The relationship between serum 25-hydroxyvitamin-D level and sweat function in patients with type 2 diabetes mellitus.

AIMS: The objective of this study is to explore the relationship between serum 25-hydroxyvitamin-D(25-(OH)2D3) level and sweat function in patients with type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional study of 1021 patients with T2DM who underwent 25-(OH)2D3 level detections and sweat function tests was carried out. These individuals were divided into deficient groups (n = 154 cases), insufficient groups (n = 593 cases) and sufficient groups (n = 274 cases). Spearman correlation analysis and multivariate stepwise linear regression analysis were implemented to determine the association of 25-(OH)2D3 level and sweat function. RESULTS: The total presence of sweating dysfunction was 38.59%. Patients with a lower level of serum 25-(OH)2D3 had more severe sweat secretion impairment (P < 0.05). As the decrease of serum 25-(OH)2D3 level, the presence of sweating dysfunction increased (P < 0.05). 25-(OH)2D3 level was positively correlated with sweat function parameters, age and duration of T2DM were negatively correlated with sweat function parameter (P < 0.05). Multivariate stepwise linear regression analysis explored a significant association between serum 25-(OH)2D3 level with sweat function (P < 0.05). CONCLUSIONS: Serum 25-(OH)2D3 level was positively correlated with sweat function in patients with T2DM.

Management of Primary Focal Hyperhidrosis: An Algorithmic Approach.

Hyperhidrosis (HH) is defined as perspiration beyond the level required to maintain temperature regulation. HH affects nearly 4.8% of the population in the United States. It can have a great impact on patient’s quality of life by disturbing daily activity, performance, confidence, social interactions, and mental health. In the majority of patients with HH (93%), the etiology of excess sweating is idiopathic, which classifies it as primary focal HH. Mild HH may be controlled with topical antiperspirants and lifestyle modifications. Based on the location of involvement, iontophoresis and botulinum toxin may be considered if the patient does not respond to topical therapies. Despite minimizing sweating, chronic use of systemic anticholinergics, in particular oxybutynin, may result in detrimental adverse effects such as dementia. Local surgery, radiofrequency, microwave, and lasers are other potential modalities for HH. Sympathectomy can be a last resort for the treatment of focal HH of the palmar, plantar, axillary, and craniofacial areas after failure of less invasive therapeutic options. In this review, we conducted a comprehensive search in the PubMed electronic database to summarize an algorithmic approach for the treatment of HH. This can help broaden options for managing this difficult disease. J Drugs Dermatol. 20(5): doi:10.36849/JDD.5774.

Electrochemical Skin Conductance and Quantitative Sensory Testing on Fibromyalgia.

BACKGROUND: An impairment of the peripheral nervous system has been suggested in fibromyalgia (FM). Noninvasive distal electrochemical skin conductance (ESC) has been studied little so far when combined with quantitative sensory testing (QST) in patients with FM. METHODS: This study (clinicaltrials.gov NCT03347669) included 50 female patients with FM and 50 matched healthy volunteers (HVs). ESC (measured in microsiemens [µS] with Sudoscan), as well as psychological, quality of life, sleep, and social characteristics, were assessed in both groups. In a subgroup of 24 patients with FM and 24 HVs, QST of cold and warm detection and pain thresholds and diffuse noxious inhibitory controls (DNICs) were explored. Statistical analysis was performed for a 2-sided type I error at 5%. RESULTS: Between patients with FM and HVs, ESC values differed (71.4 ± 11.2 µS vs. 74.4 ± 10.3 µS, respectively; P = 0.003), especially on the dominant hand (P = 0.03), where more patients with FM had ESC values < 66 µS than did HVs (P = 0.046). No difference was observed on feet. In patients with FM, all collected characteristics were impaired (P < 0.001), DNICs were less functional, detection thresholds occurred later, and pain thresholds occurred earlier. No correlation was observed between ESC and DNICs or with any parameter. CONCLUSION: This study shows that the sudomotor function is significantly impaired in patients with FM, especially on the dominant hand. This occurs in parallel with adjustments of detection and pain thresholds in the context of deficient spinal pain modulation. ESC values combined with QST values are relevant in the context of patients with FM and need to be explored further in this nociception-autonomic system intertwining.

