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Original Paper

A Long-Term Study to Evaluate Acidic Skin Care Treatment in Nursing Home Residents: Impact on Epidermal Barrier Function and Microflora in Aged Skin

Blaak J.a · Kaup O.b · Hoppe W.c · Baron-Ruppert G.c · Langheim H.e · Staib P.a · Wohlfart R.a · Lüttje D.d · Schürer N.b

Author affiliations

aResearch and Development, Kneipp GmbH, Würzburg, Departments of bDermatology, Environmental Medicine and Health Theory and cBiomedical Sciences, School of Human Sciences, University of Osnabrück, and dKlinik für Geriatrie und Palliativmedizin, Klinikum Osnabrück GmbH, Osnabrück, and eHaus am Berg, Seniorenpflege und -betreuung GmbH & Co. KG, Hasbergen, Germany

Corresponding Author

Dr. Jürgen Blaak

Research and Development, Kneipp GmbH

Winterhäuser Strasse 85

DE-97084 Würzburg (Germany)

E-Mail juergen.blaak@kneipp.de

Related Articles for ""

Skin Pharmacol Physiol 2015;28:269-279

Abstract

Background: The pH of the stratum corneum (SC) in the elderly is elevated and linked to impaired SC function. Therefore, this paper addresses the question of whether acidic skin care generates positive clinical, biophysical, and microbiological effects in aged skin. Methods: This study was performed to assess skin care effects in nursing home residents (aged 80-97 years). Visual, biophysical, and microbiological methods were used. Subjects were randomly assigned to 1 of 2 groups and treated over 7 weeks with skin care products adjusted to a pH of 4.0 (group A) or a pH of 6.0 (group B). Results: Compared to baseline, SC integrity improved significantly in group A (p = 0.007), whereas there was no change in group B (p = 0.672). SC recovery 24 h after perturbation increased significantly in group A (p = 0.004) compared to baseline. The SC recovery in group B was not significant compared to baseline (p = 0.327). Conclusion: Long-term treatment with pH 4.0 skin care results in a significant improvement in epidermal barrier function compared to identical products with a pH of 6.0. In addition, effects on skin dryness and resident flora were demonstrated, but without significant differences, between the 2 groups. Based on these results, we recommend adjustment of skin care products for the elderly to a pH of 4.0 to maintain the health of aged skin.

© 2015 S. Karger AG, Basel


Introduction

Severe xerosis is a common problem in the elderly and a serious dermatological challenge; however, its prevalence depends on the clinical setting [1] (e.g. it is present in up to 77% of nursing home residents) [2]. Due to the combination of low humidity and very high room temperatures, the prevalence of skin dryness can increase to up to 95% during winter [3]. Moreover, dry, scaly, rough skin is frequently accompanied by itching (pruritus senilis) [4]. Severe xerosis and pruritus in the elderly can induce the dry-skin cycle [5] and the itch-scratch cycle [6], which lead to cracked, fissured, eczematous, and inflamed skin.

Xerosis is linked to many functional and structural changes in aged skin which affect different cutaneous layers, i.e. the dermis, the epidermis and its outermost layer, and the stratum corneum (SC), where the epidermal permeability barrier (EPB) is located [7]. Furthermore, sebum and sweat production [8], together with the lipid content [9] and hydration [10], are decreased in aged SC.

Abnormal EPB function in aged skin has been demonstrated. Tape stripping studies on aged murine and human skin have revealed a reduced barrier integrity compared to young skin [11,12]. In addition, irritability by an alkaline noxe is known to be significantly higher in aged skin than in young skin, with an additional significant deficit in photoaged skin [13]. Recovery of the SC after perturbation by tape stripping or acetone is significantly delayed in human and murine aged skin compared to young skin [11,12], with a further significant delay in photoaged skin compared to chronologically aged skin [14].

One of the most important challenges in age-related EPB physiology appears to be the elevation of the skin surface pH (and SC pH). A correlation between higher pH values (5.7 ± 0.15) and age (67-95 years) has been shown in the elderly [15]. Furthermore, a higher skin surface pH was demonstrated by Zlotogorski et al. [16] in a group of subjects aged >80 years compared to younger groups. Man et al. [17] showed pH values of approximately 6.0 on the forearms and foreheads of elderly subjects (>70 years). Choi et al. [12] demonstrated a significant increase in skin surface pH on the forearms of 55 moderately aged humans (51-80 years) compared to 65 young subjects (13-21 years). The same investigation showed elevated pH at all levels throughout the SC in aged mice.

SC pH regulates at least 3 epidermal functions [18], i.e. SC integrity/cohesion, SC recovery, and antimicrobial barrier function. Desquamation is induced by a complex proteolytic cascade and depends on the activity of different kallikrein-related peptidases [19], especially kallikrein-5 (KLK5) and KLK7 [20]. As shown experimentally, both serine proteases exhibit a neutral pH optimum [21,22]. Desquamation is linked to the degradation of desmoglein 1 (DSG1), desmocollin 1 (DSC1), and corneodesmosin (CDSN) by these KLK [20]. DSG1, DSC1, and CDSN are extracellular protein structures of corneodesmosomes which ensure SC stability. The physiological SC pH regulates the activity of KLK5 and KLK7 by reducing, but not completely inhibiting, them. Consequently, desquamation and the integrity of the SC are balanced, regulated, and maintained [18,23].

Besides integrity, SC recovery depends on the pH gradient throughout the SC. EPB restoration is delayed if experimentally impaired skin is exposed to a neutral pH buffer [24] or to superbases [25]. These pH-induced barrier abnormalities are associated with inhibition of two lipid-processing enzymes, i.e. β-glucocerebrosidase (β-GlcCer'ase) and acid sphingomyelinase (aSMase), which exhibit a low pH optimum, and transfer of polar lipids, such as glucosylceramide and sphingomyelin, to the nonpolar barrier organization [26,27,28,29].

The relationship between skin surface pH and skin flora has been known for a long time and has been shown in many in vitro and in vivo investigations [30,31,32,33,34,35]. In vitro and in vivo studies have demonstrated that a pH of 5.0 inhibits the growth of pathogenic bacteria, such as Staphylococcus aureus; however, species of the normal resident flora are positively affected by the physiologically slightly acidic milieu [32,33,34,36]. Furthermore, dissociation of endogenous bacteria from the skin surface is enhanced in alkaline conditions [30].

In summary, the age-related pH shift increases the activity of KLK5 and KLK7 and inhibits the activity of the lipid-processing enzymes β-GlcCer'ase and aSMase. This results in excessive degradation of corneodesmosomes and inadequate formation of the lamellar lipid bilayers. The functional consequences are: (i) reduced SC integrity/cohesion [25,37,38], (ii) delayed SC recovery [24,25,38], and (iii) negative effects on skin flora [30].

