Sudomotor

{{Short description|Autonomic nervous system control of sweat gland activity}} '''Sudomotor function''' refers to the autonomic nervous system control of sweat gland activity in response to various environmental and individual factors. Sweat production is a vital thermoregulatory mechanism used by the body to prevent heat-related illness as the evaporation of sweat is the body's most effective method of heat reduction and the only cooling method available when the air temperature rises above skin temperature.<ref name="Gagnon & Crandall 20018"/> In addition, sweat plays key roles in grip, microbial defense, and wound healing.<ref name="Rittié et al 2013"/>

==Physiology== Human sweat glands are primarily classified as either eccrine or apocrine glands. Eccrine glands open directly onto the surface of the skin, while apocrine glands open into hair follicles. Eccrine glands are the predominant sweat gland in the human body with numbers totaling up to 4 million.<ref name="Baker 2019"/> They are located within the reticular dermal layer of the skin and distributed across nearly the entire surface of the body with the largest numbers occurring in the palms and soles.<ref name="Buchmann et al 2019"/><ref name="Baker 2019"/><ref name="Machado-Moreira et al 2008"/>

Eccrine sweat is secreted in response to both emotional and thermal stimulation. Eccrine glands are primarily innervated by small-diameter, unmyelinated class C-fibers from postganglionic sympathetic cholinergic neurons.<ref name="Ziemssen & Siepmann 2019"/> Increases in body and skin temperature are detected by visceral and peripheral thermoreceptors, which send signals via class C and Aδ-fiber afferent somatic neurons through the lateral spinothalamic tract to the preoptic nucleus of the hypothalamus for processing. In addition, there are warm-sensitive neurons located within the preoptic nucleus that detect increases in core body temperature.<ref name="Freeman & Chapleau 2013"/> Efferent pathways then descend ipsilaterally from the hypothalamus through the pons and medulla to preganglionic sympathetic cholinergic neurons in the intermediolateral column of the spinal cord. The preganglionic neurons synapse with postganglionic cholinergic sudomotor (and to a lesser extent adrenergic) neurons in the paravertebral sympathetic ganglia.<ref name="Ziemssen & Siepmann 2019"/> When the action potential reaches the axon terminal of the postganglionic neuron, acetylcholine is released which binds and activates muscarinic M3 receptors on the basolateral membrane of the clear cells in the secretory coil of the eccrine gland. This triggers the release of intracellular calcium storages and an influx of extracellular calcium which ultimately results in the movement of chloride ion (Cl−), sodium ion (Na+), and water into the duct lumen.<ref name="Baker 2019"/>

==Dysfunction== Impaired sudomotor function can occur in any disorder that directly and/or indirectly affects the autonomic nervous system, including diabetes mellitus, amyloidosis, infections, neurodegenerative diseases, multiple system atrophy, and pure autonomic failure.<ref name="Freeman 2005"/> Sudomotor dysfunction can manifest as increased or decreased sweating patterns. Both patterns have the potential to affect an individual's quality of life. Excessive sweating can cause social embarrassment, while insufficient sweating can result in heat intolerance and dry skin. Depending on the severity of dyshidrosis, it may result in hyperkeratosis, rhagades, ulcerations, and poor wound healing due to altered epidermal moisturization.<ref name="Ziemssen & Siepmann 2019"/>

Sudomotor dysfunction is one of the most common and earliest neurophysiological manifestations of small fiber neuropathies.<ref name="Freeman 2005"/> In some cases, it may be the only detectable neurologic manifestation.<ref name="Low et al 2006"/><ref name="Themistocleous et al 2014"/><ref name="Boger et al 2012"/>

The gold standard for diagnosis of small fiber neuropathies is Intraepidermal Nerve Fiber Density (IENFD) measured from punch skin biopsies,<ref name="Hoeijmakers et al 2012"/> but this procedure is invasive and inappropriate for long term follow-up. Sudomotor testing can be a valuable diagnostic tool for the early detection of small fiber neuropathies.<ref name="Vinik et al 2015"/>

==Assessment== There are several methods available for the assessment of sudomotor function. They vary in cost, technical complexity, reproducibility, variability and the availability of normative data.<ref name="Buchmann et al 2019"/> However, it is important to note that all sudomotor function assessments are not specific for small fiber or sudomotor neuropathy, as they can also yield abnormal results from disorders of the sweat glands themselves. The following is a list of methods used in clinical practice and clinical research for sudomotor assessment.