Botulinum toxin: Pharmacology and injectable administration for the treatment of primary hyperhidrosis.

Hyperhidrosis is a dermatological condition defined by excessive sweating beyond thermoregulatory needs with significant effects on patients' quality of life. Hyperhidrosis is categorized as primary or secondary: primary hyperhidrosis is mostly focal and idiopathic, whereas secondary hyperhidrosis is commonly generalized and caused by an underlying medical condition or use of medications. Various surgical and nonsurgical therapies exist for primary hyperhidrosis. Although botulinum toxin is one of the deadliest toxins known, when used in small doses, it is one of the most effective therapies for primary hyperhidrosis. Botulinum toxin injections are widely used as a second-line primary hyperhidrosis treatment option once topical treatment strategies have failed. This article provides an overview of the commercially available botulinum toxin formulations and their applications in the treatment of primary hyperhidrosis.

Thermoregulation in Ectodermal Dysplasia: A Case Series.

Ectodermal dysplasia (ED) is a rare genetic disorder occurring as a consequence of gene mutations that code for the ectoderm of the developing embryo and results in numerous disorders of varying severity. The lack of functioning sweat glands in those affected with ED leads to high infant mortality and frequent complaints of hyperthermia. Temperature control of two adolescents affected with ED was assessed by conducting heat and exercise exposures while monitoring insulated auditory canal (Tac) and skin temperatures, sweating rates, and skin blood flow. One participant was able to sweat and regulate his Tac while a second participant could not regulate Tac without a cooling intervention. The heterogeneous nature of ED, and these cases highlight the need for a case-by-case review of temperature control of individuals affected with ED. This will determine cooling strategies that would be of most benefit to the individual.

Prurigo nodularis as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance.

Little attention has been given to the involvement of sweat glands/ducts in the pathogenesis of prurigo nodularis (PN). According to recent studies, PN is likely to develop under conditions characterized by dry skin, such as atopic dermatitis (AD), suggesting a strong impact of skin dryness on PN development. No therapeutic modalities produced complete resolution of PN without exacerbations. We previously reported that increases in skin dryness by sweating disturbance could initiate the development of AD. We investigated whether sweating responses were impaired in refractory PN lesions; and, if so, we asked whether the PN lesions could resolve by restoring sweating disturbance. Using the impression mold technique, which allows an accurate quantification of individual sweat gland/duct activity, we examined basal sweating under quiescent conditions and inducible sweating responses to thermal stimulus in PN lesions and normal-appearing skin in the same patients before and after treatment with a moisturizer or topical corticosteroids. Sweating disturbance, either basal or inducible, was most profoundly detected in the "hub" structure corresponding to the center of PN papule before the treatment. This sweating disturbance was immunohistochemically associated with the leakage of sweat into the dermis. This disturbance was restored by treatment with a moisturizer. Our limitations include a relatively small patient cohort and lack of blinding. Sweating disturbance could be one of the aggravating factors of PN development. Refractory PN with low skin hydration may resolve by restoring sweating disturbance.

