By INAL

 

From The British Journal of Dermatology

Skin Immunosenescence: Decreased Receptor for Activated C Kinase-1 Expression Correlates With Defective Tumour Necrosis Factor-α Production in Epidermal Cells

E. Corsini; M. Racchi; L. Lucchi; E. Donetti; M. Bedoni; B. Viviani; C.L. Galli; M. Marinovich

Published: 04/24/2009

Abstract

Background: Skin immunosenescence accounts for increased susceptibility in the elderly to cutaneous infections and malignancies, and decreased contact hypersensitivity and response to vaccination. We have recently shown in immune cells that decreased expression of the receptor for activated C kinase (RACK)-1 underlies defective protein kinase C (PKC) activation and functional immune impairment with ageing.
Objectives: This study was designed to determine if an age-related decline in skin RACK-1 expression was present and whether it correlated with defective tumour necrosis factor (TNF)-α production.
Methods: PKC isoforms and RACK-1 expression were evaluated by Western blot analysis and by immunofluorescence in skin obtained from Sprague-Dawley rats of different ages. TNF-α release by epidermal cells induced by lipopolysaccharide, 12-O-tetradecanoyl-phorbol-13-acetate and the contact allergen dinitrochlorobenzene was assessed by the L929 biological assay.
Results: Skin obtained from old rats (> 18 months) showed decreased RACK-1 immunoreactivity if compared with young rats (< 3 months). RACK-1 preferentially interacts with PKC β. Despite a similar total skin content of this isoform, the reduced expression of RACK-1 was associated with a decreased translocation of PKC β in the membrane compartment. The defective PKC β translocation associated with ageing correlated with decreased TNF-α release from epidermal cells following treatment with different inflammatory stimuli.
Conclusions: Overall, we demonstrated for the first time a decrease in RACK-1 expression, defective PKC β translocation and reduced TNF-α release in epidermal cells with ageing. These alterations might be mechanistically significant, and provide a new understanding of the consequences of ageing on skin immunology.

Introduction

Normal ageing is associated with impaired immune responsiveness such as reduction in response to recall antigen and alterations in T-cell functions, which contribute to increased vulnerability to infectious disease, reduced response to vaccination and increased susceptibility to malignancy in the elderly.[1,2]

A major task of the epidermis is to defend the organism against exogenous insults. Age-related alterations in immune function also affect the skin,[3,4] and may account for the increased susceptibility in the elderly to cutaneous infections and malignancies,[5] and decreased or variable contact hypersensitivity reactions. Defective cell-mediated immunity, and altered number and function of Langerhans cells (LCs) associated with ageing,[6,7] are likely to contribute significantly, together with cumulative exposure to ultraviolet radiation, to the clinical expression of malignancy.[8]

With respect to age categories, Schäfer et al. [9] found a trend of decreasing contact sensitivity to nickel with age (P = 0·09) and an increase in sensitization to fragrance mix (P = 0·003). In a recent article, Green et al. [10] found that, as age and skin barrier perturbation increase, the prevalence of sensitivity to topical drugs increases. This may be because of the frequent use of topical medicaments and the longer time for potential exposure to various allergens owing to age.

Many factors have been proposed to contribute to immunosenescence, including stem cell defects, ageing of resting immune cells, replicative senescence of clonally expanding cells, defects in antigen-presenting cells, dysfunction in several signal transduction pathways and deregulation of the cytokine network.[11–13]

We have recently shown both in rodent and in human leucocytes that a decreased expression of receptor for activated C kinase (RACK)-1, in the absence of differences in the expression of total protein kinase C (PKC) α and β isoforms, underlies defective PKC activation and functional immune impairment with ageing, such as cytokine production and proliferation,[14–16] and response to influenza vaccination.[17]

PKC is a family of at least 12 phospholipid-dependent serine–threonine kinases involved in the signal transduction of hormones, neurotransmitters and cytokines.[18] PKC isoforms have been grouped into three subfamilies. Members of the classical subfamily (PKC α, βI, βII and γ) require calcium, diacylglycerol or phorbol esters and phosphatidylserine for activation, whereas members of the novel subfamily (PKC δ, ε, η and θ) are calcium independent. Finally, members of the atypical subfamily (PKC λ and ξ) are insensitive to diacylglycerol, phorbol esters and calcium.[19] PKC activation evokes its translocation from the cytosol to membrane compartments for exerting its function.[18] This process is mediated by a family of proteins named RACKs.[20] One such protein, RACK-1, a 36-kDa protein cloned from rat brain, is the best-characterized member of the RACK family. It preferentially interacts with PKC β and ε. RACK-1 modulates PKC activity by stabilizing its active conformation.[21,22] Other proteins such as rat synaptic vesicle specific p65 protein, phospholipase Cγ, phospholipase A2 and annexin can bind to RACK-1 via a sequence similar to the C2 domain of PKC, suggesting that RACK-1 may play a critical role in anchoring a range of proteins to the membrane and may integrate signalling pathways with different physiological functions.[23]

PKCs mediate essential cellular signals required for activation, proliferation, differentiation and survival of immune cells.[24] Defective PKC activation with ageing has been reported in human monocytes[25,26] and in human T lymphocytes,[27,28] and approximately 50% of elderly subjects have significant reduction in PKC activity in B cells.[29] It is now emerging that individual isoforms of PKC may exert specific functions in maintaining proper lymphocyte activation and tolerance.[24,30,31]

Cytokines are essential for proper antigen presentation, activation of lymphocytes and elimination of invading microorganisms. Alteration of the cytokine network is believed to play a role in the remodelling of the immune system in old age.[11] Regarding this aspect, we found that ageing was associated both in human and in rodent leucocytes with a progressive decline in lipopolysaccharide (LPS)-induced tumour necrosis factor (TNF)-α production.[14–16] TNF-α is one of the major cytokines produced during an infection, and a decrease in the ability of cells to produce this cytokine is likely to contribute to increased susceptibility to infections. We have demonstrated in leucocytes, by using a specific PKC β inhibitor and RACK-1 antisense oligonucleotides, a key role, although not exclusive, of the PKC β signalling pathway in TNF-α production.

Although an age-associated decrease in cutaneous immune cell number and function has been reported,[3,4] relatively little is known about the molecular mechanism(s) underlying such defects. The aim of the present study was to determine if an age-related decline in skin RACK-1 expression was present and whether it would be correlated with defective TNF-α production by epidermal cells. TNF-α, together with interleukin (IL)-1β, is a key player in the initiation of LC migration,[32] and it has been demonstrated that migration of LCs is PKC β dependent.[33,34] If the availability of either TNF-α or IL-1β is compromised then LC migration and dendritic cell accumulation in draining lymph nodes and the development of an appropriate immune response are largely or completely inhibited.[35]

We demonstrated in skin obtained from old rats a decrease in RACK-1 expression, PKC β activation and TNF-α production. The defective TNF-α production is likely to contribute significantly to skin immunosenescence.

Materials and Methods

Chemicals

Unless otherwise stated, all compounds were obtained from Sigma-Aldrich Company (Sigma Italia, Milan, Italy).

Animals

Male Sprague-Dawley rats (Charles River, Calco, Italy) were housed in a controlled environment and provided with standard rodent chow and water. Male rats were chosen because old female rats are not commercially available. Animal care was in compliance with Italian regulations on protection of animals used for experimental and other scientific purposes (D.M. 116192) as well as with the EU regulations (OJL 358/1, 18 December 1986).

Histological Examination

Skin biopsies obtained from rat ears were fixed in 4% (w/v) phosphate-buffered saline (PBS)-buffered formaldehyde solution for 5 h at room temperature (RT), thoroughly washed with PBS 0·1 mol L-1, dehydrated using graded ethanol, and embedded in paraffin. Paraffin serial sections were prepared at a thickness of 5 µm, deparaffinized, and stained with haematoxylin and eosin. All sections were analysed using a Nikon Eclipse 80i microscope equipped with a Nikon digital camera DS-5Mc (Nikon, Tokyo, Japan).

Immunofluorescence Analysis of Cytokeratin 10 and of Receptor for Activated C Kinase-1

For cytokeratin 10 (CK10) and RACK-1 immunofluorescence analysis, to unmask antigenicity, incubation in 0·01 mol L-1 sodium citrate buffer pH 6 was performed respectively at 95 °C or in a microwave oven. After repeated washings in PBS, nonspecific binding sites were saturated with a 1 : 10 goat serum/PBS solution for 30 min at RT. Sections were incubated either with a mouse antihuman CK10 monoclonal antibody (Progen Biotechnik, Heidelberg, Germany; dilution 1 : 10, overnight at 4 °C) or with a mouse antirat RACK-1 monoclonal antibody (BD Transduction Laboratories, Nottingham, U.K.; dilution 1 : 100, 1 h at RT). As secondary antibody, a fluorescein isothiocyanate (FITC)-conjugated goat antimouse was used (Jackson Immunoresearch Laboratories Inc., West Grove, PA, U.S.A.; dilution 1 : 200, 45 min at RT). In negative controls, the primary antibody was omitted. Further to confirm specific staining, isotype control antibodies (BD Transduction Laboratories) were tested, and no staining was observed. Nuclear counterstaining with 4′,6-diamidino-2-phenylindole dihydrochloride was performed (dilution 1 : 50 000 in PBS 0·1 mol L-1).

All sections were analysed using a Nikon Eclipse 80i microscope equipped with a Nikon digital camera DS-5Mc.

Preparation and Analysis of Epidermal Sheets

LCs were identified on the basis of expression of major histocompatibility complex class II (Ia), a characteristic membrane determinant of LCs. Ears were placed in 0·02 mol L-1 ethylenediamine tetraacetic acid (EDTA) dissolved in PBS and incubated for 2 h at 37 °C. Epidermis was separated from dermis using forceps, washed in PBS and fixed in acetone for 20 min at -20 °C. After washing in PBS, epidermal sheets were incubated at RT for 30 min with a monoclonal antibody specific for rat Ia conjugated with FITC (OX-6; BD Biosciences), diluted to 10 µg mL-1 in PBS containing 0·1% bovine serum albumin. Sheets were washed in PBS and mounted on microscope slides in Permafluor and sealed with nail varnish. Samples were examined by fluorescence microscope.

Cells

Epidermal cells were prepared from trypsinized ear skin as previously described.[36] Recovery was 10–15 × 106 cells per animal. Viability was assessed by trypan blue exclusion and was greater than 80%. Once washed and resuspended to 106 viable cells mL-1, for functional assays cells were cultured in RPMI 1640 containing 2 mmol L-1L-glutamine, 0·1 mg mL-1 streptomycin, 100 IU mL-1 penicillin, 50 µg mL-1 gentamicin sulphate, 10% heat-inactivated fetal calf serum (media) and cultured at 37 °C in 5% CO2. Cells were treated as described in the figure legends. For cytokine release 0·3–0·5 × 106 cells were plated in 24-well plates, while for Western blot analysis 4–5 × 106 cells were used.

To obtain LC-enriched cells, 3–4 × 106 cells mL-1 were layered over Lymphoprep (Axis Shield AS, Oslo, Norway) and centrifuged at 1600 r.p.m. for 20 min at RT. The interface cells were enriched Ia+ LCs, while keratinocytes were at the bottom. Interface cells usually represent 10% of the starting population, as assessed by immunofluorescence staining with antirat Ia antibody conjugated with FITC; the resulting population contains 35–40% Ia+ cells. Recovered cells were washed three times in PBS, and prepared for Western blot analysis.

Biological Measurement of Tumour Necrosis Factor-α

TNF-α content was assayed by determining the cytotoxicity of TNF-α against sensitive L929 cells, as previously described.[37] Similar results were also obtained using a commercially available enzyme-linked immunosorbent assay. The latter, however, does not measure biologically active TNF-α and is less sensitive and more expensive than the bioassay. For these reasons we preferred to use the bioassay. The results are expressed in pg mL-1. TNF-α concentration was calculated against a standard curve with known amounts of recombinant murine TNF-α. Limit of detection was 0·5 pg mL-1.