Thermoregulatory Sweat Test (TST) and Quantitative Sudomotor Axon Reflex Test (QSART) are considered the gold standards for assessment of sudomotor function. Newer methods may offer simpler, potentially more sensitive, and more widely available alternatives for screening and monitoring in the clinic of autonomic and small fiber neuropathies, particularly those associated with diabetes.

===Thermoregulatory sweat test=== The thermoregulatory sweat test (TST) was developed in the 1940s by Ludwig Guttmann to measure both preganglionic and postganglionic sudomotor function objectively.<ref name="Buchmann et al 2019"/><ref name="Guttmann 1947"/> The test is performed in a standardized room with the temperature preheated to 45–50 °C and humidity set to 35–40%.  The patient lies unclothed on an examination table. An indicator dye is evenly applied to the ventral surface of the patient's skin excluding the eyes, ears, and perioral region. The dye changes color in response to a decrease in skin pH which occurs upon the onset of sweating as the room temperature is gradually raised.<ref name="Illigens & Gibbons 2009"/> Pictures are taken to record the patient's sweating patterns. In addition, a TST% is calculated by dividing the anhidrotic skin area by the total skin area and multiplying by 100. The TST% acts as an indicator of the severity of neurologic impairment.<ref name="Illigens & Gibbons 2009"/>

When used in conjunction with postganglionic sudomotor function testing, such as the quantitative sudomotor axon reflex test (QSART), it can differentiate a preganglionic lesion from a postganglionic lesion. A distal anhidrotic pattern is characteristic of length-dependent small fiber neuropathies, such as the distal symmetric polyneuropathy commonly seen in diabetic patients.<ref name="Cheshire 2016"/>

The TST has proven to be a sensitive measure of sudomotor function.<ref name="Low et al 2006"/><ref name="Fealey et al 1989"/> However, it is time-consuming and requires a highly specialized facility with trained personnel.<ref name="Buchmann et al 2019"/>

===Quantitative sudomotor axon reflex test=== The quantitative sudomotor axon reflex test (QSART) was developed in 1983 by Phillip Low as a quantitative method for the identification of localized postganglionic sudomotor dysfunction.<ref name="Low et al 1983"/> Three-compartment sweat capsules are placed on the forearm, proximal and distal leg, as well as the dorsum of the foot. The outer compartment of the capsule is filled with a 10% acetylcholine solution, while nitrogen gas is released steadily onto the skin within the inner compartment. The middle compartment acts as a buffer between the inner and outer compartments to prevent direct stimulation of sweat glands or leakage of the acetylcholine solution. The outflow humidity of the nitrogen gas after passing across the skin is measured by a hygrometer. Once a stable baseline of outflow humidity is reached, iontophoresis of the acetylcholine fluid is initiated by using a 2mA electric current to deliver the acetylcholine into the dermal skin layers.<ref name="Illigens & Gibbons 2009"/> The acetylcholine binds to sweat glands (direct sweat response), and nicotinic and muscarinic receptors on the sudomotor nerve terminals, which transmit the action potential antidromically to axon branch points and then orthodromically to adjacent sudomotor nerves and glands (indirect sweat response).

Sweat production is measured as the change in relative humidity over time. The temporal resolution, magnitude, and onset latency of the sweat response are digitally recorded and analyzed using specialized software.<ref name="Buchmann et al 2019"/><ref name="Illigens & Gibbons 2009"/>

QSART is sensitive and specific for detecting postganglionic small fiber dysfunction. However, some studies have found it to have a high variability, poor reproducibility, and low diagnostic sensitivity.<ref name="Peltier et al 2009"/><ref name="Krieger et al 2018"/> It is also sensitive to various factors such as caffeine and medications, and the iontophoresis procedure may cause skin irritation and discomfort.<ref name="Ziemssen & Siepmann 2019"/><ref name="Buchmann et al 2019"/><ref name="Illigens & Gibbons 2009"/> QSART requires highly specialized equipment needing regular calibration, a humidity- and temperature-controlled room, and trained personnel.