The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease resulting in non-healing wounds affecting body areas of high hair follicle and sweat gland density. The pathogenesis of HS is not well understood but appears to involve dysbiosis-driven aberrant activation of the innate immune system leading to excessive inflammation. Marked dysregulation of antimicrobial peptides and proteins (AMPs) in HS is observed, which may contribute to this sustained inflammation. Here, we analyzed HS skin transcriptomes from previously published studies and integrated these findings through a comparative analysis with a published wound healing data set and with immunofluorescence and qPCR analysis from new HS patient samples. Among the top differently expressed genes between lesional and non-lesional HS skin were members of the S100 family as well as dermcidin, the latter known as a sweat gland-associated AMP and one of the most downregulated genes in HS lesions. Interestingly, many genes associated with sweat gland function, such as secretoglobins and aquaporin 5, were decreased in HS lesional skin and we discovered that these genes demonstrated opposite expression profiles in healing skin. Conversely, HS lesional and wounded skin shared a common gene signature including genes encoding for S100 proteins, defensins, and genes encoding antiviral proteins. Overall, our results suggest that the pathogenesis of HS may be driven by changes in AMP expression and altered sweat gland function, and may share a similar pathology with chronic wounds.

The etiology, diagnosis, and management of hyperhidrosis: A comprehensive review: Therapeutic options.

Hyperhidrosis (HH) is a chronic disorder of excess sweat production that may have a significant adverse effect on quality of life. A variety of treatment modalities currently exist to manage HH. Initial treatment includes lifestyle and behavioral recommendations. Antiperspirants are regarded as the first-line therapy for primary focal HH and can provide significant benefit. Iontophoresis is the primary remedy for palmar and plantar HH. Botulinum toxin injections are administered at the dermal-subcutaneous junction and serve as a safe and effective treatment option for focal HH. Oral systemic agents are reserved for treatment-resistant cases or for generalized HH. Energy-delivering devices such as lasers, ultrasound technology, microwave thermolysis, and fractional microneedle radiofrequency may also be utilized to reduce focal sweating. Surgery may be considered when more conservative treatments have failed. Local surgical techniques, particularly for axillary HH, include excision, curettage, liposuction, or a combination of these techniques. Sympathectomy is the treatment of last resort when conservative treatments are unsuccessful or intolerable, and after accepting secondary compensatory HH as a potential complication. A review of treatment modalities for HH and a sequenced approach are presented.

The etiology, diagnosis, and management of hyperhidrosis: A comprehensive review: Etiology and clinical work-up.

Hyperhidrosis (HH) is a dermatologic disorder defined by sweat production exceeding thermoregulatory needs. Clinically, HH is diagnosed when excess sweating creates significant emotional, physical, or social discomfort, causing a negative impact on the patient's quality of life. Existing data imply that this condition may affect at least 4.8% of the US population. The etiology of HH may stem from a complex autonomic nervous system dysfunction, resulting in neurogenic overactivity of otherwise normal eccrine sweat glands. Alternatively, HH may be a result of aberrant central control of emotions. This condition is categorized as primary or secondary HH. Approximately 93% of patients with HH have primary HH, of whom >90% have a typical focal and bilateral distribution affecting the axillae, palms, soles, and craniofacial areas. Secondary HH presents in a more generalized and asymmetric distribution and is generated by various underlying diseases or medications. Secondary causes of HH need to be excluded before diagnosing primary HH.

Six-Month Comparative Analysis Monitoring the Progression of the Largest Diameter of the Sweating Inhibition Halo of Different Botulinum Toxins Type-A.

BACKGROUND: Excessive sweating is a clinical condition that can be improved with type-A botulinum toxin (BTX-A). OBJECTIVES: To evaluate and compare the largest diameter of sweating inhibition halo (SIH) of 5 different commercially available BTX-A, in five different doses, in a 6-month-long clinical evaluation. METHODS: Twenty-five adult female volunteers were injected in the dorsal trunk area with both 100 units (100UI) and 500 units (500UI) BTX-A products, reconstituted in a ratio of 1:2.5 IU, respectively. Products were applied in five different concentrations (1:2.5U, 2:5U, 3:7.5U, 4:10U, and 5:12.5U). After 30, 60, 90, 120, 150, and 180 days, a starch-iodine test was performed to obtain the largest diameter of each SIH. RESULTS: The higher the number of units used, the larger the SIH p < 0.05 for all BTX-A. However, Botox®, Botulift®, Dysport®, and Prosigne® have pretty likewise SIH along the study, with some few differences for some doses and months between one and another. However, Xeomin® is the BTX-A with the smallest SIH, in comparison with all others, in any dose and period. CONCLUSIONS: Differences were observed among all brands of BTX-As, based on dose and time after injection. Xeomin® provides the smallest SIH in comparison with others BTX-A.