In a previous pilot study, we showed that topical application of an acidic emulsion (pH 4.0) normalizes the elevated skin surface pH in the elderly and improves barrier integrity as measured by tape stripping [39]. In the present work, we set out to study the effect of a long-term pH 4.0 skin care treatment in a real-life setup with regard to clinical, functional, and microbiological skin characteristics. To address this issue, we performed a randomized, controlled, double-blind, long-term study in a nursing home.

Materials and Methods

Study Population

This study was performed in cooperation with a nursing home (Haus am Berg, Osnabrück, Germany) and involved 20 residents (16 women and 4 men) aged 80-97 years (mean 87.0 ± 5.4). The inclusion criteria were: age ≥80 years, healthy skin at the test sites, SC hydration ≤35.0 AU, and pigment type I-III. Volunteers were excluded if they suffered from skin diseases, such as atopic dermatitis (AD) or psoriasis, or strong physical and/or psychological handicaps and/or if they had used topic and/or systemic antibiotics up to 4 weeks prior to the start of this study. The elderly from the nursing home were separated into 2 groups (A and B), without influence from the investigator, in a randomized procedure. This study started with 26 volunteers (13 in each group) and ended with 20 volunteers (group A, n = 12; group B, n = 8) because 6 volunteers dropped out due to internal diseases.

This study was approved by the Ethical Committee of the University of Osnabrück, which gave it unanimous approval (No. 4/71040/0/6). Written, informed consent was obtained from all volunteers according to the Declaration of Helsinki.

Study Design

This randomized, controlled, double-blind study was carried out in April and May. The test products [oil-in-water (O/W) cream, O/W lotion, and synthetic detergent] were applied twice a day as body care for 7 weeks by the volunteers themselves or by caregivers. Group A was treated with test products adjusted to a pH of 4.0 and group B was treated with test products adjusted to a pH of 6.0 (see suppl. material; for all online suppl. material, see www.karger.com/doi/10.1159/000437212).

The existing skin care products were confiscated to avoid any possibility of confusion. Measurements were taken at baseline and after the test period in a specifically arranged skin lab within the nursing home, with comparable climatic conditions (baseline: temperature 22.4°C ± 0.6, relative humidity 45.1% ± 1.9; after the treatment: temperature 22.9°C ± 0.4, relative humidity 47.9% ± 1.0). Volunteers refrained from using any skin care or cleansing products or other cosmetics for at least 24 h before measurements. Furthermore, contact between the test areas and water was avoided for at least 12 h. The measurements started after a 30-min acclimatization period.

Clinical Assessment

Clinical assessment in this context meant determination of skin dryness via visual scoring according to Serup [40]. Visual examination of the complete integument was performed by a trained assessor (N.S.) and expressed as a dry-skin area and severity index (DASI). Based on this guidance, the severity of scaling, roughness, fissures, and redness was assessed as absent (0), slight (1), moderate (2), severe (3), or very severe with eczema (4). This score was calculated in the following 4 regions: the lower extremities, the trunk, the upper extremities, and the head and neck. After adding the scores, DASI values ranged between 0 and 1,600.

Functional Assessment

The following biophysical measurements were taken on the volar forearm of the volunteers based on relevant guidelines [41,42,43]: SC hydration (Corneometer® CM825; Courage and Khazaka, Cologne, Germany), skin surface pH (Skin-pH-Meter® P905; Courage and Khazaka), and transepidermal water loss (TEWL; DermaLab® Transepidermal Water Loss Module; Cortex Technology ApS, Hadsund, Denmark).

Assessment of EPB function included: SC integrity, cohesion, and recovery as defined previously [44]. The baseline TEWL was measured, followed by sequential tape stripping (D-Squame Standard; CuDerm Corporation, Dallas, Tex., USA) until the TEWL increased by 3-fold, reflecting barrier perturbation. The integrity of the SC was expressed as the number of tape strips required to increase the TEWL by 3-fold. The TEWL measurement, taken 24 h after SC perturbation, reflects EPB restoration and is calculated as the percentage recovery rate. To study SC cohesion, every second strip of the first 15 that were taken (i.e. D-Squame No. 1, 3, 5, 7, 9, 11, 13, and 15) was analyzed by: (i) infrared densitometry (SquamScan™ 850A; Heiland Electronic, Wetzlar, Germany) and (ii) Bradford protein quantification. Eight D-Squames were selected and stored at 5°C. Absorption (%) of the D-Squames was measured with an infrared densitometer at a wavelength of 850 nm. Absorption was correlated in a linear manner with the protein content [45]. Furthermore, the protein amount was extracted from the D-Squames and assessed using a Bio-Rad Protein Assay Kit I (Bio-Rad Laboratories GmbH, Munich, Germany). The procedure was a modification of a previously described approach [38,46]. Before stripping the SC, the skin surface was cleaned with an ethanol wipe. The D-Squames were treated and shaken with 1 ml of 1 M NaOH for 1 h at 37°C to remove the corneocytes from the adhesive tape site. After neutralization with 1 ml of 1 M HCl, 0.2 ml of the solution was transferred to tubes and shaken with 0.2 ml of Bio-Rad protein dye and 0.6 ml of ddH2O for 5 min. To measure the absorption at 595 nm by spectrophotometry (U-1900; Hitachi Ltd., Tokyo, Japan), the reagent was transferred into semi-micro cuvettes (PMMA; Brand GmbH and Co. KG, Wertheim, Germany). The amount of protein was calculated as micrograms removed per tape, and it represents the mean value of the 8 analyzed D-Squames. Empty D-Squames were used as a negative control and their absorption was involved in the calculation.

Microbiological Assessment

The combined wash-scrub method of Williamson and Kligman [47] was used to sample the skin flora. A glass chamber (Ø 2.4 cm) was pressed to the skin surface, 1 ml of phosphate-buffered solution [0.0075 M NaH2PO4 (8.5 ml), 0.0075 M Na2HPO4 (91.5 ml), and Triton-X-100 to 0.1% (v/v); pH 7.9] was applied, and a scrub procedure with a Teflon spatula was carried out for 1 min. Thereafter, the solution was aspirated and transferred to sterile tubes using a single-channel pipette. This procedure was repeated once. The tubes were directly stored at 5°C. Within 4 h, a serial dilution of the each sample was produced, 0.1 ml was plated onto different agar media, i.e. COS, PVX, MCK, and SGC2 (bioMérieux SA, Marcy-l'Étoile, France), and plates were incubated at 37°C for 48 h. The skin flora was quantitatively and qualitatively analyzed via established culture-based microbiological methods. Based on this procedure, the number of colony-forming units (CFU) per square centimeter of skin was calculated and the isolated bacteria were identified.