===Electrochemical skin conductance=== Electrochemical skin conductance (ESC) is an objective, quantitative, non-invasive method for the assessment of sudomotor function that utilizes chronoamperometry (the application of rectangular direct current (DC) pulses of varying voltage amplitudes) to electrically stimulate eccrine sweat glands, and reverse iontophoresis (the migration of electrolytes from the human sweat to the electrodes) for quantitative measurement of the resulting flow of Cl- ions.

ESC can be measured with the use of a medical device called [https://www.sudoscan.com/ Sudoscan].<ref name="Casellini et al 2013"/><ref name="Khalfallah et al 2020"/>

A novel electrochemical model of the skin was devised, reproducing the behavior of chloride ions and the properties of their ion channel to develop a computational tool for measuring chloride ion flow through a sweat gland in response to an imposed voltage. ''In vitro'' electrochemical studies were then carried out in conventional three-electrode cells to identify the origin of currents measured upon the application of low voltage potentials with variable amplitudes to stainless steel electrodes applied to the skin during clinical tests. These studies also evaluated the influence of different parameters in sweat (e.g., urea, lactate) on the obtained currents. These studies formed the basis for the ESC methodology of measuring sudomotor function.<ref name="Khalfallah et al 2020"/><ref name="Khalfallah et al 2012"/>

The flow of Cl− ions in the sweat secreted from the activated sweat glands are captured by the anode. This process is repeated twice for the feet and twice for the hands with the right and left electrodes alternating as the anode and cathode. A conductance deduced from the resulting current between the electrodes and the voltages is reported as ESC, measured in microsiemens (μS), and is proportional to the Cl− flow to the skin surface, that is to say the ability to secrete Cl− ions by eccrine glands, thus providing a quantitative measurement of sudomotor function.

The measurement requires no specific patient preparation or medical personnel training. The test lasts less than 3 minutes, and is innocuous and non-invasive.

In general, decreased ESC values indicate a higher risk of sudomotor dysfunction, and thus a greater likelihood of small fiber neuropathy.<ref name="Novak 2019"/><ref name="Casellini et al 2013"/> Sudoscan has been shown to be useful in the detection of small fiber neuropathy in patients with and without type 2 diabetes mellitus (T2DM) with a sensitivity of 77 to 87% and a specificity of 67 to 92%, as well as in the screening of diabetic nephropathy.<ref name="Freedman et al 2015"/><ref name="Luk et al 2015"/><ref name="Selvarajah et al 2015"/> Sudoscan has been compared with other reference tests including Heart Rate Variability (HRV) indices, intraepidermal nerve fiber density, sweat gland nerve fiber density and quantitative sudomotor axon reflex testing (QSART).<ref name="D'Amato et al 2020"/><ref name="Porubcin & Novak 2020"/><ref name="Fabry et al 2020"/> In addition to diabetes, low ESC values have been reported in association with increased severity of diabetic kidney disease<ref name="Freedman et al 2015"/><ref name="Luk et al 2015"/> and metabolic syndrome.<ref name="Zhu et al 2016"/> It has also been shown to be sensitive to change after different interventions in subjects with T2DM.<ref name="Casellini et al 2016"/> ESC measurements are highly reproducible.<ref name="Bordier et al 2016"/> Studies have shown ESC values to be dependent on ethnicity.<ref name="Vinik et al 2016"/> For that purpose, normative reference values have been established on a total of 1,350 healthy participants.<ref name="Vinik et al 2016"/> Normative ESC values have also been established for pediatric age groups, and it has been demonstrated that ESC values begin to decrease in the eighth decade of life.<ref name="Vinik et al 2016"/> ESC has the potential to be a useful tool for detecting small fiber neuropathies. It is highly sensitive, rapid, more accessible and less technically complex than current gold standard sudomotor function tests, and causes minimal-to-no patient discomfort, so very suitable for routine use.<ref name="Fabry et al 2020"/>

===Neuropad=== Neuropad utilizes an adhesive pad with a cobalt (II) salt indicator that changes color from blue to pink in the presence of moisture due to the hydration of cobalt ions. One pad is applied to the plantar surface of each foot in between the 1st and 2nd metatarsal heads. The pad is kept on each foot for ten minutes and the final color is recorded. A full change in color from blue to pink is considered a normal sweat response, while an absent or incomplete color change is considered abnormal.<ref name="Neuropad Movie"/>