Ratiometric sweat secretion optical test in cystic fibrosis, carriers and healthy subjects.

We have simplified the published procedure (5) for measuring sweat rates in individual human sweat glands. Sweat secretion rates were obtained from sweat drops secreted on the forearm by multiple individual glands. We computed a ratio between CFTR-dependent (by intradermal microinjection of a ß adrenergic cocktail) and CFTR-independent (by methacoline as cholinergic stimulus) sweat secretion rates. We obtained a reproducible, approximately linear readout of CFTR function with measurements performed by two different independent teams. We considered three groups (CF subjects, CF carriers and non-CF controls, n=22 in each group); their mean ratios was respectively 0.000, 0.104 and 0.205 The average ratio of CF subjects was consistent with diagnosis in 3 additional cases clinically resembling CF. All groups were clearly discriminated, with sensibility and specificity ranging from 82% to 100%. A software was developed for detecting sweat droplets. This bioassay is suitabile for multicentre studies focusing on CFTR targeted therapies, controversial diagnosis and functional relevance of rare CFTR mutations.

A novel method to assess the potential role of sweating abnormalities in the pathogenesis of atopic dermatitis.

Although atopic dry skin is believed to be caused by defects in skin genes important for maintaining skin barrier function, the role of sweat in atopic dermatitis (AD) has been apparently underestimated. Given the great capacity of sweat to maintain and increase skin hydration, defective sweating responses may be a logical place to look for changes that predispose individuals to the disease. We investigated how disease process and sweating defects progress from early asymptomatic stages to the onset of clinically apparent disease by employing the impression mould technique, which allows an accurate quantification of individual sweat gland/duct activity in relation to skin surface topography. Insensible and sensible sweating responses under baseline conditions and after thermal stimulus, respectively, were measured in various stages of AD patients and healthy controls. In controls, under baseline conditions, sweat ducts/glands at the dermal folds secreted basal levels of sweat (insensible sweating), thereby maintaining skin hydration. Not only such insensible sweating but also sensible sweating markedly decreased even in the earliest asymptomatic stage and the decrease was followed by compensatory hyperhidrosis at the ridge: leakage of sweat into the dermis could represent the initial event resulting in the decreased sweating and inflammation. The defects eventually progressed involving all of the ducts/glands to develop systemic dry skin. AD skin is characterized by varying degrees of functional impairment of sweat ducts/glands depending on the stage, and this defect would be among the reasons for the inability of AD patients to maintain skin hydration.

EZSCAN for undiagnosed type 2 diabetes mellitus: A systematic review and meta-analysis.

OBJECTIVES: The EZSCAN is a non-invasive device that, by evaluating sweat gland function, may detect subjects with type 2 diabetes mellitus (T2DM). The aim of the study was to conduct a systematic review and meta-analysis including studies assessing the performance of the EZSCAN for detecting cases of undiagnosed T2DM. METHODOLOGY/PRINCIPAL FINDINGS: We searched for observational studies including diagnostic accuracy and performance results assessing EZSCAN for detecting cases of undiagnosed T2DM. OVID (Medline, Embase, Global Health), CINAHL and SCOPUS databases, plus secondary resources, were searched until March 29, 2017. The following keywords were utilized for the systematic searching: type 2 diabetes mellitus, hyperglycemia, EZSCAN, SUDOSCAN, and sudomotor function. Two investigators extracted the information for meta-analysis and assessed the quality of the data using the Revised Version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. Pooled estimates were obtained by fitting the logistic-normal random-effects model without covariates but random intercepts and using the Freeman-Tukey Arcsine Transformation to stabilize variances. Heterogeneity was also assessed using the I2 measure. Four studies (n = 7,720) were included, three of them used oral glucose tolerance test as the gold standard. Using Hierarchical Summary Receiver Operating Characteristic model, summary sensitivity was 72.0% (95%CI: 60.0%- 83.0%), whereas specificity was 56.0% (95%CI: 38.0%- 74.0%). Studies were very heterogeneous (I2 for sensitivity: 79.2% and for specificity: 99.1%) regarding the inclusion criteria and bias was present mainly due to participants selection. CONCLUSIONS: The sensitivity of EZSCAN for detecting cases of undiagnosed T2DM seems to be acceptable, but evidence of high heterogeneity and participant selection bias was detected in most of the studies included. More studies are needed to evaluate the performance of the EZSCAN for undiagnosed T2DM screening, especially at the population level.