Statistical Analyses

Statistical analysis was performed using SPSS statistic version 19.0 (IBM SPSS, Chicago, Ill., USA). To compare the nonparametric paired values of each test site, a Wilcoxon signed-rank test was used. Differences between test sites were analyzed using a Mann-Whitney U test for nonnormally distributed, nonpaired data. p ≤ 0.05 was considered statistically significant. The data are represented in box plots and in table form as medians, 25th and 75th percentiles, and ranges.

Results

Clinical Assessment

No significant differences were noted in skin dryness, calculated based on the DASI, between groups A and B before treatment (i.e. at baseline; p = 0.616). Significantly reduced skin dryness was observed after 7 weeks of treatment with the test products in groups A (p = 0.002) and B (p = 0.036) (fig. 1). The differences between both groups were not significant (p = 0.297) after treatment. In summary, a strong decrease in skin dryness was observed after long-term treatment in both groups, with only small differences between the groups.

Fig. 1

Evaluation of xerosis based on the DASI before and after treatment with the test products. Comparison between groups A (pH 4.0 products) and B (pH 6.0 products). Statistical analyses were performed using a paired Wilcoxon signed-rank test and an unpaired Mann-Whitney U test. * Extreme value; ° outlier.

http://www.karger.com/WebMaterial/ShowPic/394641

Functional Assessment

Before treatment, no significant differences in skin surface pH (p = 0.461), SC hydration (p = 0.334), or TEWL (p = 0.643) between the groups were observed, illustrating the homogeneity of the volunteers. After treatment, the skin surface pH decreased specifically in group A (i.e. from 5.57 to 5.17, p = 0.003). The skin surface pH in group B remained at the baseline level (i.e. above 5.5). Furthermore, statistical analyses revealed significant (p < 0.001) differences between the groups after treatment (fig. 2a). In both groups, the SC hydration after treatment was higher than at baseline, but the increase was significant (p = 0.005) only in group A. Skin hydration (AU) increased from 30.5 to 36.3 in group A and from 28.3 to 30.7 in group B, respectively (fig. 2b). Evaluation of the TEWL showed no significant differences between groups or time points. The TEWL showed an increase from 4.25 to 4.60 g/m2/h in group A and from 4.65 to 4.50 g/m2/h in group B (fig. 2c).

Fig. 2

Skin-surface pH(a), SC hydration (b), and TEWL (c) before and after treatment with the test products. Comparison between groups A (pH 4.0 products) and B (pH 6.0 products). Statistical analyses were performed using a paired Wilcoxon signed-rank test or an unpaired Mann-Whitney U test. * Extreme value; ° outlier.

http://www.karger.com/WebMaterial/ShowPic/394640

We then performed dynamic studies on epidermal barrier integrity/cohesion and recovery of the aged volunteers. Statistical analyses of baseline SC integrity (p = 0.699), recovery (p = 0.700), and cohesion (p = 0.396; p = 0.643) revealed no significant differences between groups A and B. Before the long-term treatment, 16.0 (group A) and 14.0 (group B) tape strippings were required to perturb the epidermal barrier of the elderly. Compared to baseline, the SC integrity in group A significantly (p = 0.007) improved after 7 weeks as indicated by the higher number of tape strippings required to disturb the EPB. Moreover, after treatment, significant (p = 0.025) differences in SC integrity were shown between groups A and B (fig. 3a). The amount of protein removed per strip (125.8 vs. 143.6 µg; p = 0.396) and the percentage absorbance (12.4 vs. 11.8%; p = 0.643) displayed no significant differences between groups A and B. After treatment, the amount of protein per strip (173.2 µg; p = 0.025) and the percentage absorbance (14.3%; p = 0.025) were significantly enhanced in group B compared to baseline values. We determined no significant changes in barrier cohesion compared to baseline in group A regardless of the assessment technique (fig. 3c, d).

Fig. 3

Epidermal barrier function in both groups before (baseline) and after treatment with the test products. SC integrity(a), SC recovery (b), and SC cohesion assessed by protein quantitation (c) and percentage absorbance(d). SC integrity was assessed as the number of D-Squame tape strippings required to increase the TEWL by 3-fold. The TEWL was measured immediately and 24 h after tape stripping and percentage recovery was calculated as described previously. SC cohesion is defined as the amount of protein per D-Squame and was measured as previously described. * Extreme value; ° outlier.

http://www.karger.com/WebMaterial/ShowPic/394639

EPB restoration was assessed 24 h after tape stripping and was expressed as percentage recovery. In both groups, SC recovery was enhanced after a 7-week treatment with the test products. Group A showed a significant increase (-0.31 vs. 55.69%; p = 0.004) in contrast to the changes in group B (19.99 vs. 22.22%; p = 0.327). Furthermore, statistical analyses showed significant (p = 0.021) differences between both groups after treatment (fig. 3b). The clinical scored and biophysical data are summarized in table 1.

Table 1

Clinical scored and physiological data

http://www.karger.com/WebMaterial/ShowPic/394644

Microbiological Assessment

Microbiological analysis revealed that group A and group B both showed quantitative differences (p = 0.015) prior to treatment with the test products. A median of 92 CFU/cm2 of skin was detected via cell counting in group A, compared to 480 CFU/cm2 of skin in group B (table 2). This difference was also significant after treatment (p = 0.003), but it was significantly higher, i.e. up to 207 (group A) and 1,336 (group B) CFU/cm2 of skin. In summary, the 7-week-long application of the test products led to higher cell counts in both groups.

Table 2

Cell count before (baseline) and after treatment by study group

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Table 3 displays the results of the qualitative microbiological evaluation. Overall, 8 different genera of bacteria and 1 fungus were detected. Altogether, coagulase-negative staphylococci were most frequently isolated. This means that 100.0% of the subjects in group A and 75.0% of the subjects in group B were colonized before treatment. The results after treatment were similar: 100.0% of the subjects in both groups were colonized by coagulase-negative staphylococci. For micrococci, an increase with treatment was noted in both groups. In contrast, the isolation rate of corynebacteria only increased in the subjects in group A after treatment. For both groups, spores of Acinetobacter spp. and Pseudomonas spp. were isolated in more subjects after treatment compared to baseline. Moreover, streptococci were only detected in 1 subject (group B) at baseline. The fungus Aspergillus fumigatus was likewise detected in 1 subject (group A) after treatment.