Western Blot Analysis

For RACK-1, PKC isoforms and β-actin expression, cells were lysed in 100 µL of homogenization buffer [50 mmol L-1 Tris, 150 mmol L-1 NaCl, 5 mmol L-1 EDTA pH 7·5, 0·5% Triton X-100, 50 µmol L-1 phenylmethylsulphonyl fluoride (PMSF), 2 µg mL-1 aprotinin, 1 µg mL-1 pepstatin and 1 µg mL-1 leupeptin] and denatured for 10 min at 100 °C.[38] For whole skin expression, tissue was incubated for 45 min on ice 1 : 10 (w/v) diluted in 0·5% Triton X-100, 0·32 mol L-1 sucrose, 150 mmol L-1 NaCl, 50 mmol L-1 Tris pH 7·4, 50 mmol L-1 2-mercaptoethanol, 5 mmol L-1 EDTA, 50 µmol L-1 PMSF, 2 µg mL-1 aprotinin, 1 µg mL-1 pepstatin and 1 µg mL-1 leupeptin. Homogenized tissues were then centrifuged at 100 000 g for 1 h and the supernatants used for Western blot analysis as described below. Western blot analysis of PKC isoform immunoreactivity in cytosolic and membrane fractions was performed as previously described.[14] The protein content of the cell lysate was measured using a commercial kit (Bio-Rad, Hercules, CA, U.S.A.). Cell proteins (20 µg for RACK-1, 60–80 µg for PKC isoforms) were electrophoresed into a 12% sodium dodecyl sulphate–polyacrylamide gel under reducing conditions. The proteins were then transferred to polyvinylidene difluoride membrane (GE Healthcare, Little Chalfont, U.K.). The different proteins were visualized using a RACK-1 antiserum (BD Transduction Laboratories; 1 : 2500), PKC isoforms (BD Biosciences; 1 : 1000) and β-actin (Sigma; 1 : 5000) as the primary antibodies and developed using enhanced chemiluminescence (ECL; GE Healthcare). The image of the blot was acquired with the Molecular Imager Gel Doc XR (Bio-Rad). The optical density of the bands was calculated and analysed by means of the Image 1.47 program for digital image processing (Wayne Rasband, Research Service Branch, NIMH, NIH, Bethesda, MD, U.S.A.).

Statistical Evaluation

All experiments were performed at least three times; representative results are shown. Data are expressed as mean ± SD. Statistical analysis was performed using GRAPHPAD INSTAT version 3.0a for Macintosh (GraphPad Software, San Diego, CA, U.S.A.). Effects were designated significant at P < 0·05.

Results

Skin Morphological Analysis

Histological examination of haematoxylin and eosin-stained skin sections (Figure 1a) revealed some atrophy of cutaneous adnexa as well as a less regular extracellular matrix organization in skin obtained from old rats compared with skin of young rats, while no evident morphological alterations in the epidermis of aged skin were observed.

 

Figure 1.  Skin histology, cytokeratin 10 (CK10) and Ia immunofluorescence. (a) Haematoxylin and eosin (H&E)-stained skin sections obtained from young (< 3 months) and old rats (> 18 months). Arrows indicate the epidermis. (b) CK10 immunohistochemistry in skin obtained from young (< 3 months) and old rats (> 18 months). Photomicrographs are representative of all rats examined. Arrows indicate the epidermis. (c) Ia immunohistochemistry in epidermal sheets obtained from young (< 3 months) and old rats (> 18 months). Photomicrographs are representative of the four rats examined. Original magnification: (a–c) × 40.

Aged and young skin displayed similar keratinocyte stratification as demonstrated by the repartition of CK10, the major marker of epidermal differentiation expressed starting from the suprabasal layer (Figure 1b).

The characteristics of epidermal Ia+ LCs within skin prepared from young and old rats are shown in fluorescence photomicrographs (Figure 1c). No marked changes in LC frequency with age were observed, while a discrete modification of LC morphology was observed with age, with preservation of Ia expression but slight decrease of their dendritic appearance.

Decrease of Receptor for Activated C Kinase-1 Expression With Age

The present study was designed to determine if an age-related decline in RACK-1 expression, as we recently described in immune cells, was also present in the skin. As shown in Figure 2a, a 35% decrease in RACK-1 expression was observed in whole skin homogenate obtained from old rats (> 18 months) in comparison with young whole skin homogenate (< 3 months), as assessed by Western blot analysis and relative densitometric analysis (P < 0·05). Further to characterize the expression of RACK-1 in the skin, epidermis was separated from dermis and epidermal cells prepared by trypsin digestion. As shown in Table 1 , the expression of RACK-1 was significantly reduced in all fractions obtained from old rats (P < 0·05), while expression levels similar to those in young rats were observed in the 12-month-old rats. In particular, a 35%, 43%, 50%, 35% and 43% reduction was observed in whole skin, dermis, epidermal cells, keratinocytes and enriched LCs, respectively.

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Table 1.

 

 

 

 

 

 

 

< 3 months

12 months

> 18 months

Whole skin

0·60 ± 0·19

0·57 ± 0·13

0·39 ± 0·14*

Dermis

0·69 ± 0·14

0·83 ± 0·16

0·39 ± 0·24*

Epidermal cells

0·80 ± 0·17

0·79 ± 0·12

0·37 ± 0·11*

Keratinocytes

0·77 ± 0·19

0·76 ± 0·16

0·49 ± 0·10*

Enriched Langerhans cells

0·68 ± 0·10

ND

0·36 ± 0·10*

 

 

 

 

 

 

 

 

RACK-1 expression was evaluated by Western blot as described in the Materials and methods section, followed by densitometric analysis. Results are expressed as RACK-1/β-actin immunoreactivity. Each value represents the mean ± SD of data obtained from four to 10 rats. Statistical analysis was performed with Tukey’s multiple comparison test, with *P < 0·05 vs. young. ND = not done.

Receptor for Activated C Kinase (RACK)-1 Expression in Rat Skin Obtained From Animals of Different Age

 

Figure 2.  Western blot analysis and immunohistochemistry of receptor for activated C kinase (RACK)-1 expression. (a) Western blot analysis and relative densitometric analysis of RACK-1 immunoreactivity in whole skin homogenate obtained from young (< 3 months) and old rats (> 18 months). β-actin immunoreactivity was used to control for protein loading. Each value represents the mean ± SD, n= 6. ANOVA followed by Student’s t-test, with # P < 0·05 vs. young. (b) RACK-1 immunohistochemistry in skin obtained from young (< 3 months) and old rats (> 18 months). Photomicrographs are representative of all rats examined. Original magnification × 40.

Consistent with the Western blot analysis, immunolocalization of RACK-1 showed a reduced staining both in the epidermis and in the dermis of skin obtained from old rats if compared with the skin obtained from young animals (Figure 2b). RACK-1 was highly expressed in the epidermis and in skin adnexa, while fibroblasts showed a less intense staining; all appeared to be reduced in aged skin.

Changes in Protein Kinase C Isoform Expression in Aged Skin

As mentioned above, PKC isoforms have been grouped into three subfamilies: the classical subfamily (PKC α, βI, βII and γ), the novel subfamily (PKC δ, ε, η and θ) and the atypical subfamily (PKC λ and ξ). In Figure 3, the expression of several PKC isoforms of the different subfamilies in whole skin homogenate obtained from young and old rats is reported. Consistent with previous results in immune cells,[14] a similar PKC β expression was observed in young and old rats, while an increase in PKC α, λ and δ expression was observed in aged skin together with decrease in total PKC ε expression.

 

Figure 3.  Expression of protein kinase C (PKC) isoforms in skin obtained from young and old rats. Western blot analysis and relative densitometric analysis of PKC α (a), β (b), δ (c), ε (d) and λ (e) immunoreactivity in whole skin homogenate, and in the cytosolic and membrane compartments obtained from young (< 3 months) and old rats (> 18 months). ?-actin immunoreactivity was used to control for protein loading. Each value represents the mean ± SD, n = 3–6. ANOVA followed by Student’s t-test, with # P < 0·05 and ## P < 0·01 vs. young.

The total expression, however, does not provide an indication of the active state of PKC. PKC activation indeed evokes its translocation from the cytosol to membrane compartments for exerting its function, a process mediated by RACK proteins. As reported in Figure 3, despite a similar or increased expression, a reduced expression of PKC β and λ isoforms in the membrane compartments was observed in skin homogenate obtained from old rats (P < 0·05), while a similar expression was observed for the α, ε and δ isoforms. Importantly, the decreased translocation of the β isoform is consistent with the reduced RACK-1 expression observed, as RACK-1 preferentially interacts with PKC β.

Tumour Necrosis Factor-α Response to Lipopolysaccharide Cutaneous Stimulation is Partially Protein Kinase C β Dependent

Next to the reduced RACK-1 expression and the defective PKC β translocation with ageing, we wanted to investigate whether this would correlate with defective TNF-α production, a key cytokine within the skin immune system.

We had previously demonstrated by using RACK-1 antisense oligonucleotides and specific PKC inhibitor in leucocytes a key role, although not exclusive, of RACK-1 and PKC β signalling pathway in LPS-induced TNF-α production.[14,16] Consistent with this result, as reported in Figure 4a, we demonstrated also in epidermal cells the involvement of PKC β in LPS-induced TNF-α release. Using a selective cell-permeable inhibitor of PCK β (PCK β pseudosubstrate) a 43% decrease in LPS-induced TNF-α was observed. Indeed, using the broad PKC inhibitor GF109203X a 71% inhibition was observed, suggesting that other activation or PKC stimulation pathways are involved in TNF-α production by skin cells.

 

 

 

 

Figure 4.  Tumour necrosis factor (TNF)-α release from epidermal cells obtained from young and old rats. (a) Role of protein kinase C (PKC) in lipopolysaccharide (LPS)-induced TNF-α release. Epidermal cells obtained from young rats were treated for 2 h with the selective cell-permeable inhibitor of PCK β (PCK β pseudosubstrate, pseudo; 5 µmol L-1) and then LPS (10 µg mL-1) was added. TNF-α release was evaluated 24 h later. Each value represents the mean ± SD, n = 3. ANOVA followed by Tukey’s multiple comparison test, with **P < 0·01 vs. control or pseudo-treated cells and # P < 0·01 vs. cells treated with LPS alone. In the inset, the percentage of inhibition on LPS-induced TNF-α release by the broad PKC inhibitor GF109203X is reported together with that obtained by the PKC β pseudosubstrate. (b) Decreased TNF-α release in LPS-stimulated epidermal cells obtained from old rats. Epidermal cells obtained from young and old rats were incubated for 24 h in the presence or absence of LPS (10 µg mL-1). Each value represents the mean ± SD, n = 3. Statistical analysis was performed by Tukey’s multiple comparison test, with **P < 0·01 vs. untreated cells (cont), and ## P < 0·01 vs. cells obtained from young rats. (c) Time-course of TNF-α release in LPS-stimulated epidermal cells obtained from young and old rats. Epidermal cells obtained from young and old rats were incubated for different times (24–48 h) with LPS (10 µg mL-1). Each value represents the mean ± SD, n = 3. Statistical analysis was performed by Tukey’s multiple comparison test, with **P < 0·01 vs. untreated cells, and # P < 0·01 vs. cells obtained from young rats.