Quantity and quality of sweating in atopic dermatitis.

Sweat may be an important factor in triggering an exacerbation of atopic dermatitis. It was the aim of this study to evaluate a possible correlation between atopic patients and hyperhidrosis-measured by a questionnaire-and to find out whether there are qualitative differences in sweat response-measured by sudomotor activity (sympathetic skin response test, SSR). Included were 100 study participants, of whom 50 were patients with atopic dermatitis and 50 were serving as control group. The frequency of hyperhidrosis is higher in atopic patients than in the control group (30 vs. 16%), but has no statistical significance. In addition, patients with hyperhidrosis and atopic dermatitis have a significantly higher exacerbation rate of atopic dermatitis in summertime. The group of atopic patients shows a statistically significant prolonged SSR latency period, which indicates an insufficient sympathetic innervation. In our tests, type IV allergic patients showed clear differences in terms of SSR latency and amplitude. Atopic patients have a higher incidence of hyperhidrosis. The study clearly shows that there is a dysfunction of sudomotor activity in the sympathetic nervous system of atopic patients. Our findings suggest that a deficient innervation of sweat glands in atopic patients may lead to an increase in the development of type IV allergies.

A device to measure secretion of individual sweat glands for diagnosis of peripheral neuropathy.

There is a need for quantitative, precise assessment of small fiber peripheral nerve function. We tested a customized camera device and protocol designed to quantify secretions of individual sweat glands (SGs). Testing was performed on 178 healthy controls and 20 neuropathy subjects. Sweating was stimulated on a 2.25 cm2 skin area by iontophoresis of pilocarpine. The camera imaged sweat from 50 to 400 sweat ducts. We calculated secretion rate of individual SGs, total sweat volume, and number of secreting SGs at four body sites. Neuropathy subjects were tested at the two distal sites to demonstrate the device's capability to detect abnormal sudomotor function. Normal ranges were calculated for each body site. Neuropathy subjects had lower sweat rates per SG, lower total sweat, and lower SG density. The normal values decreased with advancing age, were lower in females, and differed between body sites. There was good agreement with repeat testing. The device provides reliable, precise quantitative measures of sweat secretion from single SGs for characterization of sudomotor nerve function in healthy control subjects and in subjects with known peripheral neuropathy. The test combines the capabilities of existing tests of sudomotor function while providing additional capabilities.

Effect of hypohydration on postsynaptic cutaneous vasodilation and sweating in healthy men.