Table 3

Skin flora results before (baseline) and after treatment in relation to the study group

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Generally, at least 1 germ was isolated from the subjects. However, mixed flora (i.e. isolation of ≥3 germs) was only documented in 33.3% (group A) and 37.5% (group B) of the subjects. In both groups, the number of subjects with mixed flora was higher after treatment (100.0 and 87.5%).

Discussion

Xerosis is a serious dermatological problem for the elderly, especially for nursing home residents [1]. Therefore, it is necessary to improve the epidermal barrier function in the elderly to maintain the health of aged skin and to prevent serious skin problems and/or disorders such as severe xerosis, pruritus, eczema craquelé, and skin infection and inflammation. The correlation between xerosis and barrier dysfunction is commonly accepted [7] and prompted the presented research. The following question was addressed: is it possible to improve the epidermal barrier function in nursing home residents over 80 years of age?

This question is based on the described age-related enhancement of SC pH [15,16,17], leading to impaired SC integrity/cohesion and restoration [12]. No increase in skin surface pH was noted in the oldest group in a recent study; however, volunteers above the age of 80 were not included [48]. Therefore, it appears that the increase in SC pH starts at about the age of 70 years and is measurable, particularly in subjects over 80 years old.

A single application of an acidic O/W emulsion led to normalization of the increased pH in aged skin over a 7-hour time period [39]. Based on this finding, we addressed the question here of whether long-term acidic skin care treatment results in positive clinical, biophysical, and microbiological effects on aged skin. In a randomized, controlled, double-blind study, 2 groups of aged residents were nursed over 7 weeks - taking the age-related decelerated epidermal turnover time into account - with skin care products adjusted to a pH of 4.0 (group A) or a pH of 6.0 (group B). In contrast to Kim et al. [49], we discovered that skin hydration was significantly improved by application of the acidic products (p = 0.005) but not by treatment with cosmetics adjusted to a pH of 6.0 (p = 0.161). The different designs of the 2 studies do not allow a direct comparison. To our knowledge, no equivalent investigation with elderly volunteers has been performed previously.

The increase in SC hydration is related to the observed improvement in EPB, which in turn correlates with the normalized and stabilized SC pH. In addition, the loss of water-retaining osmolytes (natural moisturizing factor) seems to be enhanced in aged skin due to the reduced EPB function [11,50,51]. Thus, the described improvement in EPB likely reduces the loss of soluble natural moisturizing factor in aged skin and thereby enhances corneal water binding. Another key factor in the epidermal water balance is the water- and glycerol-transporting channel aquaporin AQP3 [52,53]. To our knowledge, until now, age-related changes in epidermal AQP3 expression have not been studied. Nevertheless, an age-related decline in the expression of aquaporins in other mammalian tissues has been demonstrated [54,55]. Based on the reported pH-sensitivity of AQP3 [56], it could be postulated that age-related changes in epidermal AQP3 expression were compensated for by the slight SC pH modification investigated in the present study. SC pH improvement likely leads to a stabilized AQP3 activity and thereby optimizes the SC water distribution. Further analysis is required to address questions concerning AQP3 expression in aged skin and the impact of acidic microdomains in SC on these important glycerol and water channels.

The known subnormal baseline TEWL in aged skin [57] was confirmed by this study, and no significant effects on water loss were measured. Xerotic skin has a lower SC water content and often shows proper barrier function, even if it is only reflected by the TEWL [58]. The conclusion can be made that static TEWL measurements are not sufficient to evaluate effects on EPB with subnormal baseline values (<5 g/m2/h) in the elderly. For this reason, it is more appropriate to measure EPB function in the elderly using dynamic methods, as previously specified [59].

Investigations on aged murine and human skin have revealed a reduced SC integrity compared to young skin [11,12]. Besides a reduced integrity, the SC recovery rate is also significantly delayed in aged skin [11,12]. Both SC integrity and recovery are even more reduced in photodamaged skin compared to intrinsic aged skin [13,14]. In the present trial, EPB integrity (p = 0.007) as well as recovery (p = 0.004) significantly improved in group A after a 7-week course of treatment with pH 4.0 products.

One possible explanation is that the measured increase in skin surface pH in group A (p = 0.003) optimized the activity of KLK5 and KLK7, leading to an improved EPB integrity compared to that in group B. Concerning the described enhancement of SC restoration following pH 4.0 skin care, the activities of the 2 key lipid-processing enzymes β-GlcCer'ase and acid aSMase are also possibly optimized. More polar lipids are transferred to nonpolar (and slightly polar) barrier lipids during the recovery period. Based on the normalized SC pH, the enhanced lamellar body lipid secretion after barrier disruption is followed by a sufficient enzyme-controlled repair process within the SC lipid matrix. The reduction in skin surface pH to a physiological level strengthens the SC structure and accelerates EPB repair mechanisms in the elderly, as described in mice by Choi et al. [12]. Buraczewska and Lodén [60] demonstrated that treatment with an acidic emulsion (pH 4.0) compared to treatment with a pH-neutral product (pH 7.5) did not result in positive effects on SC recovery in younger volunteers. In that age group (21-54 years), physiological skin surface pH levels and a sufficient skin buffering system putatively override pH modulation by acidic products. Therefore, pH modulation by products adjusted to a pH of 4.0 might not be possible as in the elderly [39] and are instead not necessary in healthy young skin.

Serine proteases, like KLK5 and KLK7, are not only regulated by the SC pH via their pH optimum but are also inhibited, for instance, by metal ions or LEKTI (lympho-epithelial kazal-type related inhibitor) [61]. The SC pH also affects LEKTI-KLK5 and LEKTI-KLK7 binding properties directly. SC acidic microdomains lead to dissociation of the LEKTI-KLK complex and thereby indirectly to the degradation of corneodesmosomes in superficial SC layers [62]. To our knowledge, no studies have been performed to investigate LEKTI and pH interactions in aged skin. It is still unclear whether age-related SC pH perturbation impacts LEKTI inhibition on KLK5 and KLK7. In addition, it is unknown whether the described SC acidification in the present work leads to stimulation or inhibition of KLK. Nevertheless, in terms of functional assessment data, i.e. on SC integrity and cohesion (table 1), we propose that KLK5 and KLK7 were slightly inhibited by SC pH normalization, which in turn is associated with homeostatic desquamation and enhanced SC integrity/cohesion [23]. This mechanism seems to overlap with the KLK activation breakdown of the LEKTI-KLK complex. However, the exact interactions between the mentioned key factors were not addressed and are still unclear.

