include disturbed sebaceous gland activity associated with hyperseborrhoea (that is, increased sebum production) and alterations in sebum fatty acid composition, dysregulation of the hormone microenvironment, interaction with neuropeptides, follicular hyperkeratinization, induction of inflammation and dysfunction of the innate and adaptive immunity. Grading of acne involves lesion counting and photographic methods. However, there is a lack of consensus on the exact grading criteria, which hampers the conduction and comparison of randomized controlled clinical trials evaluating treatments. Prevention of acne relies on the successful management of modifiable risk factors, such as underlying systemic diseases and lifestyle factors. Several treatments are available, but guidelines suffer from a lack of data to make evidence-based recommendations. In addition, the complex combination treatment regimens required to target different aspects of acne pathophysiology lead to poor adherence, which undermines treatment success. Acne commonly causes scarring and reduces the quality of life of patients. New treatment options with a shift towards targeting the early processes involved in acne development instead of suppressing the effects of end products will enhance our ability to improve the outcomes for patients with acne.