ArticlePDF AvailableLiterature Review


In Health Resort Medicine, both balneotherapy and thalassotherapy, salt waters and their peloids, or mud products are mainly used to treat rheumatic and skin disorders. These therapeutic agents act jointly via numerous mechanical, thermal, and chemical mechanisms. In this review, we examine a new mechanism of action specific to saline waters. When topically administered, this water rich in sodium and chloride penetrates the skin where it is able to modify cellular osmotic pressure and stimulate nerve receptors in the skin via cell membrane ion channels known as “Piezo” proteins. We describe several models of cutaneous adsorption/desorption and penetration of dissolved ions in mineral waters through the skin (osmosis and cell volume mechanisms in keratinocytes) and examine the role of these resources in stimulating cutaneous nerve receptors. The actions of salt mineral waters are mediated by a mechanism conditioned by the concentration and quality of their salts involving cellular osmosis-mediated activation/inhibition of cell apoptotic or necrotic processes. In turn, this osmotic mechanism modulates the recently described mechanosensitive piezoelectric channels.
1 23
International Journal of
ISSN 0020-7128
Int J Biometeorol
DOI 10.1007/s00484-018-1545-z
Salt water and skin interactions: new lines
of evidence
Jose Manuel Carbajo & Francisco
1 23
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Salt water and skin interactions: new lines of evidence
Jose Manuel Carbajo
&Francisco Maraver
Received: 28 February 2018 /Revised: 8 April 2018 /Accepted: 10 April 2018
#ISB 2018
In Health Resort Medicine, both balneotherapy and thalassotherapy, salt waters and their peloids, or mud products are mainly
used to treat rheumatic and skin disorders. These therapeutic agents act jointly via numerous mechanical, thermal, and chemical
mechanisms. In this review, we examine a new mechanism of action specific to saline waters. When topically administered, this
water rich in sodium and chloride penetrates the skin where it is able to modify cellular osmotic pressure and stimulate nerve
receptors in the skin via cell membrane ion channels known as BPiezo^proteins. We describe several models of cutaneous
adsorption/desorption and penetration of dissolved ions in mineral waters through the skin (osmosis and cell volume mechanisms
in keratinocytes) and examine the role of these resources in stimulating cutaneous nerve receptors. The actions of salt mineral
waters are mediated by a mechanism conditioned by the concentration and quality of their salts involving cellular osmosis-
mediated activation/inhibition of cell apoptotic or necrotic processes. In turn, this osmotic mechanism modulates the recently
described mechanosensitive piezoelectric channels.
Keywords Health resort medicine .Salt water .Skin .Spa therapy .Mud therapy .Review
AVD Apoptotic volume decrease
C-TEAB C-tetraethylammonium bromide
HaCaT Adult human keratinocyte cell line
HSC Human stratum corneum
KCl Potassium chloride
Octanol/water partition coefficient
MS Mechanosensitive
MT Mechanotransduction
NaCl Sodium chloride
NMF Natural moisturizing factor
NVI Necrotic volume increase
Participation coefficient
QSPR Quantitative structure permeability relationships
RVD Regulatory volume decrease
RVI Regulatory volume increase
TEA Triethanolamine
TEWL Transepidermal water loss
UVR Ultraviolet radiation
Among the core elements used in Health Resort Medicine, we
find mineral waters whose physical-chemical composition
plays a key role in their therapeutic properties (Gutenbrunner
et al. 2010; Morer et al. 2017b). The use of salt waters is
common in balneology and these waters are defined as those
with a mineral content of at least 1 g/L of dry residue consisting
of over 20% mEq/L of both chloride and sodium ions
(Maraver and Armijo 2010). Derived products such as mud
peloids are also used, and these have been defined as a
suspension/dispersion with therapeutic and/or cosmetic prop-
erties composed of a complex mixture of fine-grained geolog-
ical and/or biological materials matured in these waters
(Gomes et al. 2013; Maraver et al. 2015).
Among the numerous balneology studies and reviews ex-
amining the use of salt waters or peloids matured in these
waters, we should highlight those performed in France
(Chary-Valckenaere et al. 2018;Constantetal.1995;
Léauté-Labrèze et al. 2001), Germany (Brockow et al.
2007a,2007b; Schiener et al. 2007), Greece (Nastos 2010;
*Francisco Maraver
Department of Radiology, Rehabilitation and Physiotherapy, Faculty
of Medicine, Universidad Complutense de Madrid, Plaza Ramon y
Cajal, s/n, 28040 Madrid, Spain
Professional School of Medical Hydrology, Faculty of Medicine,
Universidad Complutense de Madrid, 28040 Madrid, Spain
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Spilioti et al. 2017), Hungary (Bálint et al. 2007;Benderetal.
2014;Hanzeletal.2018; Kulisch et al. 2009; Tefner et al.
2012), Iran (Mahboob et al. 2009); Israel (Halevy and
Sukenik 1998;Katzetal.2012;Matzetal.2003), Italy
(Bazzichi et al. 2013;Bellomettietal.1997a,1997b,2000,
2002,2007; Bellometti and Galzigna 1999; Capurso et al.
1999; Ciprian et al. 2013; Cozzi et al. 2007,2015;
Fioravanti et al. 2007,2011; Guidelli et al. 2012; Miraglia
Del Giudice et al. 2011; Staffieri et al. 1998; Tsoureli-Nikita
et al. 2002), Japan (Agishi et al. 2010; Nasermoaddeli and
Kagamimori 2005), Tunisia (Fazaa et al. 2014), Turkey
(Dönmez et al. 2005; Karagülle and Karagülle 2004,2015;
Karagülle et al. 2007,2017a,2017b,2018a,2018b;Kardeş
et al. 2018;Kesiktasetal.2012; Ozkurt et al. 2012zkuk
et al. 2017), Spain (Carretero et al. 2010), and Switzerland
(Moufarrij et al. 2014).
In thalassotherapy, sea water is used and characterized by
its high mineral content, high density, and its chemical com-
position rich in chlorides of mainly sodium besides magne-
sium, calcium, potassium, and iodine, along with marine
peloids known as limes. These applications include their ap-
plication with systematic methodic exposure to sun, total or
partial application of hot sea sand, and marine climatotherapy
(based on atmosphere, temperature, humidity, wind, air pres-
sure, etc.) (Lucchetta et al. 2007; Maraver et al. 2011;Morer
2016b). Among the studies that have examined the effects of
thalassotherapy, we should highlight those conducted in
Brazil (de Andrade et al. 2008), Bulgaria (Grozeva and
Stoicheva 2015; Kazandjieva et al. 2008), France (Bobet
1999; Duparc-Ricoux et al. 2004), Germany (Felix 1999;
Schuh 2009), Israel (Abu-Shakra et al. 2014; Codish et al.
2005; Czarnowicki et al. 2011; Elkayam et al. 1991; Flusser
et al. 2002;Halevyetal.2001;Katzetal.2012; Kopel et al.
2013;Nissenetal.1998; Sukenik et al. 1990,1992,1994,
1995,1999;Wigleretal.1995), Italy (Bonsignori 2011;
Lucchetta et al. 2007), Japan (Agishi et al. 2010), Malaysia
(MohdNanietal.2016), Russia (Rogozian et al. 2011),
Tunisia (Zijlstra et al. 2005), and Spain (Morer 2016a;
Morer et al. 2017a).
These saline water therapeutic agents have been described
to act via mechanical, thermal, and chemical mechanisms
(Bender et al. 2005; Fioravanti et al. 2011,2017; Guidelli
et al. 2012; Tenti et al. 2015).
The objective of this review was to assess a newly pro-
posed mechanism of action specific to salt waters employed
in Health Resort Medicine. When topically applied, these wa-
ters rich in Cl
and Na
act via the skin either directly or via
their mud products by modifying cell osmotic pressure, which
in turn stimulates skin nerve receptors through cell membrane
channels called BPiezos.^
To this end, we here examine models of cutaneous adsorp-
tion and desorption, dissolved ion mechanisms of penetrating
the skin (osmosis and cell volume driven mechanisms in
keratinocytes), and the behavior of salt waters as stimulators
of mechanosensitive ion channels.
Cutaneous absorption and desorption models
The human stratum corneum (HSC) is an effective barrier
against most substances, especially polar solutes such as wa-
ter, sugars, and salts (Bouwstra and Ponec 2006; Rawlings
and Harding 2004).
For skin barrier function, intercorneocyte cement is essen-
tial and is secreted by keratinocytes into intercellular spaces
during their terminal differentiation, giving rise to a Bbrick and
mortar^structure (Bouwstra et al. 2000).
Corneocytes are embedded in this intercorneal cement
which has a laminar structure, initially described by Elias
et al. (1979) and modified by Friberg and Osborne (1985),
composed of alternating hydrophilic and hydrophobic layers
which are especially capacitated to retain the organismsmois-
ture. The different types of cholesterol, ceramides, and unsat-
urated free fatty acids are responsible for this crystalline gel or
liquid crystal structure (Pappas 2009; Wertz et al. 1987).
When intact, it is practically impenetrable to ions and may
be partially or fully modified according to exogenous or en-
dogenous circumstances.
Transdermal permeation of hydrophilic solutes is usually
slow and displays various mechanisms (Kushner et al. 2007).
The main route established is through the brick and mortar
structure of the intercorneocyte cement (intercellular route),
besides absorption through pores and cutaneous follicles
(trans-appendicular route) and absorption into the interior of
corneocytes (Chen et al. 2013;Mitragotrietal.1996), or so-
called transcellular route (Mitragotri et al. 1996).
There is scarce information on hydrophilic molecules ca-
pable of crossing the stratum corneum, or on their rates of
absorption and/or desorption. However, we may reasonably
assume the absorption of hydrophilic solutes, enhanced in
specific conditions such as occlusion (Chen et al. 2006;
Tezel et al. 2003) or with the use of techniques promoting
the penetration of polar substances such as molecules that
induce cutaneous penetration (Hathout et al. 2010), electrical
fields (Kalia et al. 2004), or ultrasound (Alvarez-Román et al.
2003). In addition, we should not ignore the influence of tem-
perature and hydrostatic pressure of balneotherapy.
Small quantities of polar solutes can penetrate the HSC
in vivo (Chizmadzhev et al. 1998) and in vitro (Tang et al.
The skin permeability of various substances has been wide-
ly investigated (Mitragotri et al. 2011). Currently, the perme-
ability of more than 100 molecules has been established and
mathematical cutaneous permeability predictive models re-
main to be elucidated (Chen et al. 2013).
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Experimental studies of the skin absorption of hydrophilic
solutes have been conducted in small (Mitragotri et al. 1996)
and large (Michaels et al. 1975) molecules, and in moderately
hydrophilic (Southwell et al. 1984) and highly hydrophilic
(Anderson et al. 1988) molecules. Further studies span from
macroscopic studies that consider skin as a homogenous com-
partment (Clowes et al. 1994) to microscopy studies that con-
sider the individual cell structures of skin (Hansen et al. 2008;
Kushner et al. 2007).
Several authors have proposed mathematical models to
predict skin permeability. Among these, we should mention
the models quantitative structure permeability relationships
(QSPR) of Potts and Guy (1992) and Abraham and Martins
(2004), four pathways of Mitragotri (2003), and corneal bricks
and mortar of Wang et al. (2007) and Chen et al. (2010).
QSPR-quantitative structure-permeability
Human skin permeability data exist for over 50 hydrophilic
solutes and prediction studies of the absorption of these sol-
utes have tried to relate molecular structure to permeability.
These have been mainly statistical models fitted to experimen-
tal data (Abraham and Martins 2004).
QSPR includes simple mathematical models and mechan-
ical models that take into account the physical structure of the
corneum stratum. Most models have proved scarcely accurate
(Lian et al. 2008;Mitragotrietal.2011), though some simple
QSPR models have shown a good prediction capacity for
hydrophobic solutes while this capacity is much worse for
hydrophilic substances.
Four pathways
Mitragotri et al. (2011) considered corneocytes to be imper-
meable, and examined the skin permeability of hydrophilic
solutes through pores arising in the intercorneocyte cement.
He proposed a four pathway model, two of which were ap-
plied to lipophilic compounds (free diffusion and lateral dif-
fusion of lipids in the intercorneocyte cement) and the remain-
ing two to hydrophilic compounds (intercorneocyte pores and
shunts via skin annexes).
This model differentially includes diffusion by means of
Bshunts^through hair follicles and sweat glands, and estimates
that this contribution is practically constant due to a small
proportion of the skin surface area covered with appendages,
though it is the preferential route for hydrophilic solutes of
high molecular weight. Regarding predictions for hydrophilic
solutes, the studies of Mitragotri have provided useful results
with implications for some hydrothermal techniques
(Carretero et al. 2010; Spilioti et al. 2017).
Chen et al. (2006) also considered that corneocytes are
permeable and consequently that hydrophilic solutes are
also absorbed by HSC corneocytes via the transcellular
route. Other authors have considered other porous lipid
networks (Mitragotri et al. 2011; Potts and Francoeur
1991) related to nonspecific trans-appendicular transport
(Mitragotri et al. 2011) or have not considered this pathway
(Tezel et al. 2003).
Human stratum corneum has between 10 and 20 layers of
devitalized keratinocytes (corneocytes), elongated and
completely keratinized, embedded in a continuous intercellu-
lar lipid matrix whose goal is one of protection against the
penetration of unknown substances and the loss of body sub-
stances (Norlén 2007).