Defective Tumour Necrosis Factor-α Release in Aged Skin in Response to Different Stimuli

We next compared TNF-α release from epidermal cells obtained from young and old rats. As reported in Figure 4b, a significant 66% reduction in LPS-induced TNF-α release was observed with ageing: from 28·8 ± 3·2 pg mL-1 in young to 9·8 ± 0·7 pg mL-1 in epidermal cells obtained from old rats (P < 0·01). The decreased production of TNF-α was not due to a different kinetic because, as shown in Figure 4c, a defective release was also observed after 48 h of treatment with LPS. Furthermore, this defect was not limited to LPS, but also the release of TNF-α induced by other stimuli, such as the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate and the contact allergen dinitrochlorobenzene, was similarly reduced (60% and 59%, respectively) in epidermal cells obtained from old rats ( Table 2 ).

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Table 2.

 

 

 

 

 

Treatment

TNF-α (pg mL-1)

Young (< 3 months)

Old (> 18 months)

Control

0·9 ± 0·1

0·8 ± 0·1

TPA 10 nmol L-1

11·2 ± 1·6**

4·4 ± 0·2**, ##

DNCB 2 µmol L-1

2·9 ± 0·2**

1·2 ± 0·1##

 

 

 

 

 

 

Epidermal cells obtained from young (< 3 months) and old rats (> 18 months) were stimulated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), dinitrochlorobenzene (DNCB) or dimethylsulphoxide as vehicle control. TNF-α release was assessed 24 h later. Results are expressed as mean ± SD, with n = 3. Statistical analysis was performed with Dunnett’s multiple comparison test, with **P< 0·01 vs. relative vehicle control and ## P< 0·01 vs. young.

Decreased Tumour Necrosis Factor (TNF)-α Production in Epidermal Cells Obtained From Old Rats

Discussion

Altogether the data presented suggest a cascade of events leading to an age-associated defective activity of PKC signal transduction machinery involved in the regulation of TNF-α release by rat epidermal cells. Our findings might be mechanistically significant, and provide a new understanding of the consequences of ageing on skin immunology.

TNF-α is a potent proinflammatory cytokine produced by a multitude of cell types including keratinocytes and LCs. Keratinocytes not only form a physical barrier between external environment and internal organs, but they represent the first line of defence against pathogens in the skin as they express functional PAMPS (pathogen-associated membrane proteins) such as toll-like receptors[39] and participate to innate immunity. Keratinocytes contribute to the initiation of appropriate skin immune responses. The defective TNF-α production we described in epidermal cells obtained from old rats is likely to affect skin immunosurveillance significantly, contributing to cutaneous malignancy and infection, as well as to impaired development of contact hypersensitivity reactions and reduced response to vaccination. Decreased production of this promigratory signal is likely to affect the vigour of LC mobilization from the epidermis and to compromise the initiation of cutaneous immune response. It is important to acknowledge that the clinical observations mentioned above may also be a reflection of changes in LC frequency and responsiveness. A decrease in LC frequency and responsiveness to TNF-α-induced migration has indeed been demonstrated in elderly subjects.[7] In the skin of aged rats, however, we did not observe marked changes in LC frequency as assessed by LC staining of epidermal sheets, while we observed a discrete modification of LC morphology with increasing age, with decrease of their dendritic appearance.

Other cytokines are also important for LC migration. Of particular importance is IL-1β, which has been shown to play a permissive role in normal LC migration,[35] and reduced production with ageing has been demonstrated in mouse skin.[40] We are currently investigating the effect of ageing on the constitutive and activated production of other cytokines.

The reduced production of TNF-α in response to different stimuli can be partially attributed to a decreased RACK-1 expression, with underlying defective PKC β activation. These results are consistent with data we obtained in both rodent and human leucocytes, indicating that a similar defect also contributes to skin immunosenescence. Using the selective cell-permeable inhibitor of PKC β, the specific kinase isoform interacting with RACK-1, we demonstrated that LPS-induced TNF-α release could be significantly modulated. However, the fact that the selective inhibitor of PKC β only partially abrogates LPS-induced TNF-α production suggests that TNF-α production is not exclusively controlled by the PKC β signalling pathway. Indeed, by using the broad PKC inhibitor GF109203X a higher inhibition was achieved, indicating the involvement of other PKC isoforms. This result also points out the possible involvement of epidermal cells other than LCs, such as keratinocytes, which do not express PKC β. Keratinocytes, however, respond to LPS in term of TNF-α production, but they usually require a higher concentration (100 µg mL-1)[39] and involve different PKC isoforms, such as PKC ε. At the concentration used in our experiments (10 µg mL-1), TNF-α is mainly produced by LCs.

Apart from the β isoform, which is expressed on LCs and melanocytes, at least five PKC isoforms (α, δ, ε, η and ξ) have been reported to be expressed in the epidermis.[41] Interestingly, the different PKC isoforms, with the exception of PKC δ detected throughout the epidermis, are differentially expressed in the proliferative basal layer (i.e. PKC ε) and nonproliferative compartments (i.e. PKC α in the spinous and granular layers; PKC α in the granular layer), suggesting divergence in their role in the regulation of epidermal cell proliferation and differentiation. Here, we found an increase in the expression of the isoforms α, δ and λ with ageing, a decrease in PKC ε, while a similar expression of the β isoform was observed. It is tempting to speculate that such changes may represent an adaptive mechanism to reduce the risk of cancer. It has been demonstrated, at least for PKC δ, that PKC δ transgenic mice had suppressed formation of skin papillomas and carcinomas,[42] while PKC α overexpression has no effect on skin tumour promotion.[43] Also the decreased production of TNF-α may be important in the context of reducing the risk of skin cancer, as mice deficient in TNF-α are resistant to skin carcinogenesis.[44] PKC ε, which has been demonstrated to be an oncogene, having TNF-α as a downstream messenger in the development of squamous skin carcinoma,[45] is also reduced in aged skin, further supporting an adaptive effect to protect keratinocytes from proliferation and cancer. In this context, the decreased expression of RACK-1 with ageing and its correlation with reduced TNF-α production may be considered as a protective phenomenon. Changes in PKC isoenzyme expression may also assist in explaining an altered balance between proliferation and apoptosis with ageing: it is likely that changes in activity or concentrations of these isoenzymes exert important modulating influences on cellular homeostasis. These findings raise an exciting possibility of novel therapeutic intervention to regulate homeostatic mechanisms controlling proliferation and/or apoptosis. Further experiments are needed to explore the pathophysiological meaning of the changes observed.

Changes in RACK-1 expression and PKC isoform distribution may also contribute to the age-related functional deficit in LC responsiveness. Interestingly, it has been demonstrated that activation of PKC induces LC migration, and LCs cannot migrate from the epidermis when PKC β is inhibited.[33] Furthermore, double-labelling studies in normal skin revealed coexpression of PKC β and CD1a by LCs, and experimental evidence suggests that PKC β may transduce the signal for migration of LCs from the epidermis.[46] PKC transduces the signal which leads to LC migration from the epidermis, and disruptions in this secondary messenger may interfere with the induction of immune responses in the skin by disturbing LC migration from the epidermis to the local lymph nodes. In the context of skin cancer, a defective LC activation with ageing may also be considered as a protective phenomenon, as recently demonstrated by Strid et al. [47] They were able to show that whereas V(gamma)5 V(delta)1+ T cells limited carcinogenesis, LCs unexpectedly promoted it. However, the price to pay is an increased risk of infections and decreased responses to vaccination, which are a hallmark of the elderly. Thus, the different arms and effectors of the immune system may have a different impact on a successful ageing.

A speculation, based on analogies with leucocytes, can be made that hormonal changes in the cell environment associated with ageing (i.e. the age-related decline in the levels of dehydroepiandrosterone) are likely to contribute to the loss of RACK-1 expression.[15,16] The reduction with ageing in RACK-1 expression was observed in all leucocyte subpopulations,[14–16] brain,[48,49] and, as reported here, in skin cells, indicating that it may reflect a defect common to many cell types. Certainly, the defect cannot be ascribed to changes in the epidermal structure and differentiation as shown by histological analysis and CK10 immunofluorescence. Futher studies are also necessary to understand the role and meaning of the changes in RACK-1 expression with ageing in dermis and skin adnexa.

Overall, this paper contributes to the understanding of the complex process of ageing of the skin and its immune system and identifies a decline in RACK-1 expression with ageing. Age-related alterations in PKC signalling and TNF-α release provide a new understanding of the consequences of ageing on skin immunology. The identification of changes in the skin immune system will allow the development of better strategies for the prevention of infective diseases and reduced response to vaccination in the elderly.[50] Even in the presence of intrinsic defects in cells involved in the immune response, it is possible that these may be overcome by measures that are relatively easy in principle (e.g. whether hormonal treatment can restore immune functions declined with ageing), yet these principles need to be clearly tested in appropriate clinical protocols and settings.

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6.        Swift ME, Burns AL, Gray KL et al. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol 2001; 117:1027-35.

7.        Bhushan M, Cumberbatch M, Dearman RJ et al. Tumour necrosis factor-α-induced migration of human Langerhans cells: the influence of ageing. Br J Dermatol 2002; 146:32-40.

8.        Syrigos KN, Tzannou I, Katirtzoglou N et al. Skin cancer in the elderly. In Vivo 2005; 19:643-52.

9.        Schäfer T, Böhler E, Ruhdorfer S et al. Epidemiology of contact allergy in adults. Allergy 2001; 56:1192-6.

10.     Green CM, Holden CR, Gawkrodger DJ. Contact allergy to topical medicaments becomes more common with advancing age: an age-stratified study. Contact Allergy 2007; 56:229-31.

11.     Doria G, Frasca D. Genes, immunity, and senescence: looking for a link. Immunol Rev 1997; 160:159-70.

12.     Hirokawa K. Age-related changes of signal tranduction in T cells. Exp Gerontol 1999; 1:7-18.

13.     Pawelec G, Barnett Y, Forsey R et al. T cells and ageing, January 2002 update. Front Biosci 2002; 7:D1056-183.

14.     Corsini E, Battaini F, Lucchi L et al. A defective protein kinase C anchoring system underlying age-associated impairment in TNF-α production in rat macrophages. J Immunol 1999; 163:3468-73.

15.     Corsini E, Lucchi L, Meroni M et al.In vivodehydroepiandrosterone restores age-associated defects in protein kinase C signal transduction pathway and related functional responses. J Immunol 2002; 168:1753-8.

16.     Corsini E, Racchi M, Sinforiani E et al. Age-related decline in RACK-1 expression in human leukocytes is correlated to plasma levels of dehydroepiandrosterone. J Leukoc Biol 2005; 77:247-56.

17.     Corsini E, Vismara L, Lucchi L et al. High interleukin-10 production is associated with low antibody response to influenza vaccination in the elderly. J Leukoc Biol 2006; 80:76-82.

18.     Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 1995; 9:484-96.

19.     Jaken S, Parker PJ. Protein kinase C binding partners. Bioessays 2000; 22:245-54.

20.     Mochly-Rosen D, Khaner H, Lopez J. Identification of intracellular receptor proteins for activated protein kinase C. Proc Natl Acad Sci USA 1991; 88:3997-4000.

21.     Ron D, Mochly-Rosen D. Agonists and antagonists of protein kinase C function, derived from its binding proteins. J Biol Chem 1994; 269:21395-8.

22.     Ron D, Luo J, Mochly-Rosen D. C2 region-derived peptides inhibit translocation and function of beta protein kinase C in vivo. J Biol Chem 1995; 270:24180-7.

23.     McCahill A, Warwicker J, Bolger GB et al. The RACK-1 scaffold protein: a dynamic cog in cell response mechanisms. Mol Pharmacol 2002; 62:1261-73.

24.     Sun Z, Arendt CW, Ellmeier W et al. PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 2000; 404:402-7.

25.     McLachlan JA, Serkin CD, Morrey-Clark KM, Bakouche O. Immunological functions of aged monocytes. Pathobiology 1995; 63:148-59.

26.     Delpedro AD, Barjavel MJ, Mamdouh Z et al. Signal transduction in LPS-activated aged and young monocytes. J Interferon Cytokine Res 1998; 18:429-37.

27.     Fulop T, Leblanc C, Lacombe G et al. Cellular distribution of protein kinase C isozymes in CD3-mediated stimulation of human T lymphocytes with aging. FEBS Lett 1995; 375:69-74

28.     Miller RA. Effect of aging on T lymphocyte activation. Vaccine 2000; 18:1654-60.

29.     Whisler RL, Grants IS. Age-related alterations in the activation and expression of phosphotyrosine and protein kinase C among human B cells. Mech Ageing Dev 1993; 71:31-46.

30.     Leitges M, Schmedt C, Guinamard R et al. Immunodeficiency in protein kinase C β-deficient mice. Science 1996; 273:788-91.

31.     Miyamoto A, Nakayama K, Imaki H et al. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cdelta. Nature 2002; 416:865-9.

32.     Cumberbatch M, Dearman RJ, Griffiths CEM et al. Langerhans cells migration. Clin Exp Dermatol 2000; 25:413-18.

33.     Holliday GM, Lucas AD. Protein kinase C transduces the signal for Langerhans’ cell migration from the epidermis. Immunology 1993; 79:621-6.

34.     Goodell AL, Oh HS, Meyer SA. Epidermal protein kinase C-beta 2 is highly sensitive to downregulation and is exclusively expressed in Langerhans cells: downregulation is associated with attenuated contact hypersensitivity. J Invest Dermatol 1996; 107:354-9.

35.     Cumberbatch M, Dearman RJ, Kimber I. Langerhans cells require signals from both tumour necrosis factor-α and interleukin-1β for migration. Immunology 1997; 92:388-95.

36.     Tamaki KG, Stingl G, Guillino M et al. Ia antigens in mouse skin are predominantly expressed on Langerhans cells. J Immunol 1979; 123:784-7.

37.     Rosenthal GJ, Corsini E. Tumor necrosis factor-? in immunotoxicity assessment. In: Methods in Immunotoxicology (Burleson GR, Dean JH, Munson AE, eds), Vol. 1. New York: Wiley-Liss, Inc, 1995; 327-43.

38.     Laemmli VK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227:680-5.

39.     Lebre MC, van der Aar AMG, van Baarsen L et al. Human keratinocytes express functional toll-like receptor 3, 4, 5, and 9. J Invest Dermatol 2007; 127:331-41.

40.     Sauder DN, Ponnappan U, Cinader B. Effect of age on cutaneous interleukin 1 expression. Immunol Lett 1989; 20:111-14.

41.     Denning MF. Epidermal keratinocytes: regulation of multiple cell phenotypes by multiple protein kinase C isoforms. Int J Biochem Cell Biol 2004; 36:1141-6.

42.     Reddig PJ, Dreckschmidt NE, Oberley TD et al. Transgenic mice overexpressing protein kinase Cδ in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 1999; 59:5710-18.

43.     Jansen AP, Drechschmidt NE, Verwiebe EG et al. Relation of the induction of epidermal ODC and hyperplasia to the different skin tumor promotion of PKC α, –δ, and –ε transgenic mice. Int J Cancer 2001; 93:635-43.

44.     Moore RJ, Owens DM, Stamp G et al. Mice deficient in tumor necrosis factor alpha are resistant to skin carcinogenesis. Nat Med 1999; 5:828-31.

45.     Verma AK, Wheeler Aziz MH, Manoharan H. Protein kinase Cε and development of squamous cell carcinoma, the non melanoma human skin cancer. Mol Carcinog 2006; 45:381-8.

46.     Reynolds NJ, Yi JY, Fisher GJ et al. Down-regulation of Langerhans cell protein kinase C-beta isoenzyme expression in inflammatory and hyperplastic dermatoses. Br J Dermatol 1995; 133:157-67.

47.     Strid J, Roberts SJ, Filler RB et al. Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat Immunol 2008; 9:146-54.

48.     Battaini F, Pascale A, Paoletti R et al. The role of anchoring protein RACK1 in PCK activation in the ageing rat brain. Trends Neurosci 1997; 20:410-15.

49.     Racchi M, Govoni S, Solerte B et al. Dehydroepiandrosterone and the relationship with aging and memory: a possible link with protein kinase C functional machinery. Brain Res Rev 2001; 37:287-93.

50.     Beverley PCL, Grubeck-Loebenstein B. Is immune senescence reversible? Vaccine 2000; 18:1721-4.

[CLOSE WINDOW]

Authors and Disclosures

E. Corsini, M. Racchi,* L. Lucchi, E. Donetti, M. Bedoni, B. Viviani, C.L. Galli, M. Marinovich

Laboratory of Toxicology, Department of Pharmacological Sciences, Department of Human Morphology, University of Milan, Milan, Italy
*Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy
Disclosure: None declared.

Funding Information

This work was supported by a grant from L’Oreal Research entitled ‘Skin immunosenescence: contribution of RACK-1’ and supervised by Dr Françoise Rousset.

Reprint Address

Emanuela Corsini, Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy; E-mail: emanuela.corsini@unimi.it

The British Journal of Dermatology. 2009;160(1):16-25. © 2009 Blackwell Publishing

 

 

 

Note that our own Brook Tlougan who some of you met at Saturday’s skin workshop for NYC teachers co-sponsored by us, the UFT, and the NY Academy of Medicine , was one of the authors of this study!

 

 

 

 

 

 Miguel Sanchez, M.D.

 

Director of Dermatology

 

Bellevue Hospital Center

 

 

 

 

 

 

 

Study suggests adding bleach to bathwater may be effective treatment for chronic eczema.

 

BBC News (4/27) reports that, according to a study published in the journal Pediatrics, “adding bleach to the bath may be an effective treatment for chronic eczema.” For the study, researchers from Northwestern University in Chicago found “significant improvement in eczema in” 31 children “who had diluted bleach baths compared with normal baths.” They reached this conclusion after they “randomly assigned patients who had infection with Staphylococcus aureus to baths with half a cup of sodium hyperchlorite per full tub or normal water baths for five to 10 minutes twice a week for three months.” The team “also prescribed a topical antibiotic ointment or dummy ointment.” While “eczema severity in patients reduced five times as much as those on placebo,” there “was no improvement in eczema on the head and neck — areas not submerged in the bath.” But, Professor Mike Cork, a consultant at the UK’s Sheffield Children’s Hospital, warned that “people should not start putting bleach in their children’s bath,” because “bleach used incorrectly could cause enormous harm to a child with atopic eczema.”

 

 

 

 

 

Researchers link presence of certain variants in MC1R gene to increased risk of melanoma.

 

Shari Roan wrote in the Los Angeles Times (4/22) Booster Shots blog that, according to a study presented Apr. 21 at the annual meeting of the American Association of Cancer Research, “some dark-haired people who do not sunburn easily may have an increased risk of the disease because of a gene mutation.” Researchers from the University of Pennsylvania “analyzed 779 patients with melanoma and compared them to 325 healthy people.” The investigators found that the “presence of certain variants in the MC1R gene was linked with at least a twofold increased risk of melanoma, and was largely confined to those people who would not normally be considered at increased risk.” Notably, “people with blond or red hair who had the gene variant did not have an elevated risk.”

 

 

 

        The study authors pointed out that “previous research has identified more than 50 versions of the [MC1R] gene, about four of which have been linked to an increased risk for melanoma,” HealthDay (4/21, Thomas) added. “In the study, about 70 percent of the healthy participants had some variant of the gene, and nearly 27 percent had one of the four high-risk variants.” Of the “participants with melanoma, about 78 percent had a gene variant, and 43 percent had a high-risk variant.” Participants with “dark eyes and an [MC1R] variant had…about a threefold greater risk of developing melanoma than did those with dark eyes, but no variant. Those who did not freckle but who had the high-risk variant had an eightfold increased risk, and those who tanned moderately or deeply after repeated sun exposure had about twice the risk.” Presently, “there is no commercially available test for [MC1R] variants.” The UK’s Press Association (4/22) also covers the story.

 

 

 

Study indicates women with psoriasis may have greater risk of developing hypertension, diabetes.

 

Following a BBC News story, MedWire (4/21, Cowen) reported that, according to a study published in the April issue of the Archives of Dermatology, “women with psoriasis have a significantly greater risk of developing hypertension (high blood pressure) and diabetes than those without the condition.” For the study, researchers from Harvard Medical School “analyzed data on 78,061 women who participated in a long-term health study, of whom 1,813 had psoriasis. The participants were aged between 27 and 44 years at the start of the study,” and “none had a history of diabetes or hypertension.” The team “found that women with psoriasis were 63 percent more likely to develop diabetes and 17 percent more likely to develop hypertension over the” course of the 14-year “study period than those without the condition.” These findings “remained true after accounting for age, body mass index, and smoking status.” The authors suggested that “inflammation may be responsible for the link between these conditions.”

 

 

 

Research suggests ellagic acid may help prevent wrinkles, repair sun-damaged skin.

 

HealthDay (4/21, Thomas) reported that, according to a study presented Tuesday at the Experimental Biology meeting, ellagic acid, “a compound found in berries, nuts and other fruits, might help prevent wrinkles and repair skin damage caused by the sun.” Researchers from Hallym University in South Korea applied the acid “to human skin cells in the lab and to the skin of hairless mice that had been exposed to strong, ultraviolet rays.” The team discovered that “in the human cells,” the substance “reduced the destruction of collagen and inflammatory response, both major causes of wrinkles.” Next, the team exposed “12 hairless mice…three times a week” for eight weeks “to increasing ultraviolet radiation.” The investigators gave “half of the exposed mice…daily topical applications of ellagic acid,” but did not apply the acid to the other mice. They found that the animals “that did not receive ellagic acid developed wrinkles and thickening of the skin” indicative of “sun damage,” and the mice that did receive “ellagic acid showed less wrinkle formation.”

 

 

 

Texas House gives initial approval to bill restricting teen access to tanning beds.

 

The AP (4/22, Stone) reports, that on Apr. 21, the Texas House gave “initial approval” to HB 1310, a measure introduced by Rep. Burt Solomons (R-Carrollton) that “would require anyone under 16 1/2 years old to get a doctor’s note before using a tanning bed. Older teens would need parental consent.” The AP notes that “legislators in 17 states are” currently “pushing stronger restrictions for teens this year. The Texas bill and another in Vermont that would ban non-medical indoor tanning for anyone under 18 have been called the strictest.” In addition, 29 other “states have some form of tanning bed restrictions for minors. Most require parental approval.” Under the proposed legislation, “parents of teens older than 16 1/2” would have “to sign their consent in the tanning salon. The permission slips would also have to include Texas Medical Board warnings about indoor and outdoor tanning.”

 

 

 

        According to the Dallas Morning News (4/22, Garrett), the state currently “requires parental permission slips for children up to 18. Minors under 16 must have a parent or guardian at the tanning facility while the child is tanning,” and “children under 13 must have a doctor’s note.” Rep. Solomons explained, “The sheer increases in melanoma cases, especially in young women, are dramatic.” He added, “And it’s all in response to the growth of the indoor tanning industry, so… why are we letting minors go?” Meanwhile, Rep. Jodie Laubenberg (R-Parker) called the measure “too intrusive,” and “industry spokesmen, who say current oversight is adequate,” said that “parents should decide what health risks are acceptable for their children.” The Morning News notes that the “House will have to take another vote before the measure heads to the Senate.”

 

 

 

 

 

Study indicates showing youngsters UV photos of skin damage may prevent sunburn.

 

HealthDay (4/23, Thomas) reported that, according to a study published in the April issue of the Journal of the Dermatology Nurses’ Association, “showing middle-school students ultraviolet photographs that reveal the sun damage to their faces makes them less likely to get sunburns in the months following.” For the study, researchers from the Boston University School of Medicine “recruited 111 students aged 11 to 13 from Quincy, MA.” Next, “after receiving a sun protection lecture, 83 students also received a UV photograph of their face that shows pigment changes from chronic sun exposure and an explanation of the damage.” Meanwhile, “28 students in the control group heard the lecture, but did not have a photo taken.” The investigators discovered that after six months, “51 percent of intervention group reported a sunburn, compared to 64 percent of the control group.” Notably, “preteens with the highest risk factors for melanoma…were more greatly impacted and were significantly less likely to report sunburn.”

 

 

 

Researchers explore role milk, sugar may play in adolescent acne.

 

In the New Jersey Star-Ledger (4/23) Parental Guidance blog, Carrie Stetler wrote that, according to a review “published in this month’s International Journal of Dermatology,” teenagers’ blemishes may be linked “to dairy products and sugary foods.” For the review, researchers from the Washington Center For Clinical Research “reviewed 27 published studies and concluded that teens who drank more milk had worse skin. Sugary foods produced the same results.” The authors concluded that “milk appears to fuel hormone imbalances that can lead to acne,” and “hormones or proteins found in milk may increase skin oil production, leading to pimples.”

 

 

 

Patients with multiple hospitalizations for psoriasis may be at increased risk of developing certain cancers, research suggests.

 

MedWire (4/24, Piper) reports that, according to a study published online Apr. 7 in the British Journal of Cancer, “patients with multiple hospitalizations for” psoriasis may be “particularly at increased risk of developing esophageal and skin cancers.” For the study, researchers from Sweden’s Lund University analyzed data on “15,858 patients hospitalized with psoriasis in Sweden between 1965 and 2004.” The investigators found that “1,408 developed cancer, reflecting a 33 percent excess risk of overall cancers relative to the general Swedish population.” Among “the most common cancers identified were squamous cell skin cancer, and those of the upper aerodigestive tract, esophagus, stomach, liver, pancreas, lung, kidney, and bladder, as well as non-Hodgkin’s lymphoma.” Notably, “the excess in esophagus, pancreas, lung and squamous cell skin cancers was most pronounced for patients with more than one hospitalization.” The authors theorized that “immunological mechanisms could explain the increased risk of cancer among psoriasis patients.”

 

 

 

 

 

 

 

 Psoriasis treatment

 

 

 

Pioglitazone may offer a convenient, efficacious, and relatively safer alternative for combination with the synthetic retinoid acitretin than currently available immunosuppressive agents in treating patients with chronic plaque-type psoriasis, according to the results of a randomized, placebo-controlled trial reported in the April issue of the Archives of Dermatology.

 

 

 

“Psoriasis is a chronic, inflammatory, immune-mediated skin disorder [that] affects 2% to 3% of the world’s population, with chronic plaque-type psoriasis accounting for approximately 90% of the cases,” write Rajan Mittal, MD, from the Department of Pharmacology at the Postgraduate Institute of Medical Education and Research, Chadigarh, India, and colleagues. They write that serious toxic effects, including end-organ damage, are associated with long-term use of currently available treatments such as methotrexate, cyclosporine, and phototherapy, limiting their use as monotherapy.

 

 

 

Although acitretin, a widely used systemic antipsoriatic drug, has been largely devoid of these toxic effects, the authors write that its use as monotherapy is associated with a slow and often incomplete response. “Therefore, one way to overcome these limitations is by the use of combination therapy.”

 

 

 

With growing evidence of the potential therapeutic role of thiazolidinediones (TZDs) in psoriasis, the investigators looked at pioglitazone, a TZD used as an insulin sensitizer in patients with type 2 diabetes mellitus.

 

 

 

“Because both acitretin and pioglitazone act by normalizing cellular proliferation and differentiation, by inhibiting angiogenesis, and by exerting anti-inflammatory actions in psoriatic skin through different mechanisms at the nuclear level, we hypothesized that [combining these therapies] might lead to additive efficacy in patients with psoriasis,” write the authors.

 

 

 

In this study, the investigators compared this combination therapy with placebo plus acitretin in patients 18 to 65 years of age with moderate to severe chronic plaque-type psoriasis (body surface area involvement > 20%) who were treated at a psoriasis clinic in India from January 2007 to December 2007. Women of childbearing potential were excluded, as were all patients with impaired liver or renal function, hyperlipidemia, diabetes mellitus, coronary artery disease, or a body mass index greater than 30 kg/m2. Of the 62 patients screened, 41 met the entry criteria and were randomly assigned to receive either a daily 25-mg dose of acitretin plus a daily 15-mg dose of pioglitazone (n = 19; mean age, 42.2 years; 100% men) or the 25-mg dose of acitretin plus a daily matching placebo (n = 22; mean age, 38.1 years; 96% men).

 

 

 

A detailed evaluation of Psoriasis Area and Severity Index (PASI) scores were performed for all patients. Lab investigations were also performed and included a complete blood cell count, serum electrolyte levels, liver function tests, renal function tests, fasting serum lipid profile, and fasting blood glucose levels. All patients were followed up at 2, 4, 8, and 12 weeks after randomization, and treatment was continued until the patient achieved complete clearance of lesions or for 12 weeks, whichever came first.

 

 

 

The primary efficacy measure was a change in the PASI score between the 2 groups from baseline to 12 weeks. The secondary efficacy parameter was the proportion of patients who achieved marked improvement of at least a 75% decrease in PASI score (PASI 75) by week 2, 4, 8, or 12.

 

 

 

At the end of the study, results showed a clinical improvement in both groups by a decrease in PASI score from week 0 to week 12 (P < .05 for both groups). However, the reduction in the mean PASI score was significantly greater in the acitretin plus pioglitazone group than in the acitretin plus placebo group (P = .04). In addition, the percentage of reduction in the PASI score was greater for those treated with acitretin plus pioglitazone at 64.2% (95% confidence interval [CI], 49.2% – 79.3%) compared with 51.7% (95% CI, 38.7% – 64.7%) for those treated with acitretin plus placebo.

 

 

 

In the acitretin and pioglitazone group, PASI 75 was achieved at 12 weeks in 8 patients (42%) compared with 5 patients (23%) in the acitretin and placebo group (P = .31), and at week 8 in 2 pioglitazone-treated patients (11%) compared with 1 patient (4%) in the placebo group (P = .59).

 

 

 

Lesions were cleared or almost cleared in 7 acitretin plus pioglitazone–treated patients (37%) and in 2 acitretin plus placebo–treated patients (9%).

 

 

 

Adverse events were seen in 15 patients in each group, with the majority reported as mild to moderate, including increased erythema, dry skin, dry mouth, thirst, and cheilitis. The exception was 1 possibly unrelated episode of acute myocardial infarction in a woman in the acitretin plus placebo group after just 5 days of therapy.

 

 

 

An increase in triglyceride levels of 10% to 41% was seen in 10 patients (46%) treated with acitretin plus placebo, and an increase of 14% to 39% was seen in 5 patients (26%) treated with acitretin plus pioglitazone (P = .33). No other significant changes were noted in any of the other lab investigations.

 

 

 

Limitations of the study include the small number of participants, the underrepresentation of women (probably because of the strict entry criteria), and the use of the lowest dose of pioglitazone at 15 mg/day. “It would be interesting to evaluate 30- and 45-mg doses of pioglitazone with acitretin to clarify any dose-response relationship,” write the authors.

 

 

 

“According to our study results, the addition of pioglitazone to acitretin therapy can enhance antipsoriatic efficacy,” the authors conclude. “In comparison to other antipsoriatic drugs that have been used in combination with acitretin, pioglitazone may offer a safer alternative as it has been used in patients with diabetes mellitus for several years. Moreover, the occurrence of diabetes, hypertension, and metabolic syndrome in patients with psoriasis is not uncommon, and…pioglitazone therapy may be particularly useful in these subsets of patients.”

 

 

 

In an accompanying editorial, Jeffrey P. Callen, MD, associate editor of the Archives of Dermatology, and William H. Eaglstein, MD, from Global Medical Sciences at Stiefel Laboratories Inc, Palo Alto, California, write that this study suggests that the concomitant use of an insulin sensitizer enhances the efficacy of acitretin. However, it “leaves us with questions about the use of this insulin sensitizer alone or in combination with other therapies. Also, it is not clear from this article whether similar effects might be obtained by utilizing an approach with diet and exercise to enhance insulin sensitivity or, for that matter, whether other insulin sensitizers might have similar effects.”

 

 

 

However, the editorial authors conclude, “It does seem reasonable from data presented in [this article] that recommending attention to weight through dietary and exercise routines and being alert to the possibility of hypertension should be part of the discussion with patients with psoriasis.”

 

 

 

 

 

 

 

Research suggests need for middle-aged, older men to undergo melanoma screening.

 

Following a Reuters story, Medscape (4/23, Nelson) reported that, according to a study and analysis published in the April issue of the Archives of Dermatology, “physicians are most likely to detect melanoma in the earliest stages, but patients most at risk are not receiving regular screening during routine office visits. In addition, less than 20 percent of melanoma patients were aware of warning signs, and less than 50 percent practiced self-examination.” In both papers, researchers “found that among men 40 years or older who were newly diagnosed with melanoma, thinner tumors were associated with physician detection, a higher melanoma awareness, certain health preventive attitudes, and a higher level of education.” In addition, “patients with physician-detected melanoma…tended to be older than those in whom it was detected by self-exam or by a nonphysician, and physician-detected back lesions tended to be thinner and smaller than those detected by the patient.” The study authors suggested that patients should ask their “doctor for a full skin exam, particularly in places where” they “cannot see” moles, such as on the back.

 

 

 

FDA to allow 17-year-olds to buy Plan B birth control pill without prescription.

 

The CBS Evening News (4/22, story 8, 0:20, Couric) reported “an update…on the so-called morning-after birth control pill.” On its website, the Food and Drug Administration (FDA) announced on Apr. 22 that “it will obey a judge’s order and allow 17-year-olds to buy it without a prescription. The contraceptive, also called Plan B, is taken after unprotected sex and before an egg is fertilized.”

 

 

 

        NBC Nightly News (4/22, story 10, 0:25, Williams) reported that the FDA said that “it will comply with a federal judge’s order on this. He ruled last month the Bush Administration let politics and not science drive its decision to allow over-the-counter (OTC) access for women 18 and older.”

 

 

 

        According to the ABC World News (4/22, story 6, 1:50, Gibson), previously, “the Bush Administration had set the age limit at 18. This new order means” that the Plan B pill “will, for the first time, be available to minors.” Correspondent Lisa Stark explained, however, that “17-year-olds won’t be able to get this medication without a prescription right away. The required label changes could take months.”

 

 

 

        The FDA’s decision, “which overturns one of the most controversial health rulings of the Bush administration, was scorned by abortion opponents and hailed by their abortion rights counterparts,” the New York Times (4/23, A14, Harris) explains. The FDA’s move will allow “17-year-old women” to “be able to go to almost any pharmacy, clinic, or hospital and, after showing proof of age, buy Plan B without a prescription.” In addition, “men 17 and older may…buy Plan B for a partner.”

 

 

 

        The Washington Post (4/23, Stein) points out that “Plan B consists of higher doses of a hormone found in many standard birth-control pills. Taken within 72 hours of unprotected sex, it has been shown to be highly effective at preventing pregnancy.” In 2003, the maker of Plan B, Barr Pharmaceuticals, “asked the FDA…to allow the contraceptive to be sold without a prescription.” But, “advocacy groups and conservative members of Congress opposed the request,” questioning “the drug’s safety, and” arguing that “wider availability could encourage sexual activity and make it easier for men to have sex with underage girls.” After delaying “its decision for three years, even though its outside advisers and internal reviewers endorsed nonprescription sale,” the FDA “eventually approved nonprescription sale in Aug. 2006, allowing pharmacists to dispense the drug from behind the counter” for women 18 and older.