Aside from SC integrity and cohesion, our attention was drawn to tape strippings in 8 of the 20 elderly, which revealed no immediate barrier recovery. In fact, the TEWL continued to increase within the first 24 h after perturbation. These findings revealed an age-related initial exacerbation of barrier damage not documented in young skin [11,63,64]. Barrier perturbation leads to enhanced expression of different primary cytokines, such as IL-1α, IL-1β, IL-6, and TNF-α [65], which, in turn, might be disturbed due to age-related subclinical changes in immune function known as inflamm-aging [66]. Further investigations should be performed to clarify the relationship between EPB function and immunosenescence.

Apart from the present investigation, a further link between inflammation and skin surface pH has been demonstrated [67] and is commonly accepted [68]. Maintenance of an acidic normal SC pH by topically applied lactobionic acid improved the epidermal barrier function in healthy mice [25] and in an AD mouse model [69]. Further, external acidification reduced cytokine generation and normalized antimicrobial peptide expression [69]. In another AD mouse model, SC pH neutralization in turn correlated with cutaneous inflammation and restoration of the SC pH shift was delayed [70]. Recently, Lee et al. [71] described an atopic march animal model and demonstrated that topical acidification (acidic cream pH 2.8) reduced AD-like skin lesions and interestingly inhibited respiratory allergic inflammation. Based on these murine studies, SC acidification seems to be relevant not only as a specific skin care regime but also as an approach to counteract the allergic march. The present study transferred experimental data from aged mice [12] into a real-life setting in aged nursing home residents. As far as AD is concerned, it seems necessary to verify these new insights [70,71] in human studies.

The results of the microbiological investigations are not as clear as the results concerning EPB function. Many in vitro and in vivo investigations have demonstrated a relationship between skin surface pH and skin flora and the positive effect of a slightly acidic skin surface milieu [30,31,32,33,34,35]. Due to age-related microbiological variations [72,73,74,75], the question was raised of whether it is possible to stabilize the resident flora via long-term treatment with acidic products. No significant differences between groups A and B were detected either before or after treatment. The number of detected microorganisms (CFU/cm2 of skin) increased after the treatment course compared to baseline in both groups; only the number of corynebacteria appeared to increase after treatment with pH 4.0 products. This could be interpreted as a pH-related enhancement in the resident microflora. Korting et al. [36] and Lambers et al. [30] described beneficial pH-related effects on S. epidermidis that were not observed in the present study. Apart from the mentioned effect on corynebacteria and the increase in bacterial diversity in group A, the microbiological results might only be tendencies and should be carefully interpreted. Therefore, questions concerning the impact of long-term pH 4.0 skin care treatment on microflora in the elderly remain unanswered. One conclusion is that the documented broad distribution (in CFU/cm2 skin) in both groups and the lack of a control for various influence factors on skin flora, such as nutrition and clothing, are the reasons for the unclear microbiological results.

Conclusions

The present investigation transferred published experimental results for mice to a real-life situation in a nursing home. Long-term treatment with a pH 4.0 skin care range significantly improved the corneophysiology in aged skin, thereby helping to keep aged skin healthy. In treatment groups A (pH 4.0) and B (pH 6.0), skin hydration and the DASI were improved, but SC integrity and SC recovery were only accelerated in group A. The results led to the hypothesis that skin moisturizing in aged skin needs to be induced by skin care products that are more acidic than those available on the market and mostly used in German nursing homes [unpubl. data].

In addition to aged skin and AD, further inflammatory skin disorders, like seborrhoeic dermatitis [76] and acne [77], are accompanied by an elevated skin surface pH. Moreover, the skin surface pH is also higher in sensitive skin [78] and after sportive activities [79].

Thus, for these skin conditions, acidic skin care treatment can also be beneficial and should be evaluated via in vivo EPB measurements in humans. Finally, to maintain health in aged skin, we recommend adjusting skin care products for the elderly to a pH of 4.0.

Acknowledgements

The authors wish thank to Mrs. Juliane Liebsch for her technical assistance. This study was cosponsored by Kneipp GmbH, Würzburg, Germany.

Disclosure Statement

The authors state no conflict of interests.


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  3. Hara M, Kikuchi K, Watanabe M, Denda H, Koyama J, Horii I, Tagami H: Senile xerosis: functional, morphological and biochemical studies. J Geriatr Dermatol 1993;1:111-120.
  4. Norman RA: Xerosis and pruritus in the elderly: recognition and management. Dermatol Ther 2003;16:254-259.
  5. Rawlings AV, Matts PJ: Stratum corneum moisturization at the molecular level: an update in relation to the dry skin cycle. J Invest Dermatol 2005;124:1099-1110.
  6. Ikoma A, Rukwied R, Ständer S, Steinhoff M, Miyachi Y, Schmelz M: Neurophysiology of pruritus: interaction of itch and pain. Arch Dermatol 2003;139:1475-1478.
  7. Barco D, Giménez-Arnau A: Xerosis: a dysfunction of the epidermal barrier. Actas Dermosifiliogr 2008;99:671-682.
  8. Pochi PE, Strauss JS, Downing DT: Age-related changes in sebaceous gland activity. J Invest Dermatol 1979;73:108-111.
  9. Saint-Leger D, Francois AM, Leveque JL, Stousemayer TJ, Grove GL, Kligman AM: Age-associated changes in stratum corneum lipids and their relation to dryness. Dermatologica 1988;177:159-164.
  10. Gniadecka M, Nielsen OF, Wessel S, Heidenheim M, Christensen DH, Wulf HC: Water and protein structure in photoaged and chronically aged skin. J Invest Dermatol 1998;111:1129-1133.
  11. Ghadially R, Brown BE, Sequeira-Martin SM, Feingold KR, Elias PM: The aged epidermal permeability barrier: structural, functional, and lipid biochemical abnormalities in humans and a senescent murine model. J Clin Invest 1995;95:2281-2290.
  12. Choi EH, Man MQ, Xu P, Xin S, Liu Z, Crumrine DA, Jiang YJ, Fluhr JW, Feingold KR, Elias PM, Mauro TM: Stratum corneum acidification is impaired in moderately aged human and murine skin. J Invest Dermatol 2007;127:2847-2856.
  13. Blaak J, Lüttje D, John SM, Schürer NY: Irritability of the skin barrier: a comparison of chronologically aged and photo-aged skin in elderly and young adults. Eur Geriatr Med 2011;2:208-211.
  14. Reed JT, Elias PM, Ghadially R: Integrity and permeability barrier function of photoaged human epidermis. Arch Dermatol 1997;133:395-396.
  15. Thune P, Nilsen T, Hanstad IK, Gustavsen T, Lovig Dahl H: The water barrier function of the skin in relation to the water content of stratum corneum, pH and skin lipids: the effect of alkaline soap and syndet on dry skin in elderly, non-atopic patients. Acta Derm Venereol 1988;68:277-283.
  16. Zlotogorski A: Distribution of skin surface pH on the forehead and cheek of adults. Arch Dermatol Res 1987;279:398-401.
  17. Man MQ, Xin SJ, Song SP, Cho SY, Zhang XJ, Tu CX, Feingold KR, Elias PM: Variation of skin surface pH, sebum content and stratum corneum hydration with age and gender in a large Chinese population. Skin Res Technol 2009;22:190-199.
  18. Elias PM: Stratum corneum defensive functions: an integrated view. J Invest Dermatol 2005;125:183-200.
  19. Borgono CA, Michael IP, Komatsu N, Jayakumar A, Kapadia R, Clayman GL, Sotiropoulou G, Diamandis EP: A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem 2007;282:3640-3652.
  20. Caubet C, Jonca N, Brattsand M, Guerrin M, Bernard D, Schmidt R, Egelrud T, Simon M, Serre G: Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J Invest Dermatol 2004;122:1235-1244.
  21. Ekholm E, Egelrud T: Expression of stratum corneum chymotryptic enzyme in relation to other markers of epidermal differentiation in a skin explant model. Exp Dermatol 2000;9:65-70.
  22. Brattsand M, Egelrud T: Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation. J Biol Chem 1999;274:30033-30040.
  23. Ovaere P, Lippens S, Vandenabeele P, Declercq W: The emerging roles of serine protease cascades in the epidermis. Trends Biochem Sci 2009;34:453-463.
  24. Mauro T, Holleran WM, Grayson S, Gao WN, Man MQ, Kriehuber E, Behne M, Feingold KR, Elias PM: Barrier recovery is impeded at neutral pH, independent of ionic effects: implications for extracellular lipid processing. Arch Dermatol Res 1998;290:215-222.
  25. Hachem JP, Cumrine D, Fluhr J, Brown BE, Feingold KR, Elias PM: pH directly regulates epidermal permeability homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 2003;121:345-353.
  26. Takagi Y, Kriehuber E, Imokawa G, Elias PM, Holleran WM: Beta-glucocerebrosidase activity in mammalian stratum corneum. J Lipid Res 1999;40:861-869.
  27. Schmuth M, Man MQ, Weber F, Gao W, Feingold KR, Fritsch P, Elias PM, Holleran WM: Permeability barrier disorder in Niemann-Pick disease: sphingomyelin-ceramide processing required for normal barrier homeostasis. J Invest Dermatol 2000;115:459-466.
  28. Jensen JM, Schutze S, Forl M, Kronke M, Proksch E: Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier. J Clin Invest 1999;104:1761-1770.
  29. Holleran WM, Takagi Y, Imokawa G, Jackson S, Lee JM, Elias PM: Beta-glucocerebrosidase activity in murine epidermis: characterization and localization in relation to differentiation. J Lipid Res 1992;33:1201-1209.
  30. Lambers H, Piessens S, Bloem A, Pronk H, Finkel P: Natural skin surface pH is on average below 5, which is beneficial for its resident flora. Int J Cosmet Sci 2006;28:359-370.