The strengths of Neuropad are its high sensitivity, cost-effectiveness, and its potential as an at-home test.<ref name="Quattrini et al 2008"/><ref name="Liatis et al 2007"/><ref name="Papanas et al 2007"/> However, Neuropad has lower specificity, is not recommended for children and patients over the age of 70, and is sensitive to certain medications.<ref name="Neuropad Movie"/>

===Silicone imprint method=== Like QSART, silicone imprint utilizes the principles of iontophoresis to measure the axon-reflex sweat response; however, unlike QSART, it allows for spatial but not temporal resolution of the sweat response. Following iontophoresis of a cholinergic agonist, a thin layer of silicone is applied to the tested skin area until polymerization is complete (about 5 minutes). The silicone imprints are then analyzed, either by microscope or computer-assisted analysis, for sweat droplet size, number, and distribution, and compared to lower limits of normal.<ref name="Buchmann et al 2019"/><ref name="Illigens & Gibbons 2009"/><ref name="Hijazi et al 2020"/>

The silicone imprint method is relatively inexpensive and can be performed in non-specialized testing centers; however, the method is prone to artifacts caused by residual hair and dirt, as well as skin surface texture and air bubble formation; the accuracy of the results depends on the silicone material used; the processing of the sweat impressions is time consuming; and the technique requires standardization.<ref name="Buchmann et al 2019"/><ref name="Cheshire 2016"/><ref name="Hijazi et al 2020"/>

=== Quantitative direct and indirect test === The quantitative direct and indirect test (QDIRT) was developed in 2008 by Christopher Gibbons and colleagues as a means for the evaluation of postganglionic sudomotor function outside of specialized autonomic testing centers.<ref name="Gibbons et al 2008"/> It combines elements of TST, QSART, and the silicone imprint method. Similar to QSART, it involves the iontophoresis of 10% acetylcholine solution to induce axon-reflex sweating; however, it utilizes an automated imaging analysis software that is less technically complex.<ref name="Buchmann et al 2019"/><ref name="Loavenbruck et al 2017"/> Prior to iontophoresis, the skin is dried and covered with an indicator dye consisting of povidone-iodine mixed with corn starch and mineral oil. The indicator dye changes color with the onset of sweating. Digital photographs of the color change are recorded every 15 seconds over approximately 7 minutes.  Spatial and temporal analysis of sweat droplets as well as direct and indirect sweat response are measured.<ref name="Buchmann et al 2019"/><ref name="Gibbons et al 2008"/>

Although QDIRT is less technically demanding than QSART or TST, it still requires trained staff and an environmentally controlled room; iontophoresis may cause skin irritation or burning; the skin areas studied using QDIRT are not pre-defined, thus limiting the interindividual comparability of the test; and little normative or performance data are available.<ref name="Buchmann et al 2019"/><ref name="Illigens & Gibbons 2009"/><ref name="Gibbons et al 2008"/>

===Sensitive sweat test=== The sensitive sweat test (SST) was developed by Adam Loavenbruck and colleagues in 2017 for the evaluation of individual sweat glands.<ref name="Loavenbruck et al 2017"/> It allows for the quantification of sweat from each individual sweat gland, as well as their location and distribution, thus providing both temporal and spatial resolution. The procedure is initiated by the iontophoresis of 0.5% pilocarpine solution over a 2.25 cm2 skin area, which stimulates the underlying sweat glands directly through the activation of muscarinic M3 receptors.<ref name="Loavenbruck et al 2017"/> Immediately following iontophoresis, the skin is dried, and then covered with a 10% povidone-iodine solution. At the onset of sweating, the reaction of sweat with the povidone-iodine solution and corn starch results in the appearance of a black spot. A customized miniature camera can follow the secretions of up to 400 sweat glands at a time for up to 60 seconds, analyzing the enlargement rate and area of each spot.<ref name="Loavenbruck et al 2017"/> The test is then repeated for replicate analysis.<ref name="Loavenbruck et al 2017"/>

The procedure is relatively quick and the camera is portable. However, further testing is needed to establish normative data and to confirm its utility in autonomic testing. As the test lacks an axon-reflex response, it has a limited ability to assess nerve fiber function.

===Sympathetic skin response=== Sympathetic skin response (SSR) refers to the change in skin resistance to electrical conduction associated with the sympathetic activation of sudomotor function in response to external or internal stimuli, such as electrical stimulation, deep breathing, and mental stress.<ref name="Vetrugno et al 2003"/> It is mediated by a poorly understood somato-sympathetic reflex with spinal, bulbar, and suprabulbar components.<ref name="Vetrugno et al 2003"/> The SSR is frequently utilized in psychophysiological studies and is a well-known component of the polygraph test.