Hypohydration decreases cutaneous vasodilation and sweating during heat stress, but it is unknown if these decrements are from postsynaptic (i.e., sweat gland/blood vessel) alterations. The purpose of this study was to determine if hypohydration affects postsynaptic cutaneous vasodilation and sweating responses. Twelve healthy men participated in euhydrated (EU) and hypohydrated (HY) trials, with hypohydration induced via fluid restriction and passive heat stress. Changes in cutaneous vascular conductance (CVC; %max) in response to incremental intradermal infusion of the endothelium-independent vasodilator sodium nitroprusside (SNP) and the endothelium-dependent vasodilator methacholine chloride (MCh) were assessed by laser Doppler flowmetry. Local sweat rate (LSR) was simultaneously assessed at the MCh site via ventilated capsule. At the end of the last dose, maximal CVC was elicited by delivering a maximal dose of SNP (5 × 10-2 M) for 30 min to both sites with simultaneous local heating (~44°C) at the SNP site. The concentration of drug needed to elicit 50% of the maximal response (log EC50) was compared between hydration conditions. The percent body mass loss was greater with HY vs. EU (-2.2 ± 0.7 vs. -0.1 ± 0.7%, P < 0.001). Log EC50 of endothelium-dependent CVC was lower with EU (-3.62 ± 0.22) vs. HY (-2.93 ± 0.08; P = 0.044). Hypohydration did not significantly alter endothelium-independent CVC or LSR (both P > 0.05). In conclusion, hypohydration attenuated endothelium-dependent CVC but did not affect endothelium-independent CVC or LSR responses. These data suggest that reductions in skin blood flow accompanying hypohydration can be partially attributed to altered postsynaptic function.

Evaluation of sudomotor function in adult patients with long­lasting type 1 diabetes.

INTRODUCTION The function of the sweat glands appears to be impaired in patients with diabetic complications. OBJECTIVES The aim of the study was to evaluate sudomotor function in adult patients with type 1 diabetes (DM1) and healthy controls and its relationship with metabolic control and diabetic complications. PATIENTS AND METHODS The study group included 404 patients with DM1 (194 women), aged 41 years (interquartile range [IQR], 32-51 years) and with disease duration of 23 years (IQR, 18-31 years). The control group included 84 healthy volunteers. Electrochemical skin conductance (ESC) in the feet and hands was measured in both groups. RESULTS Patients with DM1 had lower ESC than controls (feet: 80 µS [IQR, 65-85 µS] vs 83 µS [IQR, 78.5-87 µS], P <0.001; hands: 63 µS (IQR, 51-75 µS) vs 69 µS (IQR, 61.5-78.5 µS), P <0.001). In the study group, there was a negative correlation between ESC and patients' age, duration of diabetes, waist­to­hip ratio, skin autofluorescence, vibration perception threshold, as well as hemoglobin A1c and triglyceride levels, and a positive correlation with estimated glomerular filtration rate. Microvascular complications were diagnosed in 73.3% of the patients. Patients with retinopathy, diabetic kidney disease, peripheral neuropathy, and cardiac autonomic neuropathy had lower ESC in the feet and hands compared with those without complications. In multivariate logistic regression models, ESC was associated with the presence of any microvascular complications independently of potential confounders. CONCLUSIONS Diabetic microangiopathy, and in particular neuropathy, is related with reduced sudomotor function in DM1. A longer duration of diabetes, worse metabolic control, and reduced renal function are associated with greater sudomotor dysfunction.

Role of CFTR in epithelial physiology.

Salt and fluid absorption and secretion are two processes that are fundamental to epithelial function and whole body fluid homeostasis, and as such are tightly regulated in epithelial tissues. The CFTR anion channel plays a major role in regulating both secretion and absorption in a diverse range of epithelial tissues, including the airways, the GI and reproductive tracts, sweat and salivary glands. It is not surprising then that defects in CFTR function are linked to disease, including life-threatening secretory diarrhoeas, such as cholera, as well as the inherited disease, cystic fibrosis (CF), one of the most common life-limiting genetic diseases in Caucasian populations. More recently, CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease (COPD), and the hyper-responsiveness in asthma, underscoring its fundamental role in whole body health and disease. CFTR regulates many mechanisms in epithelial physiology, such as maintaining epithelial surface hydration and regulating luminal pH. Indeed, recent studies have identified luminal pH as an important arbiter of epithelial barrier function and innate defence, particularly in the airways and GI tract. In this chapter, we will illustrate the different operational roles of CFTR in epithelial function by describing its characteristics in three different tissues: the airways, the pancreas, and the sweat gland.