 

 

 

        The Wall Street Journal (4/23, B11, Dooren) reports, however, that on Mar. 23, US District Judge Edward R. Korman “ordered the FDA to ‘reconsider its decisions regarding the Plan B switch to OTC use.'” In addition, the court “criticized top FDA officials for ‘departing’ from agency procedures governing drug approvals and bowing to political pressure in at first rejecting, and then delaying, approval of Plan B for” OTC use. The Journal notes that the court’s “ruling came in response to a lawsuit filed in 2005 by the Center for Reproductive Rights, a women’s health advocacy group.”

 

 

 

        The agency’s “announcement was another example of the new priorities of the Obama administration, which in the last three months has moved to reverse several controversial Bush-era restrictions on family-planning services,” the Chicago Tribune (4/23, Levey) notes. President Obama recently “overturned a ban on US support to international aid groups that provide abortions, and threw out a rule allowing healthcare workers to deny services that violated their moral beliefs.” These “changes were priorities of family-planning advocates and women’s groups” who “had accused the FDA of letting politics dictate scientific policy, including the restriction on the Plan B pill.”

 

 

 

 

 

 

 

Some pharmaceutical companies entering outcomes-based contracts with insurers.

 

On the front of its Business Day section, the New York Times (4/23, B1, Pollack) reports that, “pressed by insurance companies,” some pharmaceutical companies “are beginning to adjust what they charge for their drugs, based on how well the medicines improve patients’ health.” For example, “in a deal expected to be announced” on Apr. 23, “Merck has agreed to peg what the insurer Cigna pays for the diabetes drugs Januvia [sitagliptin] and Janumet [sitagliptin/metformin] to how well type 2 diabetes patients are able to control their blood sugar.” Just “last week, the two companies that jointly sell the osteoporosis drug Actonel [risedronate] agreed to reimburse the insurer Health Alliance for the costs of treating fractures suffered by patients taking that medicine.” Up until now, most “discounts and rebates that drug companies offer insurers have been based on how much drug is used, not how well patients do.” These “emerging, outcomes-based contracts” should “better align the incentives of insurers, drug companies, and the employers that provide health coverage toward improving people’s health.”

 

 

 

Chemotherapy drugs targeting specific types of cancer cells allow physicians to tailor care.

 

The Chicago Tribune (4/23, Shelton) reports, “Thanks in part to advances in genetic science,” chemotherapy “is becoming more effective and far less grueling, and is transforming treatment for many cancer patients.” In fact, “the array of cancer-fighting medications is growing, and they are aided by new drugs that help treat nausea, minimize pain, and boost levels of white cells to fight infection.” For patients who are “prescribed chemotherapy,” the “advantage over surgery and radiation is that drugs can wage war on cancer cells wherever they are in the body,” because they are “tailored to specific types of cancer and target particular types of cancer cells.” And, although “the risk of debilitating side effects remains,” physicians can “tailor care” using “genetic tests…so patients with treatable cancer receive drugs that are most likely to help them while avoiding the side effects of drugs that won’t.” As a result, “the new-generation drugs are moving patients further away from the image many people have of chemotherapy,” Richard Schilsky, MD, president of the American Society of Clinical Oncology, noted.

 

 

 

 

 

 

 

 

 
 
 

 

 

 

 

 

 

 

 

 

 

 

Researchers link presence of certain variants in MC1R gene to increased risk of melanoma.

Shari Roan wrote in the Los Angeles Times (4/22) Booster Shots blog that, according to a study presented Apr. 21 at the annual meeting of the American Association of Cancer Research, “some dark-haired people who do not sunburn easily may have an increased risk of the disease because of a gene mutation.” Researchers from the University of Pennsylvania “analyzed 779 patients with melanoma and compared them to 325 healthy people.” The investigators found that the “presence of certain variants in the MC1R gene was linked with at least a twofold increased risk of melanoma, and was largely confined to those people who would not normally be considered at increased risk.” Notably, “people with blond or red hair who had the gene variant did not have an elevated risk.”

 

        The study authors pointed out that “previous research has identified more than 50 versions of the [MC1R] gene, about four of which have been linked to an increased risk for melanoma,” HealthDay (4/21, Thomas) added. “In the study, about 70 percent of the healthy participants had some variant of the gene, and nearly 27 percent had one of the four high-risk variants.” Of the “participants with melanoma, about 78 percent had a gene variant, and 43 percent had a high-risk variant.” Participants with “dark eyes and an [MC1R] variant had…about a threefold greater risk of developing melanoma than did those with dark eyes, but no variant. Those who did not freckle but who had the high-risk variant had an eightfold increased risk, and those who tanned moderately or deeply after repeated sun exposure had about twice the risk.” Presently, “there is no commercially available test for [MC1R] variants.” The UK’s Press Association (4/22) also covers the story.

 

Study indicates women with psoriasis may have greater risk of developing hypertension, diabetes.

Following a BBC News story, MedWire (4/21, Cowen) reported that, according to a study published in the April issue of the Archives of Dermatology, “women with psoriasis have a significantly greater risk of developing hypertension (high blood pressure) and diabetes than those without the condition.” For the study, researchers from Harvard Medical School “analyzed data on 78,061 women who participated in a long-term health study, of whom 1,813 had psoriasis. The participants were aged between 27 and 44 years at the start of the study,” and “none had a history of diabetes or hypertension.” The team “found that women with psoriasis were 63 percent more likely to develop diabetes and 17 percent more likely to develop hypertension over the” course of the 14-year “study period than those without the condition.” These findings “remained true after accounting for age, body mass index, and smoking status.” The authors suggested that “inflammation may be responsible for the link between these conditions.”

 

Research suggests ellagic acid may help prevent wrinkles, repair sun-damaged skin.

HealthDay (4/21, Thomas) reported that, according to a study presented Tuesday at the Experimental Biology meeting, ellagic acid, “a compound found in berries, nuts and other fruits, might help prevent wrinkles and repair skin damage caused by the sun.” Researchers from Hallym University in South Korea applied the acid “to human skin cells in the lab and to the skin of hairless mice that had been exposed to strong, ultraviolet rays.” The team discovered that “in the human cells,” the substance “reduced the destruction of collagen and inflammatory response, both major causes of wrinkles.” Next, the team exposed “12 hairless mice…three times a week” for eight weeks “to increasing ultraviolet radiation.” The investigators gave “half of the exposed mice…daily topical applications of ellagic acid,” but did not apply the acid to the other mice. They found that the animals “that did not receive ellagic acid developed wrinkles and thickening of the skin” indicative of “sun damage,” and the mice that did receive “ellagic acid showed less wrinkle formation.”

 

Texas House gives initial approval to bill restricting teen access to tanning beds.

The AP (4/22, Stone) reports, that on Apr. 21, the Texas House gave “initial approval” to HB 1310, a measure introduced by Rep. Burt Solomons (R-Carrollton) that “would require anyone under 16 1/2 years old to get a doctor’s note before using a tanning bed. Older teens would need parental consent.” The AP notes that “legislators in 17 states are” currently “pushing stronger restrictions for teens this year. The Texas bill and another in Vermont that would ban non-medical indoor tanning for anyone under 18 have been called the strictest.” In addition, 29 other “states have some form of tanning bed restrictions for minors. Most require parental approval.” Under the proposed legislation, “parents of teens older than 16 1/2” would have “to sign their consent in the tanning salon. The permission slips would also have to include Texas Medical Board warnings about indoor and outdoor tanning.”

 

        According to the Dallas Morning News (4/22, Garrett), the state currently “requires parental permission slips for children up to 18. Minors under 16 must have a parent or guardian at the tanning facility while the child is tanning,” and “children under 13 must have a doctor’s note.” Rep. Solomons explained, “The sheer increases in melanoma cases, especially in young women, are dramatic.” He added, “And it’s all in response to the growth of the indoor tanning industry, so… why are we letting minors go?” Meanwhile, Rep. Jodie Laubenberg (R-Parker) called the measure “too intrusive,” and “industry spokesmen, who say current oversight is adequate,” said that “parents should decide what health risks are acceptable for their children.” The Morning News notes that the “House will have to take another vote before the measure heads to the Senate.”

 

 

 

 

from Heartwire — a professional news service of WebMD

 

Lisa Nainggolan

 

Published: 04/16/2009

 

April 16, 2009 (Rockville, Maryland) — The FDA has issued a class 1 recall for a number of intra-aortic balloon pump (IAB) catheters manufactured by Teleflex’s Arrow International because of a fault in the connector of the pump tubing assembly [1]. This announcement follows a voluntary urgent medical-device recall letter for the products issued by the company in February [2].

 

The IAB catheters are components in the Arrow intra-aortic balloon pump (IABP) system. Arrow said this week that there have been 25 complaints with regard to this issue, but no reports of patient injury so far [3].

 

The company said it became aware, through a small number of customers, that the blue connector for the 40-cc IAB was not properly recognized by the IABP system. It notified both domestic and foreign hospitals and distributors of the problem in its recall letter, dated February 2, 2009, as well as the FDA. The February recall involved the retrieval of unused product, issuance of mitigation instructions for patients and/or facilities in critical need, and the replacement of pump tubing assemblies.

 

The fault could result in the volume setting on the pump defaulting to 2.5 cc or 5 cc, rather than the appropriate 30-, 40-, or 50-cc volume. If the incorrect volume is pumped, poor or no augmentation support will result, reducing the therapeutic efficacy of the product and increasing the risk of ischemic events. This could, in turn, cause organ injury or infarct and possibly result in patient death, notes the FDA in its recall notice. Prolonged exposure could also result in thrombus formation on the IAB and possible subsequent systemic or cerebral thromboembolism.

 

The affected products were manufactured from January 2008 through January 2009 and were distributed from January 2008 through January 23, 2009. A list of recalled models can be found in the FDA recall notice, with a link to affected lot numbers on the Arrow website.

 

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References

 

1.       Food and Drug Administration. Arrow International 30cc, 40cc and 50cc Intra aortic balloon pump (IAB) catheters [recall notice]. April 15, 2009. Available at: http://www.fda.gov/medwatch/safety/2009/safety09.htm#Arrow.

 

2.       Arrow International. Urgent Medical Device Recall. February 2, 2009. Available at: http://www.arrowintl.com/documents/pdf/IAB%20Medical%20Device%20Recall%20Notification.pdf.

 

3.       Teleflex. Arrow International announces worldwide voluntary recall of intra aortic balloon pump (IAB) catheters [press release]. April 13, 2009. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=84306&p=irol-newsArticle&ID=1275785&highlight

 

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Authors and Disclosures

 

Journalist

 

Lisa Nainggolan

 

Lisa Nainggolan is a journalist for theheart.org, part of the WebMD Professional Network. She has been with theheart.org since 2000. Previously, she was science editor of Scrip World Pharmaceutical News, covering news about research and development in the pharmaceutical industry, and a consultant editor of Scrip Magazine. Graduating in physiology from Sheffield University, UK, she began her career as a poisons information specialist at Guy’s Hospital before becoming a medical journalist in 1995. She can be reached at LNainggolan@webmd.net.

 

Heartwire © 2009 Medscape, LLC

 

 

 

 

 

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Meta-Analysis Supports Heart-Health Benefits From a Mediterranean Diet

 

from Heartwire — a professional news service of WebMD

 

Marlene Busko

 

April 16, 2009 (Hamilton, Ontario) — Strong evidence supports the protective effect of a Mediterranean diet on risk of CHD, and overall diet pattern appears more important than individual foods [1].

 

These findings, from a review of close to 200 studies, are published in the April 13, 2009 issue of the Archives of Internal Medicine.