The thickness of this barrier is around 1020 μm(Talreja
et al. 2001) and itis composed of proteins, solublesalts,water,
and the remaining of lipids. The barrier is renewed depending
on the circumstances every 828 days through simple detach-
ment or friction.
The HSC retains endogenous water in the skin due to the
hygroscopicity of the salts it contains both inside and out of
the cells (Polefka et al. 2012).
The amount of water present in the HSC is some 6.5 times
lower than in the basal cell layer. Thus, skin isotonicity is
achieved with a 6% aqueous solution of sodium chloride.
Accordingly, more concentrated salt solutions would lead
to water loss from corneocytes and lower salt concentra-
tions, like most mineral waters, will cause corneocyte
The inside of the corneocyte is composed mainly of kera-
tins, water, and natural moisturizing factors (NMFs)
(Rawlings and Harding 2004). Because of their hygroscopic
nature, NMF have the role of keeping the corneocyte moist
(Nakagawa et al. 2004) and consequently they are an impor-
tant penetration route for hydrophilic solutes (Naegel et al.
2008; Nitsche et al. 2006).
Trancellular absorption has been confirmed by several
experimental lines of evidence. Thus, water enters
corneocytes very effectively (Kasting et al. 2003). The larg-
er hydrophilic molecules are found inside the corneocyte as
shown by transmission electron microscopy (Bodde et al.
1991) and two-photon excitation microscopy (Jacobi et al.
The human skin permeability of solutes can be determined
through the octanol-water partition coefficient (K
), also
called the partition coefficient (P
). This coefficient is the
ratio between the concentrations of the substance in a biphasic
mixture of two immiscible liquids: n-octanol and water. This
means that hydrophilic solutes have a logK
low hydrophobia 0 logK
< 0.5, and hydrophobic solutes
Skin moisturizing molecules such as butylene glycol
=0.29), glycerol (logK
=1.76), and urea
=2.11), all very hydrophilic, can promote transcel-
lular absorption (Ventura and Kasting 2017).
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Certainly, the transcellular route is an important transder-
mal permeation pathway for hydrophilic solutes and
moderately hydrophobic solutes.
Brick and mortar model
Wang et al. (2007) used the brick and mortar model to predict
the skin permeability of hydrophilic and hydrophobic solutes
through the diffusion coefficient of solutes in free water. This
model served to predict the skin permeability of hydrophobic
solutes but was unable to effectively predict the permeability
of hydrophilic solutes (Chen et al. 2010;Wangetal.2007).
Chen et al. (2010) also applied the brick and mortar model
according to the intracellular cement absorption route, the
transcellular route, and to published data of the binding capac-
ity of the different solutes to lipids, stratum corneum keratins,
and obtained accurate predictions about hydrophilic solutes
for the lipid-corneocyte interface.
Current art state and cutaneous desorption
Both the four pathway model of Mitragotri (2003) and the
brick and mortar model of Chen et al. (2010) offer the best
predictions and a similar precision for the absorption of solu-
ble solutes in water despite considering the hydrophilic path-
way in a fairly different way.
Hydrophilic solutes show low skin permeability, approxi-
mately one time lower than any hydrophobic solute. In gen-
eral, the skin permeability of hydrophilic solutes decreases as
hydrophilic behavior and molecular weight increases (Chen
et al. 2010).
Consequently, the transcellular pathway is important for
the transdermal permeation of hydrophilic solutes and may
contribute to more than 95% of the total skin permeability of
these molecules (Chen et al. 2013).
Recently, Miller et al. (2017) reported that small polar com-
pounds, whether charged or not charged, may be dispersed in
the moist HSC as if in an amount of water similar to the
tissues water content, and once absorbed, can be desorbed
in two phases: a rapid phase of some minutes and a slower
phase lasting several hours.
When validating this model, the authors determined
capture/desorption on HSC of radiolabeled solutes of three
inorganic salts,
NaCl, Na
Cl, and
bromide (14C-TEAB), and a polyalcohol,
Desorption measurements are an adequate complementary
method to permeability measurements and give an idea of the
skin permeation of solutes. From the findings of Miller et al.
(2017) shown in Fig. 1, we can deduce that desorption rates
for water, 1-propanol, testosterone, and sucrose in the HSC are
much faster than for the other molecules. This could indicate a
greater facility of the former to cross the HSC.
Highly and moderately lipophilic compounds like testos-
terone and propanol respectively, as well as the hydrophilic
molecules water and sucrose have clear desorption profiles,
and two time constants are not needed to describe the desorp-
tion process which occurs as a single phase.
For the remaining hydrophilic molecules (Na
mannitol, and glycerin), the second slow desorption phase was
very parsimonious and lengthy with cycles of longer than
3.74 h.
These determinations provide evidence that HSC allows
small hydrophilic solutes access to inside the corneocytes
and show that most of the water and salts dissolved in the
hydrated HSC are found in the corneocytes.
The specific characteristics of this desorption can be pre-
dictive of the absorption capacity of the different molecules.
The rapid desorption process lacks importance for lipid com-
pounds, yet the slow desorption phase is selective of size, and
thus large molecules show a much slower desorption than
smaller molecules.
Osmosis and cell volume mechanisms
in keratinocytes
The cell plasma membrane is permeable to water and semi-
permeable to inorganic and organic solutes. To maintain their
viability, keratinocytes have semipermeable membranes sen-
sitive to external osmotic pressure. Hydration and cell volume
are regulated, adaptingto the external osmotic pressure via the
accumulation/elimination of low molecular weight inorganic
ions (Carbajo 2014) and some organic molecules called
osmolytes (Hoffmann et al. 2009).
Aqueous flow through animal cell membranes occurs by
simple diffusion, although some specialized membrane pro-
teins exist. These are transmembrane selective pores called
aquaporines, which considerable increase aqueous permeabil-
ity in cell membranes (Agre and Kozono 2003; Verkman and
Mitra 2000).
In addition, changes in volume and cell hydration represent
an essential process for life (Lang and Waldegger 1997).
Besides playing a role in cell shape and ion transport, cell
volume regulates several cell functions such as growth and
differentiation, metabolism, epithelial transport, hormone re-
lease, excitability, migration, and even cell death (Wehner
et al. 2003).
Cells respond to changes in their volume mainly through
two mechanisms. The process through which swollen cells in
hypotonic medium recover their normal volume is called reg-
ulatory volume decrease (RVD), while the opposite process
whereby they increase their volume to recover from a hyper-
tonic medium is regulatory volume increase (RVI) (Hoffmann
et al. 2009).
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Cell volume can only be regulated through the gain or loss
of osmotically active solutes. These active solutes are mainly
ions such as Na
, or organic osmolytes that act
through a membrane transport mechanism (Lang et al. 1998;
O'Neill 1999).
Animal cells, which have thin cytoplasmic membranes,
respond to a hypotonic environment by undergoing an acute
increase in cell volume, and them via RVD (Okada et al.
2001), losing KCl through activation of K
and Cl
or activation of the K
cotransporter (Fig. 2).
Conversely, after acute shrinkage in a hypertonic medium,
volume recovers via RVI (Hoffmann and Dunham 1995). This
process is mainly mediated by the intracellular build-up of
salts (predominantly NaCl and KCl) and by the water dragged
by these electrolytes through cellular interchange of hydrogen
with sodium (Na
) and chlorides and bicarbonates (Cl
) that regulate pH or through the Na
cotransporter and Na
channels (Fig. 2).
These transport mechanisms through channels are rapid
and electrolyte transporters are activated from seconds to
some minutes after the cell volume modification takes place.
This activation is this fast because ion channels and
cotransporters occur on the plasma membrane or are stored
in vesicles on cytoplasmic submembranes and not only par-
ticipate in the transport of salts and water but also play a role in
controlling intracellular pH (Strange 2004).
Fig. 1 Desorption through the
skin of different substances.
measurements made in
hydrophilic compounds on
isolated human stratum corneum
indicate that substantial amounts
of these compounds are absorbed
into the keratinocyte interior and
are desorbed very slowly,
especially mineral salts. Other
molecules that may be absorbed
through the skin show slow
overall desorption times.
Modified from Miller et al. (2017)
Fig. 2 Mechanism of the loss and
gain of solutes that occurs in
keratinocytes when they adapt to
hypo- and hypertonic
environments (Carbajo 2014)
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Sodium is the main extracellular ion and the main element
that maintains total body water volume and contributes to the
ratio of extracellular to intracellular fluid (Häussinger 1996).
It is now known that mechanotransduction (De Palma et al.
2017) and the transcription/translation of genes can also be
controlled through signaling pathways triggered by the intra-
cellular sodium/potassium ratio. Specifically, a sodium ion
increase on the endothelium is influential on the tonicity
enhancer-binding protein (TonEBP, NFAT5), which contrib-
utes to the transcriptomic changes caused by an elevated in-
take of common salt, an effect that is enhanced by an increase
in the production of endogenous Na/K-ATPase (Orlov and
Hamet 2015).
Epidermal defense against salts
Cell defense against osmotic stress takes place in two stages: a
rapid first stage involving inorganic salts, or electrolytes, and a
second slower stage in which organic osmolytes participate
that requires enzyme synthesis and the translation and tran-
scription of genetic codes in the transporters (Strange 2004).
These osmolytes are able to ensure the constant cell volume
that keratinocytes need at each level of the epidermis and thus
prevent cell metabolism alterations, even in high salt concen-
trations. These molecules have proved effective against salin-
ity, heat, dehydration, and freezing (Welch and Brown 1996),
and even against oxidative stress (Yancey et al. 1982), ultra-
violet radiation (UVR) damage (Rosette and Karin 1996), or
in wound repair processes (Değim et al. 2002).
Osmolytes do not affect cell metabolism even at high con-
centrations. Their biophysical and biochemical properties are
unique such that cells may accumulate them in large quantities
and over long time periods without modifying their structure
and functions. The build-up of organic osmolytes is mediated
both by a transport mechanism requiring external energy and
by regulation of their synthesis/destruction processes (Burg
et al. 1997; Chamberlin and Strange 1989).
The maintenance of a constant cell volume in isotonic con-
ditions, or steady state volume, is achieved through balance
between passive flow routes and the Na
/ATPase pump,
otherwise known as the pump and leak mechanism (Hallows
and Knauf 1994). On this mechanism depends the cotransport
and build-up of the proteins, sugars, and amino acids needed
for cell metabolic functions. Its correct functioning maintains
the electrochemical gradient via the membrane, which is offset
by the expulsion of Na
and a higher osmotic pressure inside
the cell conferred by the concentration of these organic
Kleinewietfeld et al. (2013) showed that increased concen-
trations of sodium chloride drastically stimulate the induction
of murine and human Th17 cells. Under these hyperosmotic
conditions, the p38/MAPK pathway involving sensitization
via interleukin 17 (IL-17) is activated, which increases the
production of CD4
T cells (Th17), which plays a fundamen-
tal role in autoimmune diseases. It has been shown that Th17
cells dependent on pathogenic IL-23 are essential for the de-
velopment of experimental autoimmune encephalomyelitis,
an animal model for multiple sclerosis and the genetic risk
factors associated with MS that are related to the IL23/Th17
The skin is also a reservoir of excess Na
and Cl
in salt-
sensitive hypertension. Cells of the phagocytic mononuclear
system (MPS) are recruited into the skin, detect NaCl hyper-
tonicity as a chemotactic stimulus (Müller et al. 2013), migrate
in the direction of excess salt concentration, and activate the
tonicity enhancer-binding protein (TonEBP) to initiate the ex-
pression and secretion of vascular endothelial growth factor C
(VEGFC). These mechanisms, which favors the elimination
of electrolytes through the cutaneous lymphatic vessels, in-
creases the expression of endothelial nitric oxide synthase
(eNOS) in blood vessels (Wiig et al. 2013), suggesting that
electrolyte homeostasis in the body cannot be achieved by
renal excretion alone.
It is not clear whether this local response of the MPS to
osmotic stress is important for the systemic control of blood
pressure, but it seems that the interstitium/extracellular matrix
of the skin has a hypertonic behavior in which the MPS cells
exert their homeostatic and regulatory control. Blood pressure
through TonEBP and subsequent alteration of cutaneous lym-
phatic capillary function through VEGFC/VEGFR3. (Wiig
et al. 2018).
Necrosis and apoptosis via a mechanism of cell
Cells can detect small variations in volume, even lower than
3%, through a wide array of volume sensors that respond to
the magnitude and nature of the perturbation (MacLeod
In extreme conditions, a process of cell destruction takes
place through different mechanism so that their viability is
The mechanism through which RVD occurs seems simple:
a hypotonic medium leads to the expulsion of KCl and exit of
osmolytes, mainly sorbitol, inositol, and taurine, until normal
volume is recovered. However, the different cells show a num-
ber of characteristic complex molecular mechanisms (Jakab
et al. 2002). The activation of the RVD mechanism occurs via
the expulsion of NaCl (Wright and Rees 1998). This activa-
tion could lead to a loss of plasma membrane integrity, follow-
ed by the release of enzymes and unspecific DNAdegradation
(Taimor et al. 1999).
Other studies have shown that the activation of a non-
selective cation channel sensitive to Ca
by the hydroxyl
radical is involved in the necrotic death of cells with a thin
membrane (necrotic volume increase, NVI). Although this
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channel is also permeable to Na
and im-
permeable to Ca
, its activity depends on intracellular Ca
concentrations (Simon et al. 2004).
Severe cell shrinkage caused by a hypertonic environment
can recover its shape through RVI and can trigger, already in
isotonic conditions, apoptotic cellular processes known as ap-
optotic volume decrease (AVD) (Okada et al. 2001).
The main defense mechanism against AVD occurs via Na
exchangers (NHE) which are common in animal cells.
Their activity is mainly regulating homeostasis and cell vol-
ume, and controlling cell surface pH and ion transport
(Alexander and Grinstein 2006). It has been shown that when
AVD is induced, cytochrome C release precedes caspase-3
activation and DNA fragmentation.
Thus, NHE are essential for cell functions such as migra-
tion, vesicle trafficking, growth, proliferation, and cell death.
Cell survival is especially dependent on NHEs and their ab-
sence or abnormality leads to multiple diseases.
NHE1 are activated by RVI and inhibited by cell swelling
(Elsing et al. 2007). This constitutes a mechanism of volume
regulation of homeostasis.
Salt water and skin nerve receptors
The immediate sensation to the mechanical stimuli is mediat-
ed fundamentally by the mechanosensitive ion channels. Its
activity is based on conformational changes induced by me-
chanical forces that cause a selective membrane permeation
and subsequent electrical signaling.
Mechanosensitive ion channels are being identified at a
prodigious rate, including some traditional ones that are
assigned new functions.
The three most representative mechanosensitive channels
are the transient receptor potential channels (TPR), where the
TRPV4 is also known as the vanilloid receptor-related osmot-
ically activated channel, the voltage-dependent potassium
channel Kv1.1 (Kv), and Piezo channels.
TRPV4 is a non-selective cation channel, first described as
an osmo-sensor that detects hypotonic stimuli, and shares ap-
proximately 40% amino acid identity with TRPV1. The open-
ing of the TRPV4 channel to hypotonic stress but not to iso-
tonic stasis or hypertonic stress occurs in a few seconds to
They have been implicated in various osseous and nervous
system diseases in humans. The Kv1.1 channel can detect
mechanical stimuli and are widely expressed in the nervous
system and other tissues.Altogether, the alteration/mutation in
the Kv1 channels causes multiple human neurological dis-
eases (Gu and Gu 2014).
In 2010, a variety of skin nerve receptors were described
(Coste et al. 2010) which we feel could shed new light on
therapeutic mechanisms in Health Resort Medicine. These
noci-propioreceptors are identified by a series of functional
and anatomical characteristics of sensory neurons and also
play a key role in non-neuronal cells such as Merkel cells
and keratinocytes (Woo et al. 2015b).
Cell mechanotransduction (MT), known for decades, con-
sists of the transformation into biological signals of cell me-
chanical forces whereby mechanosensitive (MS) ion channels
play an essential role in detecting such mechanical forces.
However, their true identity was not revealed until the discov-
ery of cell membrane channels designated BPiezos^(Chalfie
This discovery of Piezo channels as a new family of MS
ion channels has helped unveil new molecular functions that
mediate MTin mammalian touch receptors (Bagriantsev et al.
2014;Gengetal.2017;Xu2016; Zhang et al. 2017)through
the identification of the new proteins, Piezo1 and Piezo2, and
of their MS cation channels (Coste et al. 2010; Coste et al.
Piezo proteins form ion channel pores that open in response
to mechanical stimuli, allowing positive ions including calci-
um, to be taken up by the cell (Walsh et al. 2015). However, it
has not yet been confirmed that Piezo channels are only in-
duced mechanically and are not also spontaneously or chem-
ically induced (Wu et al. 2017)(Fig.3).
Piezo1 and Piezo2 are expressed in several human organs
and tissues: brain, optic nerve head, periodontal ligament, tri-
geminal ganglion, dorsal root ganglion, skin, lungs, cardiovas-
cular system, red blood cells, gastrointestinal system, kidney,
colon, bladder, and joint cartilage (Bagriantsev et al. 2014).
The importance of Piezo proteins as physiological (Murthy
et al. 2017) and pathophysiological (Murthy et al. 2017;
Ranade et al. 2015;Suchyna2017) mechanotransducers has
been stressed in a wide variety of MT processes, as shown by
the link between mutations in the human Piezo1 or Piezo2
genes and a series of genetic diseases (Ranade et al. 2015).
Mechanotransduction has important roles in somatosensation
(touch perception, pain, propioception, hearing, and lung respi-
ration), red blood cell volume regulation, the physiology of vas-
cular tone, and in muscle and tendon stretching (Nilius 2010),
and has been linked to several human genetic disorders includ-
ing abnormal embryonic development. Thus, in theory, salt wa-
ter baths could have indirect effects on internal organs or
In this line of research, it has been shown that Piezo1 af-
fects several physiological systems (Gottlieb and Sachs 2012).
Clear effects of this protein have been observed on the blood
system as a blood flow sensor (Davies 1995), in the develop-
ment of blood vessel endothelium, and in regulating blood
pressure (Li et al. 2014; Retailleau et al. 2015). Further roles
assigned to Piezo1 include modulating the red blood cell in-
dex (Cahalan et al. 2015; Faucherre et al. 2014), cell migration
(McHugh et al. 2012), and the development of epithelial cells
(Eisenhoffer et al. 2012;Gudipatyetal.2017). In addition,
Int J Biometeorol
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Piezo1 participates in MT in cartilage and chondrocytes (Lee
et al. 2014; Servin-Vences et al. 2017), in urine osmolarity
(Martins et al. 2016), in neural stem cells (Pathak et al.
2014), and acts on neurons themselves (Koser et al. 2016).
Piezo2 is an important MT channel for smooth touch sen-
sation (Ikeda et al. 2014; Maksimovic et al. 2014; Ranade
et al. 2014; Woo et al. 2014), propioception (Woo et al.
2015a), breathing volume, and pulmonary inflation
(Nonomura et al. 2017) and effects on inflammation have
been proposed (Dubin et al. 2012).
Any force that modifies cell membrane tension could in
theory activate Piezo channels (Kung et al. 2010) including
cell membrane contraction or stretching induced by osmosis.
Any stimulus affecting Piezo1 and Piezo2 activity causing
osmotic swelling, probably through increased resting mem-
brane tension, could activate ion channels (Gottlieb et al.
2012; Jia et al. 2016).
In effect, unicellular bacteria and plants and multicellular
organisms can detect and respond to both external mechanical
forces and internal ones such as osmotic pressure with the
consequence of membrane deformation (Gu and Gu 2014).
As mentioned earlier, mechanical forces have wide impacts
on cell proliferation, migration and adhesion, morphogenesis,
fluid homeostasis, and vesicle transport (Ahern et al. 2016;
Eyckmans et al. 2011; Tyler 2012).
It has been widely accepted for many years that various
mechanical stimuli can induce ion currents that cross the
plasma membrane in different cells. Many mechanically acti-
vated currents are non-selective cation channels that are per-
meable to Na
among other cations (Hao and
Delmas 2010;Marotoetal.2005). These currents are
established through different ion channels in the cell mem-
brane, transforming mechanical stimuli into electrical signals
to allow cells to drive their own metabolism and communicate
with the outside environment (Lewis et al. 2017).
Piezo activity may also be regulated by other endogenous
and exogenous signals such as an acid extracellular pH. Thus,
a pH around 6.3 can trigger the inactivity of Piezo1 channels
(Bae et al. 2015).
Salt mineral water baths can have appreciable impacts on
activities driven by the nervous system added to the biochem-
ical and immune responses that have sparked a therapeutic
interest in these thermal waters (Karagülle et al. 2017a,
2018a,2018b). In any case, studies or evidences that clearly
define the role of balneotherapy on the disease and the in-
volvement of the revised mechanoreceptors are necessary.
The thermal waters used in balneology usually have ion con-
centrations above 1 g/l and therefore behave as a hypertonic
medium for cells. The osmotic forces of sodium chloride wa-
ters play an important role in transepidermal water loss
Fig. 3 The stimulus to activate
the protein Piezo1 is tension in its
structure. The protein is really a
trimeric protein complex that
takes the form of curved blades
around a central pore crowned by
a cap or C-terminal extracellular
domain (CED). Its architecture is
such that Piezo1 is sensitive to
mechanical insult, fluid flow, and
cell membrane tension among
other factors. An overhead and a
side view of its structure are
shown. Further, graphics
mentions the release of the pore
gate (gating spring), detection of
flows (shear flow sensing), and a
possible behavior on hypotonic
and hypertonic media. Modified
from Wu et al. (2017)andMurthy
et al. (2017)
Int J Biometeorol
Author's personal copy
(TEWL), promoting the renewal capacity of skin and the re-
covery of its barrier function (van Kemenade et al. 2004). This
idea was confirmed by the observation that keratinocytes ex-
press similar sodium channels to kidney and colon epithelial
cells (Brouard et al. 1999).
In prior work, we observed using non-invasive examina-
tion techniques that the use of a mud peloid prepared with
magnesium bentonite and salt waters from the medical spa at
Cofrentes (Valencia, Spain), after 3 months of maturing, was
theoretically ideal to treat skin desquamation conditions such
as psoriasis, as blood flow is diminished and skin elasticity
and firmness improve along with dermal density, and fatigue
following repeated skin suction is reduced without affecting
skin barrier function (Carbajo et al. 2014).
The question that arises is what is responsible for this ef-
fect: the saline hypertonic medium, the magnesium bentonite,
the matured organic matter in the mud, the accompanying
microorganisms, or are we seeing the combined effect of all
of these factors?
In a report by Yoshizawa et al. (2001), it was found that
2 weeks of bathing in seawater (500 mM NaCl, 10 mM KCl)
for 20 min per day was able to improve symptoms of dryness
and itching, both in individuals with an atopic skin condition
and in those with irritant contact dermatitis caused by sodium
lauryl sulphate (SLS), which is the standard used to provoke
experimental skin irritation. Despite their improved symp-
toms, participants with atopic dermatitis, nevertheless, report-
ed a slight stinging sensation during treatment.
Theauthors(Yoshizawaetal.2003) ascribed this incon-
venience to the salt concentration and conducted a similar
experiment consisting of 2 min of immersion in three arti-
ficial salt waters and a distilled water control. Experimental
water compositions were (a) 500 mM NaCl and 10 mM de
KCl, (b) 250 mM NaCl and 10 mM KCl, and (c) 250 mM
NaCl and 50 mM de KCl. Determinations included skin
hydration by corneometry and TEWL. Results indicated
that all three compositions increased skin hydration over
the control treatment but only the (c) type water was able
to significantly reduce TEWL compared to distilled water.
The authors concluded that salt water immersion is effec-
tive to treat atopic dermatitis, though the salt water content
is a determining factor.
Wiedow et al. (1989) demonstrated that the hyperosmotic
shock of salt waters induces the release of a leukocyte elastase
capable of inhibiting irritation processes. This enzyme prop-
erty was attributed to the waters NaCl and KCl concentrations
irrespective of calcium and magnesium chloride concentra-
tions (Levin and Maibach 2001; Yoshizawa et al. 2001).
Sasaki et al. (2017)showedthatMg
plus Si
powder (a
synthetic magnesium smectite) promoted skin tissue renewal
in the rat. Further, in a study by Proksch et al. (2005), the
efficacy of bathing in a salt solution rich in magnesium chlo-
ride was shown in participants with atopic dermatitis
measured in terms of improved skin barrier function, hydra-
tion of the stratum corneum, and skin roughness and
Finally, Kim et al. (2010) noted that a Korean marine
inhibit inflammatory reactions in irradiated human
keratinocytes (HaCaT) by 30%, and attributed this anti-
inflammatory effect both to the minerals and organic
molecules present in the mud. Similarly, Flusser et al.
(2002) concluded that salts have to be present for this ef-
fect, though Nicoletti et al. (2015) attributed these skin re-
newal properties to the non-pathogenic bacterial popula-
tions present in the mineral waters.
Léauté-Labrèze et al. (2001) examined the capacity of
naturally saline mineral water alone and in combination
with ultraviolet B (UVB) radiation to treat psoriasis.
These authors noted that saline waters considerably influ-
ence psoriatic whitening and also showed that greatest
whitening was produced by UVB radiation, irrespective
of its association or not with the saline waters.
Gambichler et al. (2011) compared the efficiency of salt
water in transmitting UV rays in psoriatic epidermis equiv-
alents pretreated with tap water or solutions of different
sodium chloride concentrations (3-15-30%). Greater UV
radiation, both of UVA and UVB, was detected for the salt
waters, with transmission increasing with increasing salt
concentration as a factor related to enhanced skin irritation
when the skin was irradiated. In parallel, these same au-
thors addressed the influence of salt waters on human back
skin. Determination was made of the expression of antimi-
crobial peptides and proteins (AMP) found in psoriasis and
other skin inflammation conditions. No differences were
detected in cathelicidins (LL-37) and psoriasins, but the
expression of human Beta-Defensin-2 (hBD-2) and skin
antileukoproteinase (SKALP/elafin) immunoreactivity
were significantly reduced as the salt concentration
In contrast, in a study by Zöller et al. (2015)inwhich
four hypotonic mineral waters, two thermal and two min-
eral, were compared with a control, the factors assessed
were DNA proliferation and membrane cytotoxicity along
with inflammatory variables with and without UVB radia-
tion in HaCaT keratinocytes. Results indicated that both
thermal waters led to reduced interleukin-6 and oxygen
reactive species levels. This effect was attributed to the
high selenium content of one of these waters, which is a
cofactor of glutathione peroxidase. The second thermal
water, which contained low selenium levels, showed anti-
inflammatory properties thought to be associated with its
relatively high zinc concentration. Paradoxically, both
mineral waters also led to good results in terms of all the
factors assessed due to the presence of boron, an
oligoelement that acts on keratinocytes.
