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Head and forehead hyperhidrosis (HFH) is a disease that causes a large amount of sweating from the head region, and it significantly reduces patients' quality of life. Only a few reports have shown the effectiveness of botulinum toxin type A (BTX-A) local injection therapy (BTX-A therapy) for HFH. To clarify the benefits of BTX-A for HFH, BTX-A therapy was performed in 15 patients, and its efficacy was evaluated. The amount of sweating was measured by the ventilation capsule method and Minor's iodine-starch test. Evaluation was also performed using the Hyperhidrosis Disease Severity Scale (HDSS) and the Dermatology Life Quality Index (DLQI). In most cases, a remarkable antiperspirant effect was observed from 2 weeks after the injection, and the effect lasted for approximately 30 weeks. HDSS and DLQI improved along with the decrease in sweating. Two patients (13.3%) complained of transient mild ptosis. There were no serious side-effects. This study showed that BTX-A therapy is a safe and effective treatment for HFH.

PDF file - 44K, Gene maps of Espin isoforms.

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PDF file - 32K, Transcript expression of Espin isoforms in melanocytic tumors that developed in RET-mice.

Espin is a multifunctional actin-bundling protein with multiple isoforms, and has special connections to hair cell stereocilia and microvillar specializations of sensory cells in the inner ear. However, there have been no reports showing the expression and function of Espin in cancers, including melanoma. Here, it is demonstrated that Espin expression is significantly increased in melanomas that spontaneously developed in RET-transgenic mice (RET-mice). Importantly, the invasion capacity of Espin-depleted Mel-ret melanoma cells derived from a tumor of the RET-mouse was dramatically less than that of control melanoma cells with reductions of lamellipodia, focal adhesion kinase (FAK), and GTP-Rac1 activities. Correspondingly, the ratio of metastatic foci in Espin-depleted Mel-ret melanoma cells was significantly less than that of control melanoma cells in an in vivo melanoma metastasis model. Moreover, Espin could be a novel biomarker of melanoma in humans, because our immunohistochemical analysis data reveal that percentages of Espin-positive cells in human primary and metastatic melanomas were significantly higher than that of cells in melanocytic nevi. Together, these results indicate that Espin is not only a metastatic regulator for melanoma but also a potential biomarker of disease progression.Implications: Actin-binding protein Espin is expressed in melanoma, affects metastasis, and is a potential target for melanoma therapy. Mol Cancer Res; 12(3); 440–6. ©2013 AACR.

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PDF file - 138K, Specification of anti-Espin-ru antibody.

The prevalence of primary axillary hyperhidrosis in Japan is 5.75% (males, 6.60%; females, 4.72%) in the population aged 5–64 years. No study on comprehensively evaluated direct medical costs, hygiene product costs, and productivity loss in axillary hyperhidrosis patients has been published in Japan. The aim of this study was to estimate the cost of illness for axillary hyperhidrosis in Japan by conducting a nationwide insurance claims database analysis and a cross‐sectional Web‐based survey. Among patients diagnosed with primary axillary hyperhidrosis at least once between November 2012 and October 2019, health insurance receipt data of 1447 patients were analyzed. A cross‐sectional Web‐based survey was conducted on 321 patients aged 16–59 years with axillary hyperhidrosis to calculate hygiene product costs and productivity loss using a Work Productivity and Activity Impairment questionnaire. Furthermore, nationwide estimation was performed for the hygiene product costs and productivity loss based on the number of patients estimated from the prevalence. The annual direct medical costs per axillary hyperhidrosis patient were ¥91 491 in 2016, ¥93 155 in 2017, and ¥75 036 in 2018. In all of these years, botulinum toxin type A injection accounted for approximately 90% of the total costs. The annual total cost of hygiene products per axillary hyperhidrosis patient was ¥9325. The overall work impairment (%) of working patients with axillary hyperhidrosis was 30.52%, and its monthly productivity loss was ¥120 593/patient. The activity impairment (%) of full‐time housewives with axillary hyperhidrosis was 49.05% and its monthly productivity loss was ¥176 368/patient. The annual hygiene product cost based on the nationwide estimation was ¥24.5 billion and the monthly productivity loss was ¥312 billion. The significant cost associated with axillary hyperhidrosis was clarified. If out‐of‐pocket expenses for treatments not covered by health insurance are included in the estimation, the cost will further increase.

Background Recent case reports have shown the efficacy of apremilast for the treatment of palmoplantar pustulosis (PPP). However, no study has statistically analyzed the clinical efficacy of oral apremilast in patients with PPP. Objectives To evaluate the effectiveness of apremilast, a phosphodiesterase 4 inhibitor, for PPP. Materials and Methods Among 13 patients who were diagnosed with PPP, 10 patients with PPP with either palmoplantar pustules (>1 mm diameter) or sternoclavicular joint pain were retrospectively analyzed. Results Palmoplantar Pustulosis Area and Severity Index (mean ± SD: baseline, 13.4 ± 9.5 vs. after treatment, 5.1 ± 5.6; P = 0.013) and the number of pustules measuring > 1 mm in diameter (3.9 ± 3.9 vs. 1.3 ± 1.9; P = 0.029) significantly improved in 2 (±1) weeks. Moreover, the Dermatology Life Quality Index (9.7 ± 7.0 vs. 3.3 ± 3.6; P = 0.009) and palmoplantar itching (visual analog scale [VAS] score) (5.6 ± 3.5 vs. 2.1 ± 2.2; P = 0.026) significantly improved in 2 weeks, whereas VAS scores of palmoplantar pain (4.8 ± 4.4 vs. 1.1 ± 2.4; P = 0.081) and sternoclavicular joint pain (3.2 ± 3.8 vs. 2.0 ± 2.6; P = 0.194) did not significantly improve. Diarrhea was observed in 60.0% of our patients. Conclusion Our study demonstrated that apremilast can effectively treat cutaneous manifestations and arthralgia in Japