Randomized controlled pilot trial with ion-exchange water softeners to prevent eczema (SOFTER trial).

BACKGROUND: Observational studies suggest an increased risk of eczema in children living in hard versus soft water areas, and there is, therefore, an interest in knowing whether softening water may prevent eczema. We evaluated the feasibility of a parallel-group assessor-blinded pilot randomized controlled trial to test whether installing a domestic ion-exchange water softener before birth in hard water areas reduces the risk of eczema in infants with a family history of atopy. METHODS: Pregnant women living in hard water areas (>250 mg/L calcium carbonate) in and around London UK, were randomized 1:1 antenatally to either have an ion-exchange water softener installed in their home or not (ie to continue to receive usual domestic hard water). Infants were assessed at birth and followed up for 6 months. The main end-points were around feasibility, the primary end-point being the proportion of eligible families screened who were willing and able to be randomized. Clinical end-points were evaluated including frequency of parent-reported doctor-diagnosed eczema and visible eczema on skin examination. Descriptive analyses were conducted, and no statistical testing was performed as this was a pilot study. RESULTS: One hundred and forty-nine families screened were eligible antenatally and 28% (41/149) could not have a water softener installed due to technical reasons or lack of landlord approval. Eighty of 149 (54%) were randomized, the primary end-point. Two participants withdrew immediately after randomization, leaving 39 participants in each arm (78 total). Attrition was 15% (12/78) by 6 months postpartum. All respondents (n = 69) to the study acceptability questionnaire reported that the study was acceptable. Fifty-six of 708 (7.9%) water samples in the water softener arm were above the hard water threshold of 20 mg/L CaCO3 . At 6 months of age 27/67 infants (40%) developed visible eczema, 12/36 (33%) vs. 15/31 (48%) in the water softener and control groups, respectively, difference -15% (95% CI -38, 8.3%), with most assessments (≥96%) remaining blinded. Similarly, a lower proportion of infants in the water softener arm had parent-reported, doctor-diagnosed eczema by 6 months compared to the control arm, 6/17 (35%) versus 9/19 (47%), difference -12% (95% CI -44, 20%). CONCLUSION: A randomized controlled trial of water softeners for the prevention of atopic eczema in high-risk infants is feasible and acceptable. TRIAL REGISTRATION: NCT03270566 (clinicaltrials.gov).

Topical corticosteroid vehicle composition and implications for clinical practice.

This narrative review highlights the therapeutic significance of topical corticosteroid (TCS) vehicles and provides subsequent guidance to improve clinical and research outcomes. A greater understanding of the relationship between the topical vehicle, corticosteroid and skin is needed to ensure safer, more effective treatment for patients. Topical vehicles are not inert and can affect TCS bioavailability, due to the ability of their composition to positively or negatively influence skin status and change the physiochemical characteristics of an inherent corticosteroid. However, this principle is not commonly understood, and has contributed to inconsistencies in potency classification systems. This review provides an insight into the research methods and standardization needed to determine TCS product bioavailability. It identifies formulation components responsible for vehicle composition that underpin the quality, stability, compounding and functionalities of vehicle ingredients. This helps to contextualize how topical vehicles can be responsible for clinically significant effects, and how their composition gives products unique properties. In turn, this facilitates a more in-depth understanding of which resources offer information to inform the best selection of TCS products and why products should be prescribed by brand or manufacturer. This review will better equip clinicians and formulary teams to appraise products. It will also inform prescribing of Specials and why products should not be manipulated. The recommendations, accompanied by patient perspectives on using TCS products, assist clinical decision-making. They also identify the need for research into concomitant application of TCS products with other topical therapies.

A functional mechanistic study of the effect of emollients on the structure and function of the skin barrier.

BACKGROUND: Preventing relapses of atopic dermatitis (AD) through the regular use of topical products to repair the skin barrier defect is an emerging concept. It is still unclear if some commonly used emollients exert a positive effect on the skin barrier. OBJECTIVES: To determine the skin barrier effects of emollients commonly prescribed in the U.K. MATERIALS AND METHODS: Two cohorts of volunteers with quiescent AD undertook observer-blind forearm-controlled studies. The first cohort (18 volunteers) treated the volar side of one forearm with two fingertip units of Doublebase™ gel twice daily for 4 weeks. The second cohort (19 volunteers) undertook the same regimen using Diprobase® cream. Transepidermal water loss (TEWL), stratum corneum integrity and hydration, skin surface pH and redness were determined at the test sites before and after treatment. RESULTS: Neither Diprobase® cream nor Doublebase™ gel significantly affected the underlying skin barrier function. Both emollients were associated with significantly increased skin surface pH immediately after application (by 0·8 ± 0·19 and 1·0 ± 0·18 units, respectively), and no erythema. Diprobase® cream artificially and transiently (6 h) improved permeability barrier function by 2·9-3·1 g m-2  h-1 TEWL and increased skin hydration by 6·0-6·2 units. Doublebase™ gel, containing humectants, was associated with a greater (between 10·1 and 13·0 units during the first 6 h) and more sustained increase in hydration, lasting more than 12 h following repeated use. CONCLUSIONS: Diprobase® cream and Doublebase™ gel are not associated with skin barrier harm and appear to be appropriate for AD treatment. While displaying emollient properties, neither formulation displayed an ability to actively improve sustained skin barrier function.