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Although it has been established that other mechanical
stimuli both general and localized can activate Piezo chan-
nels (Ranade et al. 2015), these are outside the scope of this
In view of all these lines of evidence, it seems clear that
the topically use of salt waters and their mud products in
Health Resort Medicine, both balneotherapy and thalasso-
therapy, has yielded good outcomes essentially in the treat-
ment of rheumatic and skin disorders. Among the former
conditions treated, we should highlight osteoarthritis
(Bálintetal.2007; Bellometti et al. 1997a,1997b,2007;
Elkayam et al. 1991; Fazaa et al. 2014; Hanzel et al. 2018;
Karagülle et al. 2007;Kardeşet al. 2018; Özkuk et al. 2017;
Wigler et al. 1995), rheumatoid arthritis (Bellometti et al.
2000;Codishetal.2005; Elkayam et al. 1991; Karagülle
et al. 2017a; Karagülle et al. 2018b), back pain or spondy-
litis (Abu-Shakra et al. 2014;Constantetal.1995;Cozzi
et al. 2007; Karagülle and Karagülle 2015;Kesiktasetal.
2012; Kulisch et al. 2009;Tefneretal.2012), and fibromy-
algia (Bazzichi et al. 2013; Bellometti and Galzigna 1999;
Fioravanti et al. 2007;Guidellietal.2012;Ozkurtetal.
2012). Among the latter treated with good results, we
would underscore psoriasis (Brockow et al. 2007a,2007b;
Halevy and Sukenik 1998;Schieneretal.2007;Tsoureli-
Nikita et al. 2002).
The findings of this review indicate that mineral salt waters act
via a cell osmosis mechanism conditioned by the concentra-
tion and quality of their salts that is capable of activating/
inhibiting cell apoptosis and necrosis. In turn, this osmotic
mechanism participates in mechanotransduction via piezo-
electric ion channels embedded in cell membranes. Piezo pro-
teins play important cell developmental roles such as in gene
expression, and cell volume regulation, migration, prolifera-
tion, division, and adhesion. These proteins are capable of
translating mechanical forces into the biological signals that
are pivotal for a wide range of physiological processes, includ-
ing somatosensation, red blood cell volume regulation, and
blood vessel physiology.
Funding This study was funded by grant UCM-911757 awarded to the
research group of the Universidad Complutense de Madrid (Medical
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
Abraham MH, Martins F (2004) Human skin permeation and partition:
general linear free-energy relationship analyses. J Pharm Sci 93:
Abu-Shakra M, Mayer A, Friger M, Harari M (2014) Dead Sea mud
packs for chronic low back pain. Isr Med Assoc J 16:574577
Agishi Y, Miyaji M, Shimizu T (2010) Impact of salt in balneo- and
thalassotherapy in Japan. In: proceedings of the international con-
ference; international congress. Spa therapy with saline waters in
health resorts. Österr Z Phys Med Rehabil 20:6061
Agre P, Kozono D (2003) Aquaporin water channels: molecular mecha-
nisms for human diseases. FEBS Lett 555:7278.
Ahern CA, Payandeh J, Bosmans F, Chanda B (2016) The hitchhiker's
guide to the voltage-gated sodium channel galaxy. J Gen Physiol
Alexander RT, Grinstein S (2006) Na+/H+ exchangers and the regulation
of volume. Acta Physiol (Oxf) 187:159167.
Alvarez-Román R, Merino G, Kalia YN, Naik A, Guy RH (2003) Skin
permeability enhancement by low frequency sonophoresis: lipid ex-
traction and transport pathways. J Pharm Sci 92:11381146. https://
Anderson BD, Higuchi WI, Raykar PV (1988) Heterogeneity effects on
permeability-partition coefficient relationships in human stratum
corneum. Pharm Res 5:566573
Bae C, Sachs F, Gottlieb PA (2015) Protonation of the human PIEZO1
ion cannel stabilizes inactivation. J Biol Chem 290:51675173.
Bagriantsev SN, Gracheva EO, Gallagher PG (2014) Piezo proteins: reg-
ulators of mechanosensation and other cellular processes. J Biol
Chem 289:3167331681.
Bálint GP, Buchanan WW, Adám A, Ratkó I, Poór L, Bálint PV, Somos
E, Tefner I, Bender T (2007) The effect of the thermal mineral water
of Nagybaracska on patients with knee joint osteoarthritis-a double
blind study. Clin Rheumatol 26:890894.
Bazzichi L, DaValle Y, Rossi A, Giacomelli C, Sernissi F, Giannaccini G,
Betti L, Ciregia F, Giusti L, Scarpellini P, Dell'Osso L, Marazziti D,
Bombardieri S, Lucacchini A (2013) A multidisciplinary approach
to study the effects of balneotherapy and mud-bath therapy treat-
ments on fibromyalgia. Clin Exp Rheumatol 31:S111S120
Bellometti S, Galzigna L (1999) Function of the hypothalamic adrenal
axis in patients with fibromyalgia syndrome undergoing mud-pack
treatment. Int J Clin Pharmacol Res 19:2733
Bellometti S, Giannini S, Sartori L, Crepaldi G (1997a) Cytokine levels in
osteoarthrosis patients undergoing mud bath therapy. Int J Clin
Pharmacol Res 17:149153
Bellometti S, Cecchettin M, Galzigna L (1997b) Mud pack therapy in
osteoarthrosis. Changes in serum levels of chondrocyte markers.
Clin Chim Acta 268:101106.
Bellometti S, Poletto M, Gregotti C, Richelmi P, Bertè F (2000) Mud bath
therapy influences nitric oxide, myeloperoxidase and glutathione
peroxidase serum levels in arthritic patients. Int J Clin Pharmacol
Res 20:6980
Bellometti S, Galzigna L, Richelmi P, Gregotti C, Bertè F (2002) Both
serum receptors of tumor necrosis factor are influenced by mud pack
treatment in osteoarthrotic patients. Int J Tissue React 24:5764
Bellometti S, Gallotti C, Pacileo G, Rota A, Tenconi MT (2007)
Evaluation of outcomes in SPA-treated osteoarthrosic patients. J
Prev Med Hyg 48:14.
Int J Biometeorol
Author's personal copy
Bender T, Karagülle Z, Bálint GP, Gutenbrunner C, Bálint PV, Sukenik S
(2005) Hydrotherapy, balneotherapy, and spa treatment in pain man-
agement. Rheumatol Int 25:220224.
Bender T, Bálint G, Prohászka Z, Géher P, Tefner IK (2014) Evidence-
based hydro- and balneotherapy in Hungary-a systematic review
and meta-analysis. Int J Biometeorol 58:311323.
Bobet J (1999) Il était une foisla thalassothérapie. Atlantica, Biarritz
Bodde HE, van den Brink I, Koerten HK, de Haan FHN (1991)
Visualization of in vitro percutaneous penetration of mercuric chlo-
ride; transport through intercellular space versus cellular uptake
through desmosomes. J Control Release 15:227236. https://doi.
Bonsignori F (2011) La Talassoterapia. Cure e benessere alle terme ma-
rine e al mare. ETS, Pisa
Bouwstra JA, Ponec M (2006) The skin barrier in healthy and diseased
state. Biochim Biophys Acta 1758:20802095.
Bouwstra JA, Dubbelaar FE, Gooris GS, Ponec M (2000) The lipid or-
ganisation in the skin barrier. Acta Derm Venereol Suppl (Stockh)
Brockow T, Schiener R, Franke A, Resch KL, Peter RU (2007a) A prag-
matic randomized controlled trial on the effectiveness of low con-
centrated saline spa water baths followed by ultraviolet B (UVB)
compared to UVB only in moderate to severe psoriasis. J Eur Acad
Dermatol Venereol 21:10271037.
Brockow T, Schiener R, Franke A, Resch KL, Peter RU (2007b) A prag-
matic randomized controlled trial on the effectiveness of highly
concentrated saline spa wáter baths followed by UVB compared to
UVB only in moderate to severe psoriasis. J Altern Complement
Med 13:725732.
Brouard M, Casado M, Djelidi S, Barrandon Y, Farman N (1999)
Epithelial sodium channel in human epidermal keratinocytes: ex-
pression of its subunits and relation to sodium transport and differ-
entiation. J Cell Sci 112(Pt 19):33433352
Burg MB, Kwon ED, Kültz D (1997) Regulation of gene expression by
hypertonicity. Annu Rev Physiol 59:437455.
Cahalan SM, Lukacs V, Ranade SS, Chien S, Bandell M, Patapoutian A
(2015) Piezo1 links mechanical forces to red blood cell volume.
eLife 4:e07370.
Capurso A, Solfrizzi V, Panza F, Mastroianni F, Torres F, Del Parigi A,
Colacicco AM, Capurso C, Nicoletti G, Veneziani B, Cellamare S,
Scalabrino A (1999) Increased bile acid excretion and reduction of
serum cholesterol after crenotherapy with salt-rich mineral water.
Aging (Milano) 11(4):273276
Carbajo JM (2014) Evaluación de los cambios en la piel tras la aplicación
de cosméticos elaborados a partir del sedimento de las aguas
minero-medicinales Lanjarón-Capuchina mediante métodos de
bioingenieria cutánea. PhD Thesis, Universidad Complutense
Carbajo JM, Fernández-Torán MA, Corvillo I, Aguilera L, Meijide R,
Carretero MI, Maraver F (2014) Biophysical skin effects of extem-
poraneous peloids from BHervideros de Cofrentes Spa^natural min-
eral water according to their maturity time. J Jpn Soc Balneol
Climatol Phys Med 77:507508.
Carretero MI, Pozo M, Martin-Rubi JA, Pozo E, Maraver F (2010)
Mobility of elements in interaction between artificial sweat and
peloids used in Spanish spa. Appl Clay Sci 48:506515. https://
Chalfie M (2009) Neurosensory mechanotransduction. Nat Rev Mol Cell
Biol 10:4452.
Chamberlin ME, StrangeK (1989) Anisosmotic cell volume regulation: a
comparative view. Am J Phys 257(2 Pt 1):C159C173. https://doi.
Chary-Valckenaere I, Loeuille D, Jay N, Kohler F, Tamisier JN, Roques
CF, Boulange M, Gay G (2018) Spa therapy together with super-
vised self-mobilisation improves pain, function and quality of life in
patients with chronic shoulder pain: a single-blind randomised con-
trolled trial. Int J Biometeorol.
Chen Y, Shen Y, Guo X, Zhang C, Yang W, Ma M, Liu S, Zhang M, Wen
LP (2006) Transdermal protein delivery bya coadministered peptide
identified via phage display. Nat Biotechnol 24:455460
Chen L, Lian G, Han L (2010) Modeling transdermal permeation. Part I.
Predicting skin permeability of both hydrophobic and hydrophilic
solutes. AICHE J:561136561146.
Chen L, Han L, Lian G (2013) Recent advances in predicting skin per-
meability of hydrophilic solutes. Adv Drug Deliv Rev 65:295305.
Chizmadzhev YA, Indenbom AV, Kuzmin PI, Galichenko SV, Weaver
JC, Potts RO (1998) Electrical properties of skin at moderate volt-
ages: contribution of appendageal macropores. Biophys J 74(2 Pt 1):
Ciprian L, Lo Nigro A, Rizzo M, Gava A, Ramonda R, Punzi L, Cozzi F
(2013) The effects of combined spa therapy and rehabilitation on
patients with ankylosing spondylitis being treated with TNF inhib-
itors. Rheumatol Int 33:241245.
Clowes HM, Scott RC, Heylings JR (1994) Skin absorption: flow-
through or static diffusion cells. Toxicol in Vitro 8:827830.
Codish S, Abu-Shakra M, Flusser D, Friger M, Sukenik S (2005) Mud
compress therapy for the hands of patients with rheumatoid arthritis.
Rheumatol Int 25:4954.
Constant F, Collin JF, Guillemin F, Boulangé M (1995) Effectiveness of
spa therapy in chronic low back pain: a randomized clinical trial. J
Rheumatol 22:13151320
Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin
AE, Patapoutian A (2010) Piezo1 and Piezo2 are essential compo-
nents of distinct mechanically activated cation channels. Science
Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS, Kim SE,
Schmidt M, Mathur J, Dubin AE, Montal M, Patapoutian A (2012)
Piezo proteins are pore-forming subunits of mechanically activated
channels. Nature 483:176181.
Cozzi F, Podswiadek M, Cardinale G, Oliviero F, Dani L, Sfriso P, Punzi
L (2007) Mud-bath treatment in spondylitis associated with inflam-
matory bowel diseasea pilot randomised clinical trial. Joint Bone
Spine 74:436439.
Cozzi F, Raffeiner B, Beltrame V, Ciprian L, Coran A, Botsios C,
Perissinotto E, Grisan E, Ramonda R, Oliviero F, Stramare R,
Punzi L (2015) Effects of mud-bath therapy in psoriatic arthritis
patients treated with TNF inhibitors. Clinical evaluation and assess-
ment of synovial inflammation by contrast-enhanced ultrasound
(CEUS). Joint Bone Spine 82:104108.
Czarnowicki T, Harari M, Ruzicka T, Ingber A (2011) Dead Sea
climatotherapy for vitiligo: a retrospective study of 436 patients. J
Eur Acad Dermatol Venereol 25:959963.
Davies PF (1995) Flow-mediated endothelial mechanotransduction.
Physiol Rev 75:519560.
de Andrade SC, de Carvalho RF, Soares AS, de Abreu Freitas RP, de
Medeiros Guerra LM, Vilar MJ (2008) Thalassotherapy for
Int J Biometeorol
Author's personal copy
fibromyalgia: a randomized controlled trialcomparing aquatic exer-
cises in sea water and water pool. Rheumatol Int 29:147152.
De Palma A, Cheleschi S, Pascarelli NA, Tenti S, Galeazzi M, Fioravanti
A (2017) Do MicroRNAs have a key epigenetic role in osteoarthritis
and in mechanotransduction? Clin Exp Rheumatol 35:518526
Değim Z, Celebi N, Sayan H, Babül A, Erdoğan D, Take G (2002) An
investigation on skin wound healing in mice with a taurine-chitosan
gel formulation. Amino Acids 22:187198.
Dönmez A, Karagülle MZ, Tercan N, Dinler M, Işsever H, Karagülle M,
Turan M (2005) SPA therapy in fibromyalgia: a randomised con-
trolled clinic study. Rheumatol Int 26:168172.
Patapoutian A (2012) Inflammatory signals enhance piezo2-
mediated mechanosensitive currents. Cell Rep 2:511517. https://
Duparc-Ricoux S, Monnet P, Fabry R (2004) Thalassotherapy: comple-
mentary or competitor of the hydro-mineral cure? Press Therm Clim
Eisenhoffer GT, Loftus PD, Yoshigi M, Otsuna H, Chien CB, Morcos PA,
Rosenblatt J (2012) Crowding induces live cell extrusion to maintain
homeostatic cell numbers in epithelia. Nature 484:546549. https://
Elias PM, Brown BE, Fritsch P, Goerke J, Gray GM, White RJ (1979)
Localization and composition of lipids in neonatal mouse stratum
granulosum and stratum corneum. J Invest Dermatol 73:339348.
Elkayam O, Wigler I, Tishler M, Rosenblum I, Caspi D, Segal R, Fishel
B, Yaron M (1991) Effect of spa therapy in Tiberias on patients with
rheumatoid arthritis and osteoarthritis. J Rheumatol 18:17991803
Elsing C, Gosch I, Hennings JC, Hübner CA, Herrmann T (2007)
Mechanisms of hypotonic inhibition of the sodium, proton exchang-
er type 1 (NHE1) in a biliary epithelial cell line (Mz-Cha-1). Acta
Physiol (Oxf) 190:199208.
Eyckmans J, Boudou T, Yu X, Chen CS (2011) A hitchhiker's guide to
mechanobiology. Dev Cell 21:3547.
Faucherre A, Kissa K, Nargeot J, Mangoni ME, Jopling C (2014) Piezo1
plays a role in erythrocyte volume homeostasis. Haematologica 99:
Fazaa A, Souabni L, Ben Abdelghani K, Kassab S, Chekili S, Zouari B,
Hajri R, Laatar A, Zakraoui L (2014) Comparison of the clinical
effectiveness of thermal cure and rehabilitation in knee osteoarthri-
tis. A randomized therapeutic trial. Ann Phys Rehabil Med 57(9
Felix SH (1999) Thalassotherapy in paediatrics. Press Therm Clim 136:
Fioravanti A, Perpignano G, Tirri G, Cardinale G, Gianniti C, Lanza CE,
Loi A, Tirri E, Sfriso P, Cozzi F (2007) Effects of mud-bath treat-
ment on fibromialgia patients: a randomized clinical trial.
Rheumatol Int 27:11571161.
Fioravanti A, Cantarini L, Guidelli GM, Galeazzi M (2011) Mechanisms
of action of spa therapies in rheumatic diseases: what scientific ev-
idence is there? Rheumatol Int 31:18.
Fioravanti A, Karagülle M, Bender T, Karagülle MZ (2017)
Balneotherapy in osteoarthritis: facts, fiction and gaps in knowledge.
Eur J Integr Med 9:148150.
Flusser D, Abu-Shakra M, Friger M, Codish S, Sukenik S (2002) Therapy
with mud compresses for knee osteoarthritis: comparison of natural
mud preparations with mineral-depleted mud. J Clin Rheumatol 8:
Friberg SE, Osborne DW (1985) Small angle x-ray diffraction patterns of
stratum corneum and a model structure for its lipids. J Disp Sci
Techn 6:485495
Gambichler T, Demetriou C, Terras S, Bechara FG, Skrygan M (2011)
The impact of salt water soaks on biophysical and molecular param-
eters in psoriatic epidermis equivalents. Dermatology 223:230238.
Geng J, Zhao Q, Zhang T, Xiao B (2017) In touch with the
mechanosensitive piezo channels: structure, ion permeation, and
mechanotransduction. Curr Top Membr 79:159195. https://doi.
Gomes C, Carretero MI, Pozo M, Maraver F, Cantista P, Armijo F, Legido
JL, Teixeira F, Rautureau M, Delgado R (2013) Peloids and
pelotherapy: historical evolution, classification and glossary. Appl
Clay Sci 7576:2838.
Gottlieb PA, Sachs F (2012) Piezo1: properties of a cation selective me-
chanical channel. Channels (Austin) 6:214219.
Gottlieb PA, Bae C, Sachs F (2012) Gating the mechanical channel
Piezo1: a comparison between whole-cell and patch recording.
Channels (Austin) 6:282289.
Grozeva A, Stoicheva M (2015) Thalassotherapy in diabetic
polyneuropathy: a study in Pomorie, Bulgaria. J Jpn Soc Balneol
Climatol Phys Med 78:271275.
Gu Y, Gu C (2014) Physiological and pathological functions of
mechanosensitive ion channels. Mol Neurobiol 50:339347.
Gudipaty SA, Lindblom J, Loftus PD, Redd MJ, Edes K, Davey CF,
Krishnegowda V, Rosenblatt J (2017) Mechanical stretch triggers
rapid epithelial cell division through Piezo1. Nature 543:118121.
Guidelli GM, Tenti S, De Nobili E, Fioravanti A (2012) Fibromyalgia
syndrome and spa therapy: myth or reality? Clin Med Insights
Arthritis Musculoskelet Disord 5:1926.
Gutenbrunner C, BenderT, Cantista P, Karagülle Z (2010) A proposal for
a worldwide definition of health resort medicine, balneology, med-
ical hydrology and climatology. Int J Biometeorol 54:495507.
Halevy S, Sukenik S (1998) Different modalities of spa therapy for skin
diseases at the Dead Sea area. Arch Dermatol 134:14161420.
Halevy S, Giryes H, Friger M, Grossman N, Karpas Z, Sarov B, Sukenik
S (2001) The role of trace elements in psoriatic patients undergoing
balneotherapy with Dead Sea bath salt. Isr Med Assoc J 3:828832
Hallows KR, Knauf PA (1994) Principles of cell volume regulation. In:
Strange K (ed) Cellular and molecular physiology of cell volume
regulation. CRC Press, Boca Raton, pp 329
Hansen S, Henning A, Naegel A, Heisig M, Wittum G, Neumann D,
Kostka KH, Zbytovska J, Lehr CM, Schaefer UF (2008) In-silico
model of skinpenetration based on experimentallydetermined input
parameters. Part I: experimental determination of partition and dif-
fusion coefficients. Eur J Pharm Biopharm 68:352367. https://doi.
Hanzel A, Horvát K, MolicsB, Berényi K, Németh B, Szendi K, Varga C
(2018) Clinical improvement of patients with osteoarthritis using
thermal mineral water at Szigetvár spa-results of a randomised
double-blind controlled study. Int J Biometeorol 62:253259.
Hao J, Delmas P (2010) Multiple desensitization mechanisms of
mechanotransducer channels shape firing of mechanosensory neu-
rons. J Neurosci 30:1338413395.
Int J Biometeorol
Author's personal copy
Hathout RM, Mansour S, Mortada ND, Geneidi AS, Guy RH (2010)
Uptake of microemulsion components into the stratum corneum
and their molecular effects on skin barrier function. Mol Pharm 7:
Häussinger D (1996) The role of cellular hydration in the regulation of
cell function. Biochem J 313:697710.
Hoffmann EK, Dunham PB (1995) Membrane mechanisms and intracel-
lular signalling in cell volume regulation. Int Rev Cytol 161:173
Hoffmann EK, Lambert IH, Pedersen SF (2009) Physiology of cell vol-
ume regulation in vertebrates. Physiol Rev 89:193277. https://doi.
Ikeda R, Cha M, Ling J, Jia Z, Coyle D, Gu JG (2014) Merkel cells
transduce and encode tactile stimuli to drive Aβ-afferent impulses.
Cell 157:664675.
Jacobi U, Tassopoulos T, Surber C, Lademann J (2006) Cutaneous dis-
tribution and localization of dyes affected by vehicles all with dif-
ferent lipophilicity. Arch Dermatol Res 297:303310. https://doi.
Jakab M, Fürst J, Gschwentner M, Bottà G et al (2002) Mechanisms
sensing and modulating signals arising from cell swelling. Cell
Physiol Biochem 12:235258.
Jia Z, Ikeda R, Ling J, Viatchenko-Karpinski V, Gu JG (2016) Regulation
of Piezo2 mechanotransduction by static plasma membrane tension
in primary afferent neurons. J Biol Chem 291:90879104. https://
Kalia YN, Naik A, Garrison J, Guy RH (2004) Iontophoretic drug deliv-
ery. Adv Drug Deliv Rev 56:619658.
Karagülle MZ, Karagülle M (2004) Balneotherapy and spa therapy of
rheumatic diseases in Turkey: a systematic review. Forsch
Komplementarmed Klass Naturheilkd 11:3341.
Karagülle M, Karagülle MZ (2015) Effectiveness of balneotherapy and
spa therapy for the treatment of chronic low back pain: a review on
latest evidence. Clin Rheumatol 34:207214.
KaragülleM, Karagülle MZ, Karagülle O, Dönmez A, Turan M (2007) A
10-day course of SPA therapy is beneficial for people with severe
knee osteoarthritis. A 24-weekrandomised, controlled pilot study.
Clin Rheumatol 26:20632071.
Karagülle M, KardeşS, Karagülle O, Dişçi R, AvcıA, Durak İ, Karagülle
MZ (2017a) Effect of spa therapy with saline balneotherapy on
oxidant/antioxidant status in patients with rheumatoid arthritis: a
single-blind randomized controlled trial. Int J Biometeorol 61:
Karagülle M, KardeşS, Karagülle MZ (2017b) Real-life effectiveness of
spa therapy in rheumatic and musculoskeletal diseases: a retrospec-
tive study of 819 patients. Int J Biometeorol 61:19451956. https://
Karagülle M, KardeşS, Dişçi R, Karagülle MZ (2018a) Spa therapy
adjunct to pharmacotherapy is beneficial in rheumatoid arthritis: a
crossover randomized controlled trial. Int J Biometeorol 62:195
Karagülle M, KardeşS, Karagülle MZ (2018b) Long-term efficacy of spa
therapy in patients with rheumatoid arthritis. Rheumatol Int 38:353
KardeşS, Karagülle M, Geçmen İ,Adıgüzel T, Yücesoy H, Karagülle
MZ (2018) Outpatient balneological treatment of osteoarthritis in
older persons: a retrospective study. Z Gerontol Geriatr. https://doi.
Kasting GB, Barai ND, Wang TF, Nitsche JM (2003) Mobility of water in
human stratum corneum. J Pharm Sci 92:23262340. https://doi.
Katz U, Shoenfeld Y, Zakin V, Sherer Y, Sukenik S (2012) Scientific
evidence of the therapeutic effects of dead sea treatments: a system-
atic review. Semin Arthritis Rheum 42:186200.
Kazandjieva J, Grozdev I, Darlenski R, Tsankov N (2008)
Climatotherapy of psoriasis. Clin Dermatol 26(5):477485
Kesiktas N, Karakas S, Gun K, Gun N, Murat S, Uludag M (2012)
Balneotherapy for chronic low back pain: a randomized, controlled
study. Rheumatol Int 32(10):31933199
Kim JH, Lee J, Lee HB, Shin JH, Kim EK (2010) Water-retentive and
anti-inflammatory properties of organic and inorganic substances
from Korean sea mud. Nat Prod Commun 5:395398
Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA,
Muller DN, Hafler DA (2013) Sodium chloride drives autoimmune
disease by the induction of pathogenic TH17 cells. Nature
Kopel E, Levi A, Harari M, Ruzicka T, Ingber A (2013) Effect of the
Dead Sea climatotherapy for psoriasis on quality of life. Isr Med
Assoc J 15:99102
Koser DE, Thompson AJ, Foster SK, Dwivedy A, Pillai EK, Sheridan
GK, Svoboda H, Viana M, Costa LD, Guck J, Holt CE, Franze K
(2016) Mechanosensing iscritical for axon growth in the developing
brain. Nat Neurosci 19:15921598.
Kulisch A, Bender T, Németh A, Szekeres L (2009) Effect of thermal
water and adjunctive electrotherapy on chronic low back pain: a
double-blind, randomized, follow-up study. J Rehabil Med 41:73
Kung C, Martinac B, Sukharev S (2010) Mechanosensitive channels in
microbes. Annu Rev Microbiol 64:313329.
Kushner J, Kim D, So PT, Blankschtein D, Langer RS (2007) Dual-
channel two-photon miscroscopy study of transdermal transport in
skin treated with low-frequency ultrasound and a chemical enhancer.
J Invest Dermatol 127:28322846.
Lang F, Waldegger S (1997) Regulating cell volume. Am Sci 85:456463
Lang F, Busch GL, Ritter M, Völkl H, Waldegger S, Gulbins E,
Häussinger D (1998) Functional significance of cell volume regula-
tory mechanisms. Physiol Rev 78:247306.
Léauté-Labrèze C, Saillour F, Chêne G, Cazenave C, Luxey-Bellocq ML,
Sanciaume C, Toussaint JF, Taïeb A (2001) Saline spa water or
combined water and UV-B for psoriasis vs conventional UV-B:
lessons from the Salies de Béarn randomized study. Arch
Dermatol 137:10351039
Lee W, Leddy HA, Chen Y, Lee SH, Zelenski NA, McNulty AL, Wu J,
Beicker KN, Coles J, Zauscher S, Grandl J, Sachs F, Guilak F,
Liedtke WB (2014) Synergy between Piezo1 and Piezo2 channels
confers high-strain mechanosensitivity to articular cartilage. Proc
Natl Acad Sci U S A 111:E5114E5122.
Levin CY, Maibach HI (2001) Do cool water or physiologic saline com-
presses enhance resolution of experimentally-induced irritant con-
tact dermatitis? Contact Dermatitis 45:146150.
Lewis AH, Cui AF, McDonald MF, Grandl J (2017) Transduction of
repetitive mechanical stimuli by Piezo1 and Piezo2 ion channels.
Cell Rep 19:25722585.
Li J, Hou B, Tumova S, Muraki K, Bruns A, Ludlow MJ, Sedo A, Hyman
AJ, McKeown L, Young RS, Yuldasheva NY, Majeed Y, Wilson
LA, Rode B, Bailey MA, Kim HR, Fu Z, Carter DAL, Bilton J,
Imrie H, Ajuh P, Dear TN, Cubbon RM, Kearney MT, Prasad KR,
Evans PC, Ainscough JFX, Beech DJ (2014) Piezo1 integration of
vascular architecture with physiological force. Nature 515:279282.
Int J Biometeorol
Author's personal copy
Lian G, Chen L, Han L (2008) An evaluation of mathematical modelsfor
predicting skin permeability. J Pharm Sci 97:584598. https://doi.
Lucchetta MC, Monaco G, Valenzi VI, Russo MV, Campanella J, Nocchi
S, Mennuni G, Fraioli A (2007) The historical-scientific foundations
of thalassotherapy: state of the art. Clin Ter 158:533541
MacLeod RJ (1994) How an epithelial cell swells is a determinant of the
signaling pathways that activate RVD. In: Strange K (ed) Cellular
and molecular physiology of cell volume regulation. CRC Press,
Boca Raton, pp 191200
Mahboob N, Sousan K, Shirzad A, Amir G, Mohammad V, Reza M,
Mansour VA, Hadi V (2009) The efficacy of a topical gel prepared
using Lake Urmia mud in patients with knee osteoarthritis. J Altern
Complement Med 15:12391242.
Maksimovic S, Nakatani M, Baba Y, Nelson AM, Marshall KL, Wellnitz
SA, Firozi P, Woo SH, Ranade S, Patapoutian A, Lumpkin EA
(2014) Epidermal Merkel cells are mechanosensory cells that tune
mammalian touch receptors. Nature 509:617621.
Maraver F, Armijo F (2010) Vademecum II de aguas mineromedicinales
españolas. Complutense, Madrid
Maraver F, Michan A, Morer C, Aguilera L (2011) Is thalassotherapy
simply a type of climatotherapy? Int J Biometeorol 55:107108.
Maraver F, Fernández-Torán MA, Corvillo I, Morer C, Vázquez I,
Aguilera L, Armijo F (2015) Pelotherapy, a review. Med Naturista
Maroto R, RasoA, Wood TG, Kurosky A, Martinac B, Hamill OP (2005)
TRPC1 forms thestretch-activated cation channel in vertebrate cells.
Nat Cell Biol 7:179185.
Martins JR, Penton D, Peyronnet R, Arhatte M, Moro C, Picard N, Kurt
B, Patel A, Honoré E, Demolombe S (2016) Piezo1-dependent reg-
ulation of urinary osmolarity. Pflugers Arch 468:11971206. https://
Matz H, Orion E, Wolf R (2003) Balneotherapy in dermatology.
Dermatol Ther 16:132140.
McHugh BJ, Murdoch A, Haslett C, Sethi T (2012) Loss of the integrin-
activating transmembrane protein Fam38A (Piezo1) promotes a
switch to a reduced integrin-dependent mode of cell migration.
PLoS One 7:e40346.
Michaels AS, Chandrasekaran SK, Shaw JE (1975) Drug permeation
through human skin: theory and in-vitro experimental measurement.
AICHE J 21:985996.
Miller MA, Yu F, Kim KI, Kasting GB (2017) Uptake and desorption of
hydrophilic compounds from human stratum corneum. J Control
Release 261:307317.
Miraglia Del Giudice M, Decimo F, Maiello N, Leonardi S, Parisi G,
Golluccio M, Capasso M, Balestrieri U, Rocco A, Perrone L,
Ciprandi G (2011) Effectiveness of ischia thermal water nasal aero-
sol in children with seasonal allergic rhinitis: a randomized and
controlled study. Int J Immunopathol Pharmacol 24(4):11031109.
Mitragotri S (2003) Modeling skin permeability to hydrophilic and hy-
drophobic solutes based on four permeation pathways. J Control
Release 86:6992.
Mitragotri S, Blankschtein D, Langer R (1996) Transdermal drug deliv-
ery using low-frequency sonophoresis. Pharm Res 13:411420
Mitragotri S, Anissimov YG, Bunge AL, Frasch HF, Guy RH, Hadgraft J,
Kasting GB, Lane ME, Roberts MS (2011) Mathematical models of
skin permeability: an overview. Int J Pharm 418:115129. https://
Mohd Nani SZ, Majid FA, Jaafar AB, Mahdzir A, Musa MN (2016)
Potential health benefits of deep sea water: a review. Evid Based
Complement Alternat Med 2016:65204756520418. https://doi.
Morer C (2016a) Talasoterapia y enfermedad neurológica. PhD Thesis,
Universidad Complutense Madrid
Morer C (2016b) Talasoterapia. Bol Soc Esp Hidrol Med 31:119146.
Morer C, Boestad C, Zuluaga P, Alvarez-Badillo A, Maraver F (2017a)
Effects of an intensive thalassotherapy and aquatic therapy program
in stroke patients. A pilot study. Rev Neurol 65:249256
Morer C, Roques CF, Françon A, Forestier R, Maraver F (2017b) The
role of mineral elements and other chemical compounds used in
balneology: data from double-blind randomized clinical trials. Int J
Biometeorol 61:21592173.
Moufarrij S, Deghayli L, Raffoul W, Hirt-Burri N, Michetti M, de Buys
RA, Norberg M, Applegate LA (2014) How important is hydrother-
apy? Effects of dynamic action of hot spring water as a rehabilitative
treatment for burn patients in Switzerland. Ann Burns Fire Disasters
Müller S, Quast T, Schröder A, Hucke S, Klotz L, Jantsch J, Gerzer R,
Hemmersbach R, Kolanus W (2013) Salt-dependent chemotaxis of
macrophages. PLoS One 8(9):e73439.
Murthy SE, Dubin AE, Patapoutian A (2017) Piezos thrive under pressure:
mechanically activated ion channels in health and disease. Nat Rev
Naegel A, Hansen S, Neumann D, Lehr CM, Schaefer UF, Wittum G,
Heisig M (2008) In-silico model of skin penetration based on exper-
imentally determined input parameters. Part II: mathematical model-
ling of in-vitro diffusion experiments. Identification of critical input
parameters. Eur J Pharm Biopharm 68:368379.
Nakagawa N, Sakai S, Matsumoto M, Yamada K, Nagano M, Yuki T,
Sumida Y, Uchiwa H (2004) Relationship between NMF (lactate
and potassium) content and the physical properties of the stratum
corneum in healthy subjects. J Invest Dermatol 122:755763.
Nasermoaddeli A, Kagamimori S (2005) Balneotherapy in medicine: a
review. Environ Health Prev Med 10(4):171179
Nastos VE (2010) Saline mud therapy for headache secondary to cervical
osteoarthritis. In: proceedings of the international conference; inter-
national congress. Spa therapy with saline waters in health resorts.
Österr Z Phys Med Rehabil 20:56
Nicoletti G, Corbella M, Jaber O, Marone P, Scevola D, Faga A (2015)
Non-pathogenic microflora of a spring water with regenerative prop-
erties. Biomed Rep 3:758762.
Nilius B (2010) Pressing and squeezing with Piezos. EMBO Rep11:902
Nissen JB, Avrach WW, Hansen ES, Stengaard-Pedersen K, Kragballe K
(1998) Increased levels of enkephalin following natural sunlight
(combined with salt water bathing at the Dead Sea) and ultraviolet
A irradiation. Br J Dermatol 139:10121019.
Nitsche JM, Wang TF, Kasting GB (2006) A two-phase analysis of solute
partitioning into the stratum corneum. J Pharm Sci 95:649666.
Nonomura K, Woo SH, Chang RB, Gillich A, Qiu Z, Francisco AG,
Ranade SS, Liberles SD, Patapoutian A (2017) Piezo2 senses airway
stretch and mediates lung inflation-induced apnoea. Nature 541:
Norlén L (2007) Nanostructure of the stratum corneum extracellular lipid
matrix as observed by cryo-electron microscopy of vitreous skin
sections. Int J Cosmet Sci 29:335352.
Okada Y, Maeno E, Shimizu T, Dezaki K, Wang J, Morishima S (2001)
Receptor-mediated control of regulatory volume decrease (RVD)
Int J Biometeorol
Author's personal copy
and apoptotic volume decrease (AVD). J Physiol 532:316. https://
O'Neill WC (1999) Physiological significance of volume-regulatory
transporters. Am J Phys 276(5 Pt 1):C995C1011.
Orlov SN, Hamet P (2015) Salt and gene expression: evidence for [Na+]i/
[K+]i-mediated signaling pathways. Pflugers Arch 467:489498.
Özkuk K, Gürdal H, Karagülle M, Barut Y, Eröksüz R, Karagülle MZ
(2017) Balneological outpatient treatment for patients with knee
osteoarthritis; an effective non-drug therapy option in daily routine?
Int J Biometeorol 61:719728.
Ozkurt S, Dönmez A, ZekiKaragülle M, Uzunoğlu E, Turan M, Erdoğan
N (2012) Balneotherapy in fibromyalgia: a single blind randomized
controlled clinical study. Rheumatol Int 32(7):19491954. https://
Pappas A (2009) Epidermal surface lipids. Dermato-endocrinology 1:72
Pathak MM, Nourse JL, Tran T, Hwe J, Arulmoli J, Le DT, Bernardis E,
Flanagan LA, Tombola F (2014) Stretch-activated ion channel
Piezo1 directs lineage choice in human neural stem cells. Proc
Natl Acad Sci U S A 111:1614816153.
Polefka TG, Bianchini RJ, Shapiro S (2012) Interaction of mineral salts
with the skin: a literature survey. Int J Cosmet Sci 34:416423.
Potts RO, Francoeur ML (1991) The influence of stratum corneum mor-
phology on wáter permeability. J Invest Dermatol 96:495499.
Potts RO, Guy RH (1992) Predicting skin permeability. Pharm Res 9:
Proksch E, Nissen HP, Bremgartner M, Urquhart C (2005) Bathing in a
magnesium-rich Dead Sea salt solution improves skin barrier func-
tion, enhances skin hydration, and reduces inflammation in atopic
dry skin. Int J Dermatol 44:151157.
Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C, Petrus M,
Mathur J, Bégay V, Coste B, Mainquist J, Wilson AJ, Francisco AG,
Reddy K, Qiu Z, Wood JN, Lewin GR, Patapoutian A (2014) Piezo2
is the major transducer of mechanical forces for touch sensation in
mice. Nature 516:121125.
Ranade SS, Syeda R, Patapoutian A (2015) Mechanically activated ion
channels. Neuron 87:11621179.
Rawlings AV, Harding CR (2004) Moisturization and skin barrier func-
tion. Dermatol Ther 17(Suppl 1):4348.
Retailleau K, Duprat F, Arhatte M, Ranade SS, Peyronnet R, Martins JR,
Jodar M, Moro C, Offermanns S, Feng Y, Demolombe S, Patel A,
Honoré E (2015) Piezo1 in smooth muscle cells is involved in
hypertension-dependent arterial remodeling. Cell Rep 13:1161
Rogozian BN, Efimenko NV, Kaĭsinova AS, Babiakin AF (2011)
Thalassotherapy for the patients suffering osteoarthrosis. The med-
ical technology. Vopr Kurortol Fizioter Lech Fiz Kult 88:5154.
Rosette C, Karin M (1996) Ultraviolet light and osmotic stress: activation
of the JNK cascade through multiple growth factor and cytokine
receptors. Science 274:11941197.
Sasaki Y, Sathi GA, Yamamoto O (2017) Wound healing effect of bioac-
tive ion released from Mg-smectite. Mater Sci Eng C Mater Biol
Appl 77:5257.
Schiener R, Brockow T, Franke A, Salzer B, Peter RU, Resch KL (2007)
Bath PUVA and saltwater baths followed by UV-B phototherapy as
treatments for psoriasis: a randomized controlled trial. Arch
Dermatol 143:586596.
Schuh A (2009) Die Evidenz der Klima- und Thalassotherapie. Ein
Review. Schweiz Z Ganzheitsmed 21:96104.
Servin-Vences MR, Moroni M, Lewin GR, Poole K (2017) Direct mea-
surement of TRPV4 and PIEZO1 activity reveals multiple
mechanotransduction pathways in chondrocytes. elife 6:e21074.
Simon F, Varela D, Eguiguren AL, Díaz LF, Sala F, Stutzin A (2004)
Hydroxyl radical activation of a Ca(2+)-sensitive nonselective cat-
ion channel involved in epithelial cell necrosis. Am J Physiol Cell
Physiol 287:C963C970.
Southwell D, Barry BW, Woodford R (1984) Variations in permeability
of human skin within and between specimens. Int J Pharm 18:299
Spilioti E,Vargiami M, Letsiou S, Gardikis K, Sygouni V, Koutsoukos P,
Chinou I, Kassi E, Moutsatsou P (2017) Biological properties of
mud extracts derived from various spa resorts. Environ Geochem
Health 39(4):821833.
Staffieri A, Miani C, Bergamin AM, Arcangeli P, Canzi P (1998) Effect of
sulfur salt-bromine-iodine thermal waters on albumin and IgA con-
centrations in nasal secretions. Acta Otorhinolaryngol Ital 18(4):
Strange K (2004) Cellularvolume homeostasis. Adv Physiol Educ 28(1
Suchyna TM (2017) Piezo channels and GsMTx4:two milestones in our
understanding of excitatory mechanosensitive channels and their
role in pathology. Prog Biophys Mol Biol 130(Pt B):244253.
Sukenik S, Neumann L, Buskila D, Kleiner-Baumgarten A, Zimlichman
S, Horowitz J (1990) Dead Sea bath salts for the treatment of rheu-
matoid arthritis. Clin Exp Rheumatol 8:353357
Sukenik S, Buskila D, Neumann L, Kleiner-Baumgarten A (1992) Mud
pack therapy in rheumatoid arthritis. Clin Rheumatol 11:243247.
Sukenik S, Giryes H, Halevy S, Neumann L, Flusser D, Buskila D (1994)
Treatment of psoriatic arthritis at the Dead Sea. J Rheumatol 21:
Sukenik S, Neumann L, Flusser D, Kleiner-Baumgarten A, Buskila D
(1995) Balneotherapy for rheumatoid arthritis at the Dead Sea. Isr J
Med Sci 31:210214
Sukenik S, Flusser D, Abu-Shakra M (1999) The role of spa therapy in
various rheumatic diseases. Rheum Dis Clin N Am 25:883897
Taimor G, Lorenz H, Hofstaetter B, Schlüter KD, Piper HM (1999)
Induction of necrosis but not apoptosis after anoxia and reoxygena-
tion in isolated adult cardiomyocytes of rat. Cardiovasc Res 41:147
Talreja P, Kleene NK, Pickens WL, Wang TF, Kasting GB (2001)
Visualization of the lipid barrier and measurement of lipid path
length in human stratum corneum. AAPS PharmSci 3:E13
Tang H, Blankschtein D, Langer R (2002) Prediction of steady-state skin
permeabilities of polar and nonpolar permeants across excised pig
skin based on measurements of transient diffusion: characterization
of hydration effects on the skin porous pathway. J Pharm Sci 91:
Tefner IK, Németh A, Lászlófi A, Kis T, Gyetvai G, Bender T (2012) The
effect of spa therapy in chronic low back pain: a randomized con-
trolled, single-blind, follow-up study. Rheumatol Int 32(10):3163
Tenti S, Cheleschi S, Galeazzi M, Fioravanti A (2015) Spa therapy: can
be a valid option for treating knee osteoarthritis? Int J Biometeorol
Int J Biometeorol
Author's personal copy
Tezel A, Sens A, Mitragotri S (2003) Description of transdermal transport
of hydrophilic solutes during low-frequency sonophoresis based on
a modifiedporous pathway model. J Pharm Sci 92:381393. https://
Tsoureli-Nikita E, Menchini G, Ghersetich I, Hercogova J (2002)
Alternative treatment of psoriasis with balneotherapy using
Leopoldine spa water. J Eur Acad Dermatol Venereol 16:260262
Tyler WJ (2012) The mechanobiology of brain function. Nat Rev
Neurosci 13:867878.
van Kemenade PM, Houben MM, Huyghe JM, Douven LF (2004) Do
osmotic forces play a role in the uptake of water by human skin?
Skin Res Technol 10:109112.
Ventura SA, Kasting GB (2017) Dynamics of glycerine and water trans-
port across human skin from binary mixtures. Int J Cosmet Sci 39:
Verkman AS, Mitra AK (2000) Structure and function of aquaporin water
channels. Am J Physiol Renal Physiol 278:F13F28.
Walsh CM, Bautista DM, Lumpkin EA (2015) Mammalian touch catches
up. Curr Opin Neurobiol 34:133139.
Wang TF, Kasting GB, Nitsche JM (2007) A multiphase microscopic
diffusion model for stratum corneum permeability. II. Estimation
of physicochemical parameters, and application to a large perme-
ability database. J Pharm Sci 96:30243051.
Wehner F, Olsen H, Tinel H, Kinne-Saffran E, Kinne RK (2003) Cell
volume regulation: osmolytes, osmolyte transport, and signal trans-
duction. Rev Physiol Biochem Pharmacol 148:180.
Welch WJ, Brown CR (1996) Influence of molecular and chemical chap-
erones on protein folding. Cell Stress Chaperones 1:109115
Wertz PW, Swartzendruber DC, Madison KC, Downing DT (1987)
Composition and morphology of epidermal cyst lipids. J Invest
Dermatol 89:419425
Wiedow O, Streit V, Christophers E, Ständer M (1989) Liberation of
human leukocyte elastase by hypertonic saline baths in psoriasis.
Hautarzt 40:518522
Wigler I, Elkayam O, Paran D, Yaron M (1995) Spa therapy for
gonarthrosis: a prospective study. Rheumatol Int 15:6568. https://
Wiig H, Schröder A, Neuhofer W, Jantsch J, Kopp C, Karlsen TV,
Boschmann M, Goss J, Bry M, Rakova N, Dahlmann A, Brenner
S, Tenstad O, Nurmi H, Mervaala E, Wagner H, Beck FX, Müller
DN, Kerjaschki D, Luft FC, Harrison DG, Alitalo K, Titze J (2013)
Immune cells control skin lymphatic electrolyte homeostasis and
blood pressure. J Clin Invest 123:28032815.
Wiig H, Luft FC, Titze JM (2018) The interstitium conducts extrarenal
storage of sodium and represents a third compartment essential for
extracellular volume and blood pressure homeostasis. Acta Physiol
(Oxf) 222:e13006.
Woo SH, Ranade S, Weyer AD, Dubin AE, Baba Y, Qiu Z, Petrus M,
Miyamoto T, Reddy K, Lumpkin EA, Stucky CL, Patapoutian A
(2014) Piezo2 is required for Merkel-cell mechanotransduction.
Nature 509(7502):622626.
Woo SH, Lukacs V, de Nooij JC, Zaytseva D, Criddle CR, Francisco A,
Jessell TM, Wilkinson KA, Patapoutian A (2015a) Piezo2 is the
principal mechanotransduction channel for proprioception. Nat
Neurosci 18:17561762.
Woo SH, Lumpkin EA, Patapoutian A (2015b) Merkel cells and neurons
keep in touch. Trends Cell Biol 25:7481.
Wright AR, Rees SA (1998) Cardiac cell volume: crystal clear or murky
waters? A comparison with other cell types. Pharmacol Ther 80:89
Wu J, Lewis AH, Grandl J (2017) Touch, tension, and transductionthe
function and regulation of piezo ion channels. Trends Biochem Sci
Xu XZ (2016) Demystifying mechanosensitive piezo ion channels.
Neurosci Bull 32:307309.
Yancey PH, Clark ME, Hand SC, Bowlus RD, Somero GN (1982) Living
with water stress: evolution of osmolyte systems. Science 217:
Yoshizawa Y, Tanojo H, Kim SJ, Maibach HI (2001) Sea water or its
components alter experimental irritant dermatitis in man. Skin Res
Technol 7:3639.
Yoshizawa Y, Kitamura K, Kawana S, Maibach HI (2003) Water, salts
and skin barrier of normal skin. Skin Res Technol 9:3133. https://
Zhang T, Chi S, Jiang F, Zhao Q, Xiao B (2017) A protein interaction
mechanism for suppressing the mechanosensitive Piezo channels.
Nat Commun 8:1797.
Zijlstra TR, van de Laar MA, Bernelot Moens HJ, Taal E, Zakraoui L,
Rasker JJ (2005) Spa treatment for primary fibromyalgia syndrome:
a combination of thalassotherapy, exercise and patient education
improves symptoms and quality of life. Rheumatology (Oxford)
Zöller N, Valesky E, Hofmann M, Bereiter-Hahn J, Bernd A, Kaufmann
R, Meissner M, Kippenberger S (2015) Impact of different spa wa-
ters on inflammation parameters in human keratinocyte HaCaT
cells. Ann Dermatol 27:709714.
Int J Biometeorol
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... In addition, shortly after cerebral blood flow is reduced or stopped, energy-dependent cell pumps [40] fail because of the decreased glucose-dependent ATP generation, resulting in the flow of many ionic species inside the cell. This generates cellular swelling through cellular depolarization [20] and osmosis [41]. ...
... CO 2 is a low-fat, soluble molecular gas with a strong diffusion capacity, which can cross the blood-brain barrier. In healthy people, CO 2 is maintained in a narrow homeostatic serum titer (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) by specific physiological mechanisms. PaCO 2 is the balance between CO 2 production and disposal. ...
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Background: Cerebral circulation delivers the blood flow to the brain through a dedicated network of sanguine vessels. A healthy human brain can regulate cerebral blood flow (CBF) according to any physiological or pathological challenges. The brain is protected by its self-regulatory mechanisms, which are dependent on neuronal and support cellular populations, including endothelial ones, as well as metabolic, and even myogenic factors. Objectives: Accumulating data suggest that "non-pharmacological" approaches might provide new opportunities for stroke therapy, such as electro-/acupuncture, hyperbaric oxygen therapy, hypothermia/cooling, photobiomodulation, therapeutic gases, transcranial direct current stimulations, or transcranial magnetic stimulations. We reviewed the recent data on the mechanisms and clinical implications of these non-pharmaceutical treatments. Methods: To present the state-of-the-art for currently available non-invasive, non-pharmacological-related interventions in acute ischemic stroke, we accomplished this synthetic and systematic literature review based on the Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses (PRISMA). Results: The initial number of obtained articles was 313. After fulfilling the five steps in the filtering/selection methodology, 54 fully eligible papers were selected for synthetic review. We enhanced our documentation with other bibliographic resources connected to our subject, identified in the literature within a non-standardized search, to fill the knowledge gaps. Fifteen clinical trials were also identified. Discussion: Non-invasive, non-pharmacological therapeutic/rehabilitative interventions for acute ischemic stroke are mainly holistic therapies. Therefore, most of them are not yet routinely used in clinical practice, despite some possible beneficial effects, which have yet to be supplementarily proven in more related studies. Moreover, few of the identified clinical trials are already completed and most do not have final results. Conclusions: This review synthesizes the current findings on acute ischemic stroke therapeutic/rehabilitative interventions, described as non-invasive and non-pharmacological.
... Traditionally, balneotherapy treatments are used in the prevention, treatment and rehabilitation of musculoskeletal and rheumatoid disorders [21]. Nonetheless, there are other applications, such as in dermatologic processes [22], chronic pain-based and immuno-inflammatory diseases [23,24], neurologic diseases and even in psychiatric illnesses [25]. ...
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The aim of this article is to assess both the economic and social value of balneotherapy and spa tourism, being the first paper in carrying out this analysis. The study has been conducted in Maresme, a region of Catalonia, Spain. On the one hand, an Input-Output (IO) model with a Social Accounting Matrix (SAM) has been carried out to assess the economic value. On the other hand, a Cost-Benefit Analysis (CBA) has been used to monetise the social value in this region, taking into account, among other concepts, direct and indirect health profits, given that balneotherapy helps to alleviate various diseases. The results show that whereas the economic multiplier is 1.529 considering the direct and indirect effects and 1.712 taking into account also the induced effects, which are similar to health and medical tourism multipliers, social value generates additional positive value, given that the cost-benefit ratio is 1.858. The theoretical implications of the paper as well as the findings’ implications for policy so as to encourage investments in spa tourism are discussed.