The test is performed using standard electromyography (EMG) equipment in a lightly dimmed, humidity- and temperature-controlled room. A surface electrode is positioned on the patient's palm or sole, along with a reference electrode on the dorsal side of the same body area. A change in skin potential is then induced either through electrical stimulation or deep breathing. The recorded SSR is then plotted on a graph and analyzed for presence or absence, latency, and amplitude.<ref name="Buchmann et al 2019"/><ref name="Illigens & Gibbons 2009"/><ref name="Linden et al 1995"/>

The SSR is thought to be mainly influenced by the electrolyte content of sweat secreted from eccrine glands.<ref name="Buchmann et al 2019"/> In addition, there is significant intra-individual and inter-individual variability, and SSR declines with age and is commonly absent in individuals over the age of 50.<ref name="Linden et al 1995"/>  SSR is only considered a surrogate marker of sudomotor function and its results should be interpreted in the context of other sudomotor testing.<ref name="Buchmann et al 2019"/><ref name="Illigens & Gibbons 2009"/><ref name="Linden et al 1995"/><ref name="Gibbons et al 2004"/>

===Spoon test=== The spoon test, developed in 1964 by Ernest Bors, relies on assessment of the smooth movement of the convex side of a spoon along the surface of the patient's skin. In patients with sudomotor dysfunction, the spoon will slide in a smooth and uninterrupted fashion. Conversely, the spoon's movement in normal controls will be frequently interrupted by the presence of sweat on the skin.<ref name="Bors 1964"/>

The spoon test is inexpensive, easy to perform, but subjective and not quantitative.

===Sweat gland nerve fiber density=== Sweat gland nerve fiber density (SGNFD) can be quantified in skin biopsies taken from the distal leg, distal thigh, and proximal thigh prepared for standard analysis of intraepidermal nerve fiber density (IENFD).<ref name="Gibbons et al 2009"/> Nerve fibers innervating sweat glands are stained with Protein Gene Product 9.5 and quantified using manual morphometry with light microscopy.<ref name="Gibbons et al 2009"/>

SGNFD can potentially be used as a surrogate anatomical marker for sudomotor function. However, it is not a direct assessment of the sweat response, and normative data must be established.

===Minor's Test=== {{main|Minor test}}{{expand section|date=June 2022}}

===Physical examination=== Inspection of the patient's skin, particularly on the lower extremities, in conjunction with a thorough medical history, can provide valuable information regarding the possible presence of sudomotor dysfunction. Evidence of altered skin hydration, such as hyperkeratosis, excessive skin dander, rhagades, and ulcers, can be suggestive of sudomotor dysfunction. Presence of intense foot odor may be another presentation.<ref name="Coon et al 2017"/>

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== Further reading== * {{cite journal |last1=Agashe |first1=Shruti |last2=Petak |first2=Steven |title=Cardiac Autonomic Neuropathy in Diabetes Mellitus |journal=Methodist DeBakey Cardiovascular Journal |date=2018 |volume=14 |issue=4 |pages=251–256 |doi=10.14797/mdcj-14-4-251 |pmid=30788010 |pmc=6369622 }} * {{cite journal |last1=Itch |first1=Hiroshi |last2=Uebori |first2=Seiji |last3=Asai |first3=Mahito |last4=Kashiwaya |first4=Tagui |last5=Atoh |first5=Keita |last6=Making |first6=Isao |title=Early Detection of Orthostatic Hypotension by Quantitative Sudomotor Axon Reflex Test (QSART) in Type 2 Diabetic Patients |journal=Internal Medicine |date=2003 |volume=42 |issue=7 |pages=560–564 |doi=10.2169/internalmedicine.42.560 |pmid=12879946 |doi-access=free }} * {{cite journal |last1=Yajnik |first1=C.S. |last2=Kantikar |first2=V. |last3=Pande |first3=A. |last4=Deslypere |first4=J.-P. |last5=Dupin |first5=J. |last6=Calvet |first6=J.-H. |last7=Bauduceau |first7=B. |title=Screening of cardiovascular autonomic neuropathy in patients with diabetes using non-invasive quick and simple assessment of sudomotor function |journal=Diabetes & Metabolism |date=April 2013 |volume=39 |issue=2 |pages=126–131 |doi=10.1016/j.diabet.2012.09.004 |pmid=23159130 }} * {{cite journal |last1=Gerrett |first1=Nicola |last2=Griggs |first2=Katy |last3=Redortier |first3=Bernard |last4=Voelcker |first4=Thomas |last5=Kondo |first5=Narihiko |last6=Havenith |first6=George |title=Sweat from gland to skin surface: production, transport, and skin absorption |journal=Journal of Applied Physiology |date=1 August 2018 |volume=125 |issue=2 |pages=459–469 |doi=10.1152/japplphysiol.00872.2017 |pmid=29745799 |s2cid=13675424 |url=https://radar.brookes.ac.uk/radar/file/e1154609-d893-48f6-a952-b0afbbd63c97/1/japplphysiol.00872.2017.pdf }} * {{cite journal |last1=Quinton |first1=Paul M. |title=Cystic Fibrosis: Lessons from the Sweat Gland |journal=Physiology |date=June 2007 |volume=22 |issue=3 |pages=212–225 |doi=10.1152/physiol.00041.2006 |pmid=17557942 }} * {{cite journal |last1=Gibbons |first1=Christopher H |last2=Wang |first2=Ningshan |last3=Freeman |first3=Roy |title=Capsaicin Induces Degeneration of Cutaneous Autonomic Nerve Fibers |journal=Annals of Neurology |date=December 2010 |volume=68 |issue=6 |pages=888–898 |doi=10.1002/ana.22126 |pmid=21061393 |pmc=3057686 }} * {{cite journal |last1=Dyck |first1=Peter J. |last2=Overland |first2=Carol J. |last3=Low |first3=Phillip A. |last4=Litchy |first4=William J. |last5=Davies |first5=Jenny L. |last6=Dyck |first6=P. James B. |last7=O'Brien |first7=Peter C. |title=Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial: Cl vs. NPhys Trial |journal=Muscle & Nerve |date=August 2010 |volume=42 |issue=2 |pages=157–164 |doi=10.1002/mus.21661 |pmid=20658599 |pmc=2956592 }} * {{cite journal |last1=Vitale |first1=G.I. |last2=Quatrale |first2=R.P. |last3=Giles |first3=P.J. |last4=Birnbaum |first4=J.E. |title=Electrical field stimulation of isolated primate sweat glands |journal=British Journal of Dermatology |date=July 1986 |volume=115 |issue=1 |pages=39–47 |doi=10.1111/j.1365-2133.1986.tb06218.x |pmid=3524654 |s2cid=23529777 }} * {{cite journal |last1=Freedman |first1=Barry I. |last2=Bowden |first2=Donald W. |last3=Smith |first3=Susan Carrie |last4=Xu |first4=Jianzhao |last5=Divers |first5=Jasmin |title=Relationships between electrochemical skin conductance and kidney disease in Type 2 diabetes |journal=Journal of Diabetes and Its Complications |date=January 2014 |volume=28 |issue=1 |pages=56–60 |doi=10.1016/j.jdiacomp.2013.09.006 |pmid=24140119 |pmc=3877197 }} * {{cite journal |last1=Ramachandran |first1=Ambady |last2=Moses |first2=Anand |last3=Shetty |first3=Samith |last4=Thirupurasundari |first4=Chandragiri Janakiraman |last5=Seeli |first5=Abraham Catherin |last6=Snehalatha |first6=Chamukuttan |last7=Singvi |first7=Sunil |last8=Deslypere |first8=Jean-Paul |title=A new non-invasive technology to screen for dysglycaemia including diabetes |journal=Diabetes Research and Clinical Practice |date=June 2010 |volume=88 |issue=3 |pages=302–306 |doi=10.1016/j.diabres.2010.01.023 |pmid=20188429 }} * {{cite journal |last1=Raisanen |first1=Anu |last2=Eklund |first2=Jyrki |last3=Calvet |first3=Jean-Henri |last4=Tuomilehto |first4=Jaakko |title=Sudomotor Function as a Tool for Cardiorespiratory Fitness Level Evaluation: Comparison with Maximal Exercise Capacity |journal=International Journal of Environmental Research and 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Category:Medical terminology