Development of stratum corneum chymotrypsin-like protease activity and natural moisturizing factors from birth to 4 weeks of age compared with adults.

BACKGROUND: From birth, the functional properties of the neonatal epidermal barrier mature whereby the stratum corneum (SC) hydrates and the skin surface acidifies. The identification of a thinner infant SC compared with adults suggests underdeveloped mechanisms underlying differentiation and desquamation. OBJECTIVES: To assess the functional properties of the neonatal SC from birth, in conjunction with the quantification of superficial chymotrypsin-like protease activity [kallikrein-7 (KLK-7)] and filaggrin-derived natural moisturizing factors (NMF). METHODS: A total of 115 neonates recruited to the Oil in Baby SkincaRE (OBSeRvE) randomized controlled trial underwent a full evaluation of the SC at birth (< 72 h old) and at 4 weeks of age (n = 39, no oil control group) using minimally invasive instrumentation and methodology. A cohort of 20 unrelated adults was recruited for comparison. RESULTS: At birth NMF levels correlated with SC hydration (r = 0·50) and skin-surface pH (r = -0·54). From birth to 4 weeks, transepidermal water loss (TEWL), superficial KLK-7 activity and filaggrin-derived NMF significantly elevated. Impaired epidermal barrier function at birth (> 75th percentile TEWL) was accompanied by significantly elevated chymotrypsin-like protease activity and reduced levels of NMF. CONCLUSIONS: The biophysical, biological and functional properties of the developing neonatal SC are transitional from birth to 4 weeks of age and differ significantly from adults. The presence of impaired barrier function with elevated protease activity and reduced NMF at birth suggests why certain infants are predisposed to epidermal barrier breakdown and the development of atopic dermatitis.

The effect of tacrolimus compared with betamethasone valerate on the skin barrier in volunteers with quiescent atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin disease arising as a result of immune system and skin barrier defects. Topical corticosteroids are safe and effective treatments for AD, when used in short courses. Prolonged use is associated with skin barrier damage. Topical calcineurin inhibitors are alternative immune-modulating treatments for AD purported to have no negative effects on the skin barrier. OBJECTIVES: To compare the effects of betamethasone valerate 0·1% cream (BMVc) and tacrolimus 0·1% ointment (TACo) on the skin barrier. METHODS: Twenty volunteers with quiescent AD (no active signs for 6 months) participated in a randomized observer-blind study, wherein BMVc was applied to one forearm and TACo to the other, twice daily for 4 weeks. The biophysical/biological properties of the stratum corneum were assessed before and after treatment. Nine volunteers with active disease and 10 with healthy skin were assessed at untreated sites. RESULTS: BMVc significantly reduced skin barrier function, integrity and cohesion, and the levels of pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA) towards the subclinical barrier defect observed in patients with AD (nonlesional sites). TACo preserved skin barrier function, integrity, cohesion and PCA and UCA levels, while significantly increasing skin hydration to levels comparable with healthy skin. Both treatments reduced skin surface pH and trypsin-like protease activity, with TACo doing so to a significantly greater degree. CONCLUSION: In quiescent AD, 4 weeks of BMVc treatment adversely affected the biophysical properties of the skin and reduced the levels of natural moisturizing factor, whereas TACo improved the condition of the skin barrier.

The effect of aqueous cream BP on the skin barrier in volunteers with a previous history of atopic dermatitis.

BACKGROUND: The emollient aqueous cream BP is frequently used for the treatment of atopic dermatitis (AD), yet it is associated with a high rate of adverse cutaneous reactions. It contains the harsh anionic surfactant sodium lauryl sulphate, a known negative environmental factor associated with the exacerbation of AD. OBJECTIVES: To investigate the effect of aqueous cream BP on stratum corneum (SC) integrity and skin barrier function in volunteers with a predisposition to a defective skin barrier. METHODS: Thirteen volunteers with a previous history of AD (no symptoms for 6 months) applied aqueous cream BP twice daily to the volar side of one forearm for 4 weeks. The other forearm was left untreated as a control. Permeability barrier function and SC integrity were determined before and after treatment by measuring transepidermal water loss (TEWL) in conjunction with tape-stripping. For comparison, 13 volunteers with current AD were recruited for assessment, without treatment, of SC integrity and skin barrier function at unaffected sites. RESULTS: Topical application of aqueous cream BP resulted in significant elevation of baseline TEWL and a concomitant decrease in SC integrity. Measurements made after no treatment in volunteers with current AD, at unaffected sites, suggest that application of aqueous cream BP negatively affects the skin barrier towards the damaged state associated with onset of flares of the disease. CONCLUSIONS: Aqueous cream BP used as a leave-on emollient caused severe damage to the skin barrier in volunteers with a previous history of AD. Aqueous cream BP should not be used as a leave-on emollient in patients with AD.