... Compared to conventional dosage forms, liposomes were found to deliver efficiently and at high concentrations hydrophilic substances to deeper skin tissues (Verma et al., 2003, Betz et al., 2005. The encapsulation of TWs in liposomes is an interesting alternative to improve skin permeation (Araujo et al., 2015), as long as percutaneous penetration of water increases as the stratum corneum is damaged or decreases as the latter is intact (Blattner et al., 2014, Carbajo andMaraver, 2018). To date, the encapsulation of TWs into liposomes has received little interest. ...
The main objectives of this work were to formulate liposomes encapsulating highly mineralized thermal waters (TWs) and to study anti-inflammatory effect of free and encapsulated thermal waters on RAW 264.7 macrophage cells stimulated with lipopolysaccharide (LPS). TWs-loaded conventional and deformable liposomes (TWs-Lip and TWs-DLip) were prepared by sonication and extrusion, respectively. They were considered for their vesicle size, zeta potential, entrapment efficiency, physical stability and in vitro anti-inflammatory effect. Formulated liposome suspensions have a low polydispersity and nanometric size range with zeta potential values close to zero. The vesicle size was stable for 30 days. Entrapment efficiency of TWs was above 90 % in conventional liposomes and 70 % in deformable liposomes. Pretreatment of LPS-stimulated murine macrophages, with free and liposome-encapsulated TWs, resulted in a significant reduction in nitric oxide (NO) production and modulated tumor necrosis factor-α (TNF-α) production suggesting an anti-inflammatory effect which was even more striking with TWs-Lip and TWs-DLip. Liposome formulations may offer a suitable approach for transdermal delivery of TWs, indicated in inflammatory skin diseases.
... The topical administration of salt water rich in Cl− and Na+, changes the cell osmotic pressure and produces a mechanical stimulus and stimulates the opening of Piezo ion channels. With the opening of Piezo ion channels, the skin nerve receptors are stimulated and the neurological response affecting the brain are generated (Carbajo and Maraver, 2018). The neurological system stimulated by the effect of salt water bath on the skin plays a role in reducing chemotherapy related fatigue. ...
Objectives : In a clinical setting, patients have been observed to complain of discomfort and to discontinue treatment because of chemotherapy-induced peripheral neuropathy. This experimental study was conducted to determine the effect of a salt-water bath in the management of chemotherapy-induced peripheral neuropathy. Method : One hundred and three patients who received taxane and platinum-based chemotherapy due to cancer and developed peripheral neuropathy associated with the treatment between December 2018 and June 2020 were included in the study. The patients were assigned to the control and experimental groups (1-warm salt-water and 2-cold salt-water) following the randomization checklist. While control groups did not receive any interventions, the patients in the salt-water group were asked to apply warm (41°C) or cold-water (23–26°C) baths to their hands/feet for 30 minutes every other day for 14 days. The data were collected at the beginning of the study and at the end of its first and second weeks using the Patient Information Form and National Cancer Institute (NCI)-CTCAE v5.0 toxicity criteria as well as the EORTC QLQ-C30 and EORTC QLQ-CIPN20 quality of life scales. Results : The patients had a mean age of 55.6 ± 10.3, and most of them were treated following a breast cancer diagnosis. At the beginning of the study, Grade 3 peripheral neuropathy severity and quality of life scores of the cold/warm salt-water and control groups were similar. Due to repeated follow-ups, it was determined that the peripheral neuropathy severity decreased and the quality of life scores increased statistically significantly in the patients in the cold salt-water bath group compared to the control group. Conclusion : This study's results suggest that a cold salt-water bath can be an effective approach in managing the development of peripheral neuropathy due to taxane and platinum-based treatment.
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Mud is a semi-colloidal substance formed by the mixture of inorganic, organic and water under the influence of various physical and chemical factors through geological and biological processes. The chemical composition of mud is complex, rich in Ca²⁺, Zn²⁺, Mg²⁺, Na⁺ and other mineral elements, also contains organic matter such as humic acid, fulvic acid and acetic acid. In cosmetic field, mud can improve the activity of glutathione enzyme and superoxide dismutase in skin, which helps the skin anti-aging. Besides, it also can improve the skin microbial community, due to its distinctively physical properties, mineral ions, microorganisms, etc. In medical field, mud can treat osteoarthritis, especially knee osteoarthritis which has been studied extensively, and it can also increase the chemotaxis of macrophages. On the one hand, the use of clay (a kind of refined mud) can protect the gastrointestinal tract and treat some gastrointestinal diseases. On the other hand, clay is often used as carriers or composites in drug delivery, especially in skin drug delivery, showing very positive results. The purpose of this review is to present an overview of current knowledge about the application of mud in cosmetic and medical fields and to provide ideas for further research in mud.
Clay, or more precisely, certain clay typologies, have been used traditionally by humans for therapeutic, nutritional, and skin-care purposes though they may be responsible for some relatively rare but significant health and skin-care risks. For example, clay particles could adsorb and make available for elimination or excretion any potential toxic elements or toxins being ingested or produced, but they could also adsorb and make available for incorporation, through ingestion or through dermal absorption, toxic elements, e.g. heavy metals. Geophagy has been observed in all parts of the world since Antiquity, reflecting cultural practices, religious beliefs, and physiological needs, be they nutritional (dietary supplementation) or as a remedy for disease. Some clays and clay minerals are employed widely in both the pharmaceutical and cosmetics industries as active compounds/agents and as excipients. In the biomedical field, some clay minerals such as halloysite and montmorillonite are known for their effective role as carriers for the control and sustainable delivery of active drug molecules, and in the biomaterials field some clay minerals are used for scaffold, hydrogel, foam, and film production. Constraints, both chemical and microbiological, on the use of clay-based products for therapeutic and cosmetic topical applications are generally imposed by sanitary regulations, and some solutions are proposed herein to control and reduce such restrictions. Particular emphasis is placed here on peloids and pelotherapy, as well as on manipulated and modified peloids, and specifically on tailored peloids or ‘designed and engineered’ peloids, and their derivatives, bactericidal peloids and ointments. As far as the so-called ‘killer clays’ are concerned, their pre-requisites, mechanisms of action, and disinfection role are also enhanced. Podoconiosis is an environment-related or geochemical disease that occurs in tropical highland areas, and is caused by long-term exposure of bare feet to volcanic, red-clay soil and affects some people, particularly those working in agriculture in some regions of Africa, Asia, and South America.
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Mechanosensory inputs arising from dynamic interactions between the skin and moisture, such as when sliding a finger over a wet substrate, contribute to the perception of skin wetness. Yet, the exact relationship between the mechanical properties of a wet substrate, such as friction, and the resulting wetness perception, remains to be established under naturalistic haptic interactions. We modelled the relationship between mechanical and thermal properties of substrates varying in moisture levels (0.49x10 ⁻⁴ ; 1.10x10 ⁻⁴ ; 2.67x10 ⁻⁴ ml mm ⁻² ), coefficient of friction (0.783, 0.848, 1.033, 0.839, 0.876, 0.763), and maximum thermal transfer rate (Q max , ranging from 511 to 1260 W m ⁻² K ⁻¹ ), and wetness perception arising from the index finger pad's contact with such substrates. Forty young participants (20M/20F) performed dynamic interactions with 21 different stimuli using their index finger pad at a controlled angle, pressure, and speed. Participants rated their wetness perception using a 100 mm visual analogue scale (very dry to very wet). Partial least squares regression analysis indicated that coefficient of friction explained only ~11% of the variance in wetness perception, while Q max and moisture content accounted for ~22% and 18% of the variance, respectively. These parameters shared positive relationships with wetness perception, such that the greater the Q max , moisture content, and coefficient of friction, the wetter the perception experienced. We found no differences in wetness perception between males and females. Our findings indicate that while the friction of a wet substrate modulates wetness perception, it is still secondary to thermal parameters such as Q max .
Objectives Mud pack or compress is an easily accessible, cost-effective, efficient treatment modality used in naturopathy to manage and prevent various chronic illnesses. This study sought to elucidate the effectiveness of cold spinal mud packs on improving neuro-cardiac parameters among hypertensive individuals. Methods A total of 100 hypertensive subjects aged 30–50 years were randomly allocated into two groups: Cold spinal mud pack (CSMP) and prone rest. Blood Pressure (BP) and Heart Rate Variability (HRV) were assessed at three-time points: Baseline, After 20 min (T1), After 60 min (T2). This single-blinded randomized controlled trial was registered in the Clinical Trials Registry-India (CTRI/2019/12/022492). Results After 20 min of CSMP showed a statistically significant reduction (p<0.01) in mean values of Systolic BP, Diastolic BP, and in HRV attained statistically significant change (p<0.01) in mean score in the frequency domain except for Very low-frequency power (VLF) and a significant difference found in the mean score of time-domain values (p<0.01) when compared to control group and 95% confidence interval (CI) will be provided for each effect. Conclusions CSMP reduces the sympathetic tone and shifts the sympathovagal balance in favor of parasympathetic dominance, contributing to a decrease in BP and effective changes in components of HRV.
A scientific review is devoted to the study of the coastal climate in the resort treatment role of patients with chronic diseases and its impact on the health and life quality of the population of the seacoasts. The sources were the Cochrane Library, PubMed MEDLINE, MedlinePlus, PedRO, Google Scholar, British Medical Journal, Elsevier, The Global Wellness Institute, The review includes 40 publications including 22 domestic and 18 foreign ones on clinical and surrogate outcomes of climate-therapy at seaside resorts in the structure of spa treatment in patients with chronic diseases. The health problems among the population of the seacoasts are considered. The features of conducting evidence-based studies in assessing the effects of climate procedures are noted. The analysis of the therapeutic and health-improving effect results of the seaside climate and the associated forms of thalassotherapy - terrenkur, swimming, aqua gymnastics, sea bathing, heliotherapy, landscape therapy, and the use of maricultureis carried out. The article presents statistically reliable data on the favorable outcomes of treatment of chronic forms of musculoskeletal, skin, pulmonary and cardiac pathology under the influence of thalassotherapy methods. It was found that the effectiveness of climate-therapy in oncological practice, the treatment of pollinosis, the use of algae and other maricultures has been insufficiently proven: the possibility of percutaneous permeability to seawater and its components. The risk of developing negative meteorological reactions during climate-therapy was noted.
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To determine whether spa therapy has a beneficial effect on pain and disability in patients with chronic shoulder pain, this single-blind randomised controlled clinical trial included patients with chronic shoulder pain due to miscellaneous conditions attending one of four spa centres as outpatients. Patients were randomised into two groups: spa therapy (18 days of standardised treatment combining thermal therapy together with supervised mobilisation in a thermal pool) and controls (spa therapy delayed for 6 months: ‘immediate versus delayed treatment’ paradigm). All patients continued usual treatments during the 6-month follow-up period. The main endpoint was the mean change in the French-Quick DASH (F-QD) score at 6 months. The effect size of spa therapy was calculated, and the proportion of patients reaching minimal clinically important improvement (MCII) was compared. Secondary endpoints were the mean change in SF-36, treatment use and tolerance. One hundred eighty-six patients were included (94 patients as controls, 92 in the spa group) and analysed by intention to treat. At 6 months, the mean change in the F-QD score was statistically significantly greater among spa therapy patients than controls (− 32.6 versus − 8.15%; p < 0.001) with an effect size of 1.32 (95%CI: 0.97–1.68). A significantly greater proportion of spa therapy patients reached MCII (59.3 versus 17.9%). Spa therapy was well tolerated with a significant impact on SF-36 components but not on drug intake. Spa therapy provided a statistically significant benefit on pain, function and quality of life in patients with chronic shoulder pain after 6 months compared with usual care.
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Our previous crossover randomized trial suggested that spa therapy added to usual pharmacotherapy provides benefits that lasted 6 months over pharmacotherapy alone in rheumatoid arthritis patients. We now extend, and report the long-term results of that study. In the crossover trial, patients were randomized to spa therapy first group or control first group (first assignment, period 1, 6 months); after this period and washout phase (9 months), they crossed over to the other arm (second assignment, period 2, 6 months). In this long-term study, we now analyze the 15-month results of the first assignment, and 12-month results of the second assignment in the opposite side with a 6-month extension of the follow-up period. The clinical outcome measures were pain, patient and physician global assessment, Health Assessment Questionnaire, and Disease Activity Score-28. The 15-month results of first assignment revealed no statistically significant differences between the groups in any of the efficacy outcomes (p > 0.05 for all). The 12-month results for the second assignment after crossover revealed a statistically significant decrease between the groups regarding the patient global assessment scores (p = 0.016), physician global assessment scores (p = 0.003) and swollen joints counts (p = 0.030); however, no statistically significant difference was found between the groups in any of the other efficacy outcomes (p > 0.05 for all). The short- and medium-term beneficial effects of the 2-week spa therapy added to the usual pharmacotherapy observed through the initial 6-month evaluation period may be maintained mildly to moderately to the 12-month mark in rheumatoid arthritis patients receiving conventional disease-modifying antirheumatic drugs. Further studies with a larger sample size are needed for the confirmation of the study results.