  31. Korting HC, Greiner K, Hübner K, Hamm G: Changes in skin pH and resident flora by washing with synthetic detergent preparations at pH 5.5 and 8.5. J Soc Cosmet Chem 1991;42:147-158.
  32. Korting HC: Das Säuremantelkonzept von Marchioni und die Beeinflussung der Resident-flora der Haut durch Waschungen in Abhängigkeit vom pH-Wert; in Braun-Falco O, Korting HC (eds): Hautreinigung mit Syndets. Berlin, Springer, 1990, pp 93-103.
  33. Kurabayashi H, Tamura K, Machida I, Kubota K: Inhibiting bacteria and skin pH in hemiplegia: effects of washing hands with acidic mineral water. Am J Phys Med Rehabil 2002;81:40-46.
  34. Holland KT, Cunliffe WJ, Roberts CD: The role of bacteria in acne vulgaris: a new approach. Clin Exp Dermatol 1978;3:253-257.
  35. Pillsbury DM, Rebell G: The bacterial flora of the skin. J Invest Dermatol 1952;18:173-186.
  36. Korting HC, Lukacs A, Vogt N, Urban J, Ehret W, Ruckdeschel G: Influence of the pH-value on the growth of Staphylococcus epidermidis,Staphylococcus aureus and Propionibacterium acnes in continuous culture. Zentralbl Hyg Umweltmed 1992;193:78-90.
  37. Fluhr JW, Man MQ, Brown BE, Hachem JP, Moskowitz DG, Demerijan M, Haftek M, Serre G, Crumrine D, Mauro TM, Elias PM, Feingold KR: Functional consequences of a neutral pH in neonatal rat stratum corneum. J Invest Dermatol 2004;123:140-151.
  38. Fluhr JW, Kao J, Jain M, Ahn SK, Feingold KR, Elias PM: Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity. J Invest Dermatol 2001;117:44-51.
  39. Blaak J, Wohlfart R, Schürer NY: Treatment of aged skin with a pH 4 skin care product normalizes increased skin surface pH and improves barrier function: results of a pilot study. J Cosmet Dermatol Sci Appl 2011;1:50-58.
  40. Serup J: EEMCO guidance for the assessment of dry skin (xerosis) and ichthyosis: clinical scoring systems. Skin Res Technol 1995;1:109-114.
  41. Berardesca E: EEMCO guidance for the assessment of stratum corneum hydration: electrical methods. Skin Res Technol 1997;3:126-132.
  42. Rogiers V: EEMCO guidance for the assessment of transepidermal water loss in cosmetic sciences. Skin Pharmacol Appl Skin Physiol 2001;14:117-128.
  43. Parra JL, Paye M: EEMCO guidance for the in vivo assessment of skin surface pH. Skin Pharmacol Appl Skin Physiol 2003;16:188-202.
  44. Gunathilake R, Schurer NY, Shoo BA, Celli A, Hachem JP, Crumrine D, Sirimanna G, Feingold KR, Mauro TM, Elias PM: pH-regulated mechanisms account for pigment-type differences in epidermal barrier function. J Invest Dermatol 2009;129:1719-1729.
  45. Voegeli R, Heiland J, Doppler S, Rawlings AV, Schreier T: Efficient and simple quantification of stratum corneum proteins on tape strippings by infrared densitometry. Skin Res Technol 2007;13:242-251.
  46. Dreher F, Arens A, Hostýnek JJ, Mudumba S, Ademola J, Maibach HI: Colorimetric method for quantifying human stratum corenum removed by adhesive-tape-stripping. Acta Derm Venereol 1998;78:186-189.
  47. Williamson P, Kligman AM: A new method for the quantitative investigation of cutaneous bacteria. J Invest Dermatol 1965;45:498-503.
  48. Luebberding S, Krueger N, Kerscher M: Age-related changes in skin barrier function - quantitative evaluation of 150 female subjects. Int J Cosmet Sci 2013;35:183-190.
  49. Kim E, Kim S, Nam GW, Lee H, Moon S, Chang I: The alkaline pH-adapted skin barrier is disrupted severely by SLS-induced irrtation. Int J Cosmet Sci 2009;31:263-269.
  50. Tezuka T: Electron-microscopic changes in xerosis senilis epidermis: its abnormal membrane coating granule formation. Dermatologica 1983;166:57-61.
  51. Rawlings AV, Scott IR, Harding CR, Bowser PA: Stratum corneum moisturization at the molecular level. J Invest Dermatol 1994;103:731-740.
  52. Hara-Chikuma M, Verkmann AS: Aquaporin-3 functions as a glycerol transporter in mammalian skin. Biol Cell 2005;97:479-486.
  53. Sougrat R, Morand M, Gondran C, Barré P, Gobin R, Bonté F, Mara, Dumas M, Verbavatz JM: Functional expression of AQP3 in human skin epidermis and reconstructed epidermis. J Invest Dermatol 2002;118:678-685.
  54. Tas U, Cayli S, Inanir A, Özyurt B, Ocakli S, Karaca ZI, Sarsilmaz M: Aquaporin-1 and aquaporin-3 expressions in the Intervertebral disc of rats with aging. Balkan Med J 2012;29:349-353.
  55. Preisser L, Teillet L, Alliotti S, Gobin R, Berthonaud V, Chevalier J, Corman B, Verbavatz JM: Downregulation of aquaporin-2 and -3 in aging kidney is independent of V(2) vasopressin receptor. Am J Physiol Renal Physiol 2000;279:F144-F152.
  56. Zeuthen T, Klaerke DA: Transport of water and glycecrol in aquaporin 3 is gated by H+. J Biol Chem 1999;274:21631-21636.
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  64. Blaak J, Strothmann L, Hoppe W, Baron-Ruppert G, Kaup O, Lüttje D, John SM, Schürer NY: Impact of age on epidermal barrier function and skin microbiota: comparison of elderly and middle aged adults. Exp Dermatol 2012;21:e50.
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Author Contacts