 

“We found strong evidence that a ‘Western’ diet–which is high in processed meats, red meats, butter, eggs, refined grains, and high-fat dairy products–is associated with an increased risk of CAD, so we could say [to patients]: ‘You should consume less of those types of foods and gravitate more toward a “prudent” diet or a Mediterranean diet, which are both high in fruits and vegetables, legumes, whole grains, and fish,’ ” senior author Dr Sonia Anand (McMaster University, Hamilton, ON) told heartwire .

 

Although this message is not really new, what is new is the way that this review assessed the strength of the evidence, she noted.

 

The study also found strong evidence of increased CHD risk from consuming trans-fatty acids and foods with a high glycemic index such as white potatoes, sugar, white rice, and white bread.

 

Physicians should advise patients: “Lower your trans-fats, lower your saturated fats, but also watch for some of these simple carbohydrates, because they can have adverse effects as well,” said Anand.

 

Diet Dilemma

 

The relationship between diet and CHD has been studied for decades, yet there is still some confusion about which foods or diets are best, since cohort studies and randomized controlled trials have often produced discrepant results, the researchers write.

 

To examine the strength of the evidence supporting a causal link between diet and CHD, the researchers reviewed 146 prospective cohort studies and 43 randomized controlled trials (RCTs).

 

Studies were scored on how well they met four criteria of strength, consistency, temporality, and coherence. A score of 4 was considered strong evidence of a cause-and-effect relationship between dietary exposure and disease.

 

Dietary Pattern vs Single Food

 

In the cohort studies, a Mediterranean diet–characterized by higher intake of vegetables, legumes, fruits, nuts, whole grains, cheese or yogurt, fish, and monounsaturated as opposed to saturated fatty acids–and a “prudent diet”–characterized by high intake of vegetables, fruit, legumes, whole grains, fish, and other seafood–were each associated with significantly lower risk of CHD. Similarly, strong evidence supported the benefits from monounsaturated fatty acids and foods such as vegetables and nuts and the harm from trans-fatty acids and foods with a high glycemic index.

 

In the RCTs, however, only the Mediterranean diet was strongly linked to risk of CHD.

 

“Our findings support the strategy of investigating dietary patterns in cohort studies and RCTs for common and chronic complex diseases such as CHD,” the researchers write.

 

Study Reinforces Heart-Healthy Diet

 

Commenting on the results for heartwire , Dr Robert Eckel (University of Colorado, Denver) said that the study confirms previous notions about what a heart-healthy diet is all about.

 

It’s not a matter of good foods and bad foods. It’s what the overall quality of the diet is.

 

“I think cardiologists need to increasingly make lifestyle-related issues an important part of their practice,” he added. “This is another article reinforcing that a heart-healthy diet contains certain constituents and avoids certain constituents.”

 

Concurring with the study authors, he noted: “Overall, the dietary pattern is what needs to be emphasized. It’s not a matter of good foods and bad foods. It’s what the overall quality of the diet is. The Western pattern is high in saturated fat, trans-fat, and cholesterol, whereas a Mediterranean diet and ‘prudent’ diet include more monounsaturated or polyunsaturated fats, and there is more fish consumption.”

 

No financial disclosures were reported.

 

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References

 

1.       Mente A, de Koning L, Shannon HS, et al. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med 2009; 169:659-669. Abstract

 

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Authors and Disclosures

 

Journalist

 

Marlene Busko

 

Marlene Busko is a freelance writer for Medscape and Heartwire.

 

Heartwire © 2009 Medscape, LLC

 

 

 

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Chronic Sleep Problems Linked to Increased Risk for Suicidal Behavior

 

Caroline Cassels

 

April 16, 2009 — Chronic sleep problems significantly increase the risk for suicidal behavior, new research suggests.

 

A large population-based study shows that individuals with sleep problems are almost 3 times more likely to report a suicide attempt than those without insomnia complaints.

 

Furthermore, difficulty initiating or maintaining sleep as well as early morning wakening were all significantly associated with suicidal thoughts, plans, and attempts.

 

“Our study suggests individuals with sleep disturbances are at heightened risk of suicide even in the absence of a psychiatric condition. These data also suggest that insomnia may be an important modifiable risk factor for suicide in the general population,” principal investigator Marcin Wojnar, MD, PhD, a research fellow at the University of Michigan, in Ann Arbor, and associate professor of psychiatry at the Medical University, in Warsaw, Poland, told Medscape Psychiatry.

 

The study findings were recently presented at the World Psychiatric Association International Congress on Treatments in Psychiatry, in Florence, Italy, and were also published in the February issue of the Journal of Psychiatric Research (Wojnar M et al. J Psychiatr Res. 2009;43:526-531).

 

First Population-Based Study

 

Suicide is a common cause of premature mortality; approximately 30,000 people in the United States die by suicide every year. Furthermore, it is estimated that over 395,000 emergency-department visits are for the treatment of nonfatal self-injury.

 

Sleep problems are also common, with approximately one-third of US adults reporting 1 or more sleep complaints within the past year. Further, the authors note that sleep problems are strongly associated with co-occurring psychiatric disorders, which in turn are linked to an increased risk for suicidality.

 

According to Dr. Wojnar, while links between sleep problems and suicidality have been frequently described in clinical samples, the issue has not been well studied in the general population.

 

Using data from the National Comorbidity Survey–Replications study (NCS-R), a national sample representative of the US population, the investigators examined the relationship over 1 year between 3 characteristics of insomnia and 3 suicidal behaviors in 5692 subjects. Approximately 35% of those studied reported experiencing at least 1 type of sleep disturbance in the preceding 12 months.

 

Early morning wakening had the most consistent link for all suicidal behaviors, with odds ratios (ORs) of 2.0, 2.1, and 2.7 for suicidal ideation, planning, and attempts, respectively. Further, the investigators found that difficulty initiating sleep was a significant predictor of suicidal ideation (OR, 1.9) and planning (OR, 2.2).

 

Difficulty maintaining sleep was a significant predictor of suicidal ideation (OR, 2.0) and attempt (OR, 3.0).

 

Underlying Mechanism Not Well Understood

 

Exactly how sleep problems influence suicidal behavior is not well understood, said Dr. Wojnar. However, he said, it is possible that insufficient sleep may have a negative impact on cognitive function, leading to poor judgment, less impulse control, and increased fatigue and hopelessness, all of which may contribute to suicidal thoughts and behavior.

 

It is also possible that poor sleep quality causes dysfunction of the serotonin system, which has been shown to play an important role in sleep, psychiatric disorders, and suicide.

 

Whatever the underlying mechanism, Dr. Wojnar said the study’s findings have important clinical implications and suggest physicians should routinely screen their patients for sleep disturbances.

 

Dr. Wojnar added that his next research steps include an attempt to replicate these results in a similar population-based study in Poland.

 

The study was funded by the US Department of Veterans Affairs, the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute of Mental Health. The authors report no disclosures.

 

World Psychiatric Association International Congress: Abstract NRS4.5. Presented April 1, 2009.

 

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Authors and Disclosures

 

Journalist

 

Caroline Cassels

 

Caroline Cassels is the news editor for Medscape Psychiatry. A medical and health journalist for 20 years, Caroline has written extensively for both physician and consumer audiences. She helped launch and was the editor of Health Digest, an award-winning Canadian consumer health publication. She was also national editor of the Heart & Stroke Foundation of Canada’s Web site before joining Medscape Neurology & Neurosurgery in 2005. She is the recipient of the 2008 American Academy of Neurology Journalism Fellowship Award. She can be contacted at CCassels@webmd.net.

 

Medscape Medical News © 2009 Medscape, LLC

 

 

 

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New Sleep Environment Risk Factors for SIDS Identified CME

 

News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd

 

CME Released: 04/17/2009; Valid for credit through 04/17/2010

 

April 17, 2009 — Novel risk factors for sudden infant death syndrome (SIDS) include sleeping outside the parental home, in the living room, or prone on a sheepskin, according to the results of a population-based, case-control study reported in the April issue of Pediatrics.

 

“A number of case-control studies in the late 1980s and early 1990s identified prone sleeping as a major risk factor for SIDS,” write Mechtild M. Vennemann, MD, PD, MPH, from the University of Münster in Münster, Germany, and colleagues from the German Sudden Infant Death Syndrome Study Group. “Following advice to put infants only on their back for sleeping, the rates in all developed countries for SIDS have decreased dramatically.”

 

The purpose of this study, which took place from 1998 to 2001 in Germany, was to identify risk factors for SIDS in the sleep environment for a population in which few infants sleep prone because of widespread education campaigns.

 

During the study period, there were 333 SIDS cases and 998 matched controls. Only 4.1% of the infants were placed in a prone position to sleep, but the risk for SIDS was increased in those infants. The risk was very high in those infants who were unaccustomed to sleeping prone or who were turned to prone.

 

Factors associated with an increased risk for SIDS were bed sharing, particularly for infants younger than 13 weeks; use of duvets; sleeping prone on a sheepskin; sleeping in the house of a friend or a relative vs sleeping in the parental home; and sleeping in the living room vs in the parental bedroom.

 

Pacifier use during the last sleep was associated with a significantly decreased risk for SIDS.

 

Limitations of this study include small numbers of cases in groups with some of the novel risk factors.

 

“This study has clarified the risk factors for…SIDS in a population where few infants sleep prone,” the study authors write. “This study supports the current recommendations of the American Academy of Pediatrics. This study has identified several novel risk factors for…SIDS: an increased risk if the infants sleeps outside the parental home, death in the living room, and the high risk when sleeping prone on a sheepskin; however, because the numbers of cases in these groups are small, additional studies are needed to confirm these findings.”

 

The German Federal Ministry for Science and Education supported this study on SIDS from 1998 to 2003. One of the study authors is supported by the Child Health Research Foundation (New Zealand). The other study authors have disclosed no relevant financial relationships.

 

Pediatrics. 2009;123:1162-1170.

 

Clinical Context

 

SIDS is the leading cause of death in infants younger than 1 year in developed countries. Sleeping in a prone position has been identified as a significant risk, leading to the Back to Sleep campaign, which resulted in a reduction in SIDS mortality rates in many countries. Since that campaign was initiated, other risk factors such as sleep environment have not been fully examined.

 

This is a population-based case-control study conducted in a part of Germany with more than 50% of its live births to determine risk factors associated with SIDS during a 3-year period (1998-2001).

 

Study Highlights

 

  • The German SIDS study was implemented to identify risk factors for SIDS with a special emphasis on the sleep environment.
  • There were 2.3 million live births in the study region during the 3 years of the study.
  • 333 SIDS cases occurred and 998 controls matched for age, sex, region, and sleep time were recruited.
  • Control infants were born 4 to 6 weeks after case infants and had the same age as the index case by the time of the interview.
  • A detailed questionnaire was completed by a trained interviewer in the parents’ homes.
  • Information collected included likely time of death; morning, afternoon, evening, and night sleep; sleep environment; reference sleep; previous illnesses; feeding patterns; previous sleep arrangements; and shared bedding.
  • Using a standardized protocol, forensic pathologists performed an autopsy on all SIDS cases.
  • Univariate and multivariate odds ratios (ORs) were calculated based on comparison of SIDS vs control data.
  • Only 4.1% of infants were placed prone to sleep.
  • The risk for SIDS was significantly higher with prone sleep position (adjusted OR, 7.08) and bed sharing (adjusted OR, 2.73).
  • Not being placed prone but being found prone was a risk factor (adjusted OR, 18.54).
  • When a sheepskin was placed under the infant, sleeping prone increased the risk for SIDS (adjusted OR, 37.73), whereas sleeping supine reduced the risk (adjusted OR, 0.88).
  • The risk was increased when the infant slept at a friend or relative’s home vs the parents’ home (adjusted OR, 4.39).
  • There was an increased risk for SIDS with sleeping in the living room vs sleeping alone in one’s own bedroom or in a bedroom with siblings (adjusted OR, 1.72).
  • There was no increased risk for SIDS when infants were placed on a sofa to sleep.
  • Bed sharing was associated with an increased risk for SIDS (adjusted OR, 2.73).
  • The risk for SIDS was not associated with socioeconomic status.
  • Use of a pacifier was protective, with a reduced adjusted OR of 0.39.
  • Pacifier use in the previous 4 weeks was associated with a protective effect, with an adjusted OR of 0.49, but stopping pacifier use was associated with an increased risk.
  • Use of duvets doubled the risk for SIDS (adjusted OR, 2.20 for thick duvets and 1.92 for thin duvets).
  • The authors concluded that the study confirmed previous observations that sleeping prone was associated with an increased risk for SIDS and supported recommendations of the American Academy of Pediatrics for infants to sleep in the nonprone position (ie, either on their side or back).
  • They added newly identified risk factors as sleeping outside the parental home, sleeping in the living room, and sleeping prone on a sheepskin.