The conformation of histone H5 bound to DNA. Maintenance of the globular structure after binding.

Trypsin digestion is used to investigate the conformation of histone H5 when bound to DNA. A central region of H5 comprising residues (22--100) is found to be resistant to digestion and it is concluded that this region is compacted whilst the remaining N- and C-terminal regions are more extended. Since this is the same result found previously for the free solution conformation of histone H5 it follows that a 3-domain structure is preserved on DNA binding. The binding of H5 and the central region (22--100) to DNA is also studied using proton magnetic resonance (270 MHz) and a precipitation approach. It is concluded that all 3 domains of H5 bind to DNA at low ionic strengths. The central domain (residues 22--100) is released at 0.3--0.4 M NaCl, but 0.7 M NaCl is required to release the N- and C-terminal regions. Comparison is made of H5 binding to DNA with that of the related histone H1.

Studies on the role and mode of operation of the very-lysine-rich histones in eukaryote chromatin. Effect of A and B site phosphorylation on the conformation and interaction of histone H1.

270-MHz proton magnetic resonance has been used to study the effect of phosphorylation of histone H1 in vitro on the structure of isolated H1 molecules and on the interaction of H1 with DNA. Phosphorylation at serine-105, which is located in the globular region of H1, was found to reduce the enthalpy of structure formation from 24 +/- 2 kcal mol-1 (100 +/- 8 kJ mol-1) to 13 +/- 2 kcal mol-1 (55 +/- 8 kJ mol-1). Phosphorylation at either or both of serine-37 and serine-105 was found to reduce the strength of binding of the histone to DNA considerably at some ionic strengths.

Studies on the role and mode of operation of the very-lysine-rich histone H1 (F1) in eukaryote chromatin. Histone H1 in chromatin and in H1 - DNA complexes.

The nuclear magnetic resonance (NMR) spectrum of chromatin at ionic strengths below about 0.5 M may be attributed solely to its histone H1 component. The effect of various ions and urea on the complex has been investigated using NMR and confirm that the contraction of the complex on increase of ionic strength is largely due to electrostatic interactions. A detailed study of the H1 - DNA complex has also been undertaken. The behaviour of H1 in the two cases is virtually identical, implying that in chromatin the H1 is complexed with the DNA rather than with the other histones. Microcalorimetric measurements reveal that the binding of H1 to DNA is athermic or involves a heat of reaction which is very small indeed.

Studies on the role and mode of operation of the very-lysine-rich histone H1 (F1) in eukaryote chromatin. The properties of the N-terminal and C-terminal halves of histone H1.

Restricted chymotrypsin digestion of calf thymus H1 histone gives two fragments, residues 1--106 and 107--C-terminal. These were studied by proton magnetic resonance and circular dichroism. The N-terminal fragment exhibited some salt-induced structure in aqueous solution, but this did not parallel the globular structure of the intact H1 molecule. Comparison of circular dichroism results with helix predictions for this portion of the molecule suggests that the secondary structure may be the same in this fragment as it is in the corresponding region of the whole molecule. The C-terminal fragments show very little salt-induced structure. The N-terminal fragments binds to DNA very weakly, but the C-terminal fragment binds as strongly as the whole molecule. In the C-terminal fragment, about one quarter of the lysine residues are not bound to the DNA in water, but initial increase of salt concentration causes them to become bound. This increasing binding occurs under the same ionic conditions that cause chromatin condensation and condensation of H1 - DNA complexes, and it is suggested that there may be a connection between these phenomena.

Studies on the role and mode of operation of the very-lysine-rich histone H1 (F1) in eukaryote chromatin. The conformation of histone H1.

Proton magnetic resonance, circular dichroism and other studies of whole and cleaved calf thymus histone H1 (formerly F1) reveal the presence of specific folded structures in the region approximately from residue 40--115. Ionic, hydrogen-bond and hydrophobic interactions all appear to contribute to the stability of the structure, which is predicted to contain alpha-helices in regions 42--55 and 58--75. No evidence was found for beta-structures, either inter or intramolecular, or for any structure formation outside the region 40--115. At 18 degrees C and a protein concentration of 2 mM the first-order exchange rate between random-coil and structured forms is slower than 80 s-1; at 40 degrees C the exchange rate is faster than 330 s-1.