Dr. Jürgen Blaak

Research and Development, Kneipp GmbH

Winterhäuser Strasse 85

DE-97084 Würzburg (Germany)

E-Mail juergen.blaak@kneipp.de


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: July 25, 2014
Accepted: June 23, 2015
Published online: August 01, 2015
Issue release date: August 2015

Number of Print Pages: 11
Number of Figures: 3
Number of Tables: 3

ISSN: 1660-5527 (Print)
eISSN: 1660-5535 (Online)

For additional information: https://www.karger.com/SPP


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References

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  2. Adam JE, Reilly S: The prevalence of skin disease in the geriatric age group. Australas J Dermatol 1987;28:72-76.
  3. Hara M, Kikuchi K, Watanabe M, Denda H, Koyama J, Horii I, Tagami H: Senile xerosis: functional, morphological and biochemical studies. J Geriatr Dermatol 1993;1:111-120.
  4. Norman RA: Xerosis and pruritus in the elderly: recognition and management. Dermatol Ther 2003;16:254-259.
  5. Rawlings AV, Matts PJ: Stratum corneum moisturization at the molecular level: an update in relation to the dry skin cycle. J Invest Dermatol 2005;124:1099-1110.
  6. Ikoma A, Rukwied R, Ständer S, Steinhoff M, Miyachi Y, Schmelz M: Neurophysiology of pruritus: interaction of itch and pain. Arch Dermatol 2003;139:1475-1478.
  7. Barco D, Giménez-Arnau A: Xerosis: a dysfunction of the epidermal barrier. Actas Dermosifiliogr 2008;99:671-682.
  8. Pochi PE, Strauss JS, Downing DT: Age-related changes in sebaceous gland activity. J Invest Dermatol 1979;73:108-111.
  9. Saint-Leger D, Francois AM, Leveque JL, Stousemayer TJ, Grove GL, Kligman AM: Age-associated changes in stratum corneum lipids and their relation to dryness. Dermatologica 1988;177:159-164.
  10. Gniadecka M, Nielsen OF, Wessel S, Heidenheim M, Christensen DH, Wulf HC: Water and protein structure in photoaged and chronically aged skin. J Invest Dermatol 1998;111:1129-1133.
  11. Ghadially R, Brown BE, Sequeira-Martin SM, Feingold KR, Elias PM: The aged epidermal permeability barrier: structural, functional, and lipid biochemical abnormalities in humans and a senescent murine model. J Clin Invest 1995;95:2281-2290.
  12. Choi EH, Man MQ, Xu P, Xin S, Liu Z, Crumrine DA, Jiang YJ, Fluhr JW, Feingold KR, Elias PM, Mauro TM: Stratum corneum acidification is impaired in moderately aged human and murine skin. J Invest Dermatol 2007;127:2847-2856.
  13. Blaak J, Lüttje D, John SM, Schürer NY: Irritability of the skin barrier: a comparison of chronologically aged and photo-aged skin in elderly and young adults. Eur Geriatr Med 2011;2:208-211.
  14. Reed JT, Elias PM, Ghadially R: Integrity and permeability barrier function of photoaged human epidermis. Arch Dermatol 1997;133:395-396.
  15. Thune P, Nilsen T, Hanstad IK, Gustavsen T, Lovig Dahl H: The water barrier function of the skin in relation to the water content of stratum corneum, pH and skin lipids: the effect of alkaline soap and syndet on dry skin in elderly, non-atopic patients. Acta Derm Venereol 1988;68:277-283.
  16. Zlotogorski A: Distribution of skin surface pH on the forehead and cheek of adults. Arch Dermatol Res 1987;279:398-401.
  17. Man MQ, Xin SJ, Song SP, Cho SY, Zhang XJ, Tu CX, Feingold KR, Elias PM: Variation of skin surface pH, sebum content and stratum corneum hydration with age and gender in a large Chinese population. Skin Res Technol 2009;22:190-199.
  18. Elias PM: Stratum corneum defensive functions: an integrated view. J Invest Dermatol 2005;125:183-200.
  19. Borgono CA, Michael IP, Komatsu N, Jayakumar A, Kapadia R, Clayman GL, Sotiropoulou G, Diamandis EP: A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem 2007;282:3640-3652.
  20. Caubet C, Jonca N, Brattsand M, Guerrin M, Bernard D, Schmidt R, Egelrud T, Simon M, Serre G: Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J Invest Dermatol 2004;122:1235-1244.
  21. Ekholm E, Egelrud T: Expression of stratum corneum chymotryptic enzyme in relation to other markers of epidermal differentiation in a skin explant model. Exp Dermatol 2000;9:65-70.
  22. Brattsand M, Egelrud T: Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation. J Biol Chem 1999;274:30033-30040.
  23. Ovaere P, Lippens S, Vandenabeele P, Declercq W: The emerging roles of serine protease cascades in the epidermis. Trends Biochem Sci 2009;34:453-463.
  24. Mauro T, Holleran WM, Grayson S, Gao WN, Man MQ, Kriehuber E, Behne M, Feingold KR, Elias PM: Barrier recovery is impeded at neutral pH, independent of ionic effects: implications for extracellular lipid processing. Arch Dermatol Res 1998;290:215-222.
  25. Hachem JP, Cumrine D, Fluhr J, Brown BE, Feingold KR, Elias PM: pH directly regulates epidermal permeability homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 2003;121:345-353.
  26. Takagi Y, Kriehuber E, Imokawa G, Elias PM, Holleran WM: Beta-glucocerebrosidase activity in mammalian stratum corneum. J Lipid Res 1999;40:861-869.
  27. Schmuth M, Man MQ, Weber F, Gao W, Feingold KR, Fritsch P, Elias PM, Holleran WM: Permeability barrier disorder in Niemann-Pick disease: sphingomyelin-ceramide processing required for normal barrier homeostasis. J Invest Dermatol 2000;115:459-466.
  28. Jensen JM, Schutze S, Forl M, Kronke M, Proksch E: Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier. J Clin Invest 1999;104:1761-1770.
  29. Holleran WM, Takagi Y, Imokawa G, Jackson S, Lee JM, Elias PM: Beta-glucocerebrosidase activity in murine epidermis: characterization and localization in relation to differentiation. J Lipid Res 1992;33:1201-1209.
  30. Lambers H, Piessens S, Bloem A, Pronk H, Finkel P: Natural skin surface pH is on average below 5, which is beneficial for its resident flora. Int J Cosmet Sci 2006;28:359-370.
  31. Korting HC, Greiner K, Hübner K, Hamm G: Changes in skin pH and resident flora by washing with synthetic detergent preparations at pH 5.5 and 8.5. J Soc Cosmet Chem 1991;42:147-158.
  32. Korting HC: Das Säuremantelkonzept von Marchioni und die Beeinflussung der Resident-flora der Haut durch Waschungen in Abhängigkeit vom pH-Wert; in Braun-Falco O, Korting HC (eds): Hautreinigung mit Syndets. Berlin, Springer, 1990, pp 93-103.
  33. Kurabayashi H, Tamura K, Machida I, Kubota K: Inhibiting bacteria and skin pH in hemiplegia: effects of washing hands with acidic mineral water. Am J Phys Med Rehabil 2002;81:40-46.
  34. Holland KT, Cunliffe WJ, Roberts CD: The role of bacteria in acne vulgaris: a new approach. Clin Exp Dermatol 1978;3:253-257.
  35. Pillsbury DM, Rebell G: The bacterial flora of the skin. J Invest Dermatol 1952;18:173-186.
  36. Korting HC, Lukacs A, Vogt N, Urban J, Ehret W, Ruckdeschel G: Influence of the pH-value on the growth of Staphylococcus epidermidis,Staphylococcus aureus and Propionibacterium acnes in continuous culture. Zentralbl Hyg Umweltmed 1992;193:78-90.
  37. Fluhr JW, Man MQ, Brown BE, Hachem JP, Moskowitz DG, Demerijan M, Haftek M, Serre G, Crumrine D, Mauro TM, Elias PM, Feingold KR: Functional consequences of a neutral pH in neonatal rat stratum corneum. J Invest Dermatol 2004;123:140-151.
  38. Fluhr JW, Kao J, Jain M, Ahn SK, Feingold KR, Elias PM: Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity. J Invest Dermatol 2001;117:44-51.
  39. Blaak J, Wohlfart R, Schürer NY: Treatment of aged skin with a pH 4 skin care product normalizes increased skin surface pH and improves barrier function: results of a pilot study. J Cosmet Dermatol Sci Appl 2011;1:50-58.
  40. Serup J: EEMCO guidance for the assessment of dry skin (xerosis) and ichthyosis: clinical scoring systems. Skin Res Technol 1995;1:109-114.
  41. Berardesca E: EEMCO guidance for the assessment of stratum corneum hydration: electrical methods. Skin Res Technol 1997;3:126-132.
  42. Rogiers V: EEMCO guidance for the assessment of transepidermal water loss in cosmetic sciences. Skin Pharmacol Appl Skin Physiol 2001;14:117-128.
  43. Parra JL, Paye M: EEMCO guidance for the in vivo assessment of skin surface pH. Skin Pharmacol Appl Skin Physiol 2003;16:188-202.
  44. Gunathilake R, Schurer NY, Shoo BA, Celli A, Hachem JP, Crumrine D, Sirimanna G, Feingold KR, Mauro TM, Elias PM: pH-regulated mechanisms account for pigment-type differences in epidermal barrier function. J Invest Dermatol 2009;129:1719-1729.
  45. Voegeli R, Heiland J, Doppler S, Rawlings AV, Schreier T: Efficient and simple quantification of stratum corneum proteins on tape strippings by infrared densitometry. Skin Res Technol 2007;13:242-251.
  46. Dreher F, Arens A, Hostýnek JJ, Mudumba S, Ademola J, Maibach HI: Colorimetric method for quantifying human stratum corenum removed by adhesive-tape-stripping. Acta Derm Venereol 1998;78:186-189.
  47. Williamson P, Kligman AM: A new method for the quantitative investigation of cutaneous bacteria. J Invest Dermatol 1965;45:498-503.
  48. Luebberding S, Krueger N, Kerscher M: Age-related changes in skin barrier function - quantitative evaluation of 150 female subjects. Int J Cosmet Sci 2013;35:183-190.
  49. Kim E, Kim S, Nam GW, Lee H, Moon S, Chang I: The alkaline pH-adapted skin barrier is disrupted severely by SLS-induced irrtation. Int J Cosmet Sci 2009;31:263-269.
  50. Tezuka T: Electron-microscopic changes in xerosis senilis epidermis: its abnormal membrane coating granule formation. Dermatologica 1983;166:57-61.
  51. Rawlings AV, Scott IR, Harding CR, Bowser PA: Stratum corneum moisturization at the molecular level. J Invest Dermatol 1994;103:731-740.
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