 

Pearls for Practice

 

  • Being placed or found in the prone position is associated with a higher risk for SIDS in infants.
  • Other risk factors for SIDS include bed sharing, use of duvets, sleeping at a relative’s or a friend’s home, and sleeping in the living room, whereas pacifier use has a protective effect.

 

CME/CE Test

 

Top of Form

 

 

 

Questions answered incorrectly will be highlighted.

 

 

 

Which of the following variables is associated with the highest risk for SIDS?

 

Being placed prone to sleep

 

Being found prone

 

Sleeping prone on a sheepskin

 

Sleeping on the side

 

 

 

Which of the following factors is least likely to increase the risk for SIDS in infants?

 

Low socioeconomic status

 

Sleeping in the living room

 

Bed sharing

 

Use of duvets

 

 

 

Bottom of Form

 

This article is a CME certified activity. To earn credit for this activity visit:
http://cme.medscape.com/viewarticle/591213

 

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Authors and Disclosures

 

As an organization accredited by the ACCME, Medscape, LLC requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

 

Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

 

Author(s)

 

Laurie Barclay, MD

 

 

Laurie Barclay, MD, is a freelance writer and reviewer for Medscape.

 

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

 

 

 

 

 

 

 

 

 

 

 

 


 

Editor(s)

 

Brande Nicole Martin

 

 

Brande Nicole Martin, is the News CME editor for Medscape Medical News.

 

Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

 

 

 

 

 

 

 

 

 

 

 

 


 

CME Author(s)

 

Désirée Lie, MD, MSEd

 

 

Clinical Professor, Family Medicine, University of California, Orange; Director, Division of Faculty Development, UCI Medical Center, Orange, California

 

Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.

 

 

 

 

 

 

 

 

 

 

 

 


 

 

Medscape Medical News © 2009 Medscape, LLC
The material presented here does not necessarily reflect the views of Medscape or companies that support educational programming on http://www.medscape.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

 

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This article is a CME certified activity. To earn credit for this activity visit:
http://cme.medscape.com/viewarticle/591213

 

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CME Information

 

CME Released: 04/17/2009; Valid for credit through 04/17/2010

 

Target Audience

 

This article is intended for primary care clinicians and specialists who care for infants.

 

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The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

 

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Upon completion of this activity, participants will be able to:

 

1.       Describe the role of sleeping position on the risk for sudden infant death syndrome.

 

2.       Identify risk factors for sudden infant death syndrome.

 

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U.S. Veterans Health Administration Announcements Highlight Need for Comprehensive Endoscopy-Reprocessing Protocols

 

 

 

 

 

 

Device Term(s): Cystoscopes, Flexible [17-144];

 

Disinfectors, Liquid Germicide, Flexible Endoscope [11-279];

 

Endoscopes, Gastrointestinal Tract [20-477];

 

Endoscopes, Respiratory Tract [20-476]

 

 

 

 

 

 

 

 


 
 
 

Geographic Regions: Worldwide

 

Summary: Recent media coverage of potential endoscopy-related cross-contamination at several U.S. Veterans Health Administration hospitals helps illustrate the need for strict adherence to comprehensive, model-specific reprocessing protocols. Facilities must ensure that such protocols cover not only the proper reprocessing, handling, and storage of flexible endoscopes but also similar precautions for related components and auxiliary devices.

 

Background: Since December 2008, U.S. Department of Veterans Affairs (VA) hospitals have notified more than 10,000 patients that they may have been exposed to bloodborne pathogens during procedures involving improperly reprocessed endoscopy equipment or accessories.  Although the VA believes that the risk of resulting infection is low, it has offered free screening to potentially affected patients. According to an April 3, 2009, press release, of the approximately 3,200 patients who had received screening results by the press release date, 5 tested positive for hepatitis B virus, 11 tested positive for hepatitis C virus, and 1 tested positive for human immunodeficiency virus. These infections have not been definitively linked to endoscopic treatment at VA hospitals, but the department has announced that it is undertaking an epidemiologic study to determine whether such an association exists.     

 

The VA’s actions stem from the discovery of the following reprocessing inadequcies at three facilities:

 

 

 

(1) In December 2008, VA investigators discovered that staff at a facility in Murfreesboro, Tennessee, had, in at least some colonoscopies, connected the colonoscope to the flushing pump using tubing with an incorrect valve, potentially allowing backflow of contaminated fluid into the irrigation system. Investigators also determined that staff were not following manufacturer recommendations when reprocessing the auxiliary water tubing and other irrigation components between patient procedures. Following the investigation, the facility informed patients who had undergone a colonoscopy from April 2003 to December 2008 of the possibility of cross-contamination.  On December 22, 2008, the VA issued a Patient Safety Alert to inform its facilities about the event at Murfreesboro and mandating  that all facilities review their setup and endoscope accessory reprocessing procedures.  In addition, the VA implemented a “Step Up” week that required all facilties to participate in a special training campaign focusing on endoscope safety and proper reprocessing protcols.  The manufacturer of the endoscopy equipment, Olympus, subsequently distributed two related Important Safety Notices to remind users of model-specific reprocessing guidelines. (For further information about these Safety Notices, see Alert Accession Nos. A11909 and A12075.)

 

 

 

(2) In February 2009, a VA facility in Augusta, Georgia, informed approximately 1,200 patients that endoscopes used on them during ear, nose, and throat procedures may not have been adequately disinfected or sterilized.

 

 

 

(3) In March 2009, the Miami VA Healthcare System notifed patients who had undergone a colonoscopy during the preceding 5 years of potential cross-contamination including the failure to disinfect “tubing” between procedures.

 

ECRI Institute Perspectives: The developments at the VA facilities help illustrate a critical point that is sometimes not fully appreciated: reprocessing of the endoscope alone is not sufficient to prepare equipment for safe patient use. A variety of accessories and auxiliary equipment may be used in concert with the endosope—to irrigate, insufflate, suction, sample, or provide therapy to the treatment site—and like the endoscope, these items may become contaminated during use. To adequately protect patients, facilities must ensure adherence to appropriate reprocessing procedures not only for the endoscope but for other equipment used during the endoscopy procedure (e.g., irrigation tubing, suction valves) and in the reprocessing procedure itself (e.g., cleaning brushes). These procedures may also require adherence to manufacturer-recommended replacement schedules for key single-use or limited-use components (e.g., adapters used in some automated endoscope reprocessors) . Failure to properly account for those items may increase the risk of cross-contamination considerably.

 

ECRI Institute Recommendations: The best defense against endoscopy-related cross-contamination continues to be careful development of and strict adherence to comprehensive, model-specific reprocessing protocols. To that end, ECRI Institute recommends the following:   

 

(1) Ensure that a model-specific reprocessing protocol exists for each flexible-endoscope model in your facility’s inventory. Refer to the device’s user manual or consult the endoscope manufacturer to identify unique requirements (e.g., cleaning procedures, channel adapters) that need to be addressed within each document. Remember to repeat this review for each newly purchased endoscope model (or related equipment).

 

 

 

(2) Periodically review protocols to ensure that they are clear and comprehensive and that they reflect the current environment (e.g., obsolete workflows or equipment/chemicals that are no longer in use at the facility are not included).

 

 

 

(3) In reviewing or developing protocols, ensure that the following issues are addressed and documented in adequate detail:

 

·                         Precleaning of equipment at the treatment site.

 

·                         Safe transport of contaminated equipment from the treatment site to the reprocessing room.

 

·                         Leak testing of the endoscope.

 

·                         Thorough manual cleaning of all channels, components, and (if appropriate) auxiliary devices, even if they were not used in the procedure.

 

·                         High-level disinfection or sterilization of equipment with compatible methods/chemicals.

 

·                         Terminal rinsing and drying of equipment.

 

·                         Proper disposal and replacement of single-use or limited-use components.

 

·                         Appropriate storage of reprocessed equipment.

 

·                         Proper documentation of the reprocessing procedure (e.g., date, reprocessing staff, equipment reprocessed, outcome).

 

·                         Safe transport of equipment back to the treatment site for subsequent use.

 

 

 

(4) If your facility reprocesses endoscopy equipment using an automated endoscope reprocessor (AER), ensure that:

 

·                         Endoscopes (and related equipment) in your facility’s inventory are compatible with the AER and its disinfecting/sterilizing agent.

 

·                         Reprocessing staff have the appropriate channel adapters to connect the endoscope to the AER and are familiar with the correct endoscope/connector combinations.

 

·                         Staff are familiar with and adhere to appropriate AER maintenance schedules, including the periodic replacement of particulate and bacterial filters.

 

 

 

(5) Ensure that documented protocols are readily available to staff and that staff are adequately trained to understand and follow them. Training should be provided not only to reprocessing staff but also to clinicians who may be responsible for setup and precleaning or handling of equipment. Remember to periodically repeat training to ensure that staff remain familiar with protocol and to address turnover.

 

 

 

For additional information on reprocessing of flexible endoscopes and associated equipment, refer to the guidance article “Ensuring the Effective Reprocessing of Flexible Endoscopes,” in the November 2007 issue of the Health Devices journal.

 

Source:  

 

ECRI Institute. Ensuring the effective reprocessing of flexible endoscopes [guidance article]. Health Devices 2007 Nov;36(11):352-61.  

 

 

 

United States. Department of Veterans Affairs:

 

·                         Improper set-up and reprocessing of flexible endoscope tubing and accessories [VHA Patient Safety Alert online]. 2008 Dec 22 [cited 2009 Apr 16].  Available from Internet: Click here.

 

·                         VA continues notification process for veterans affected by reprocessing issues [press release]. 2009 Apr 3 [cited 2009 Apr 15]. Available from Internet: Click here.

 

·                         Endoscopy notification questions and answers [online]. 2009 Feb 9 [cited 2009 Apr 15]. Available from Internet: Click here.

 

·                         Charlie Norwood VA offers veterans free screening [press release online]. 2009 Feb 9 [cited 2009 Apr 15]. Available from Internet: Click here.

 

·                         VA Healthcare System establishes a Special Care Clinic [press release online]. 2009 Apr 6 [cited 2009 AAvailablefrom Internet: Click here.

 

Comment:

 

·                         This alert is a living document and may be updated when ECRI Institute receives additional information.  In circumstances in which we determine that it is appropriate for customers to repeat their review of an issue (e.g., when additional affected product has been identified), we will post a separate update alert. In other cases, we may add information, such as additional commentary, recommendations, and/or source documents, to the original alert.

 

Suggested Distribution: Clinical/Biomedical Engineering, Gastroenterology, Infection Control, Otolaryngology, Pulmonology/Respiratory Therapy, Risk Management/Continuous Quality Improvement, Staff Education

 

Verification History: Fully verified[4/16/2009 1:55:33 PM]

 

 

 

 

 

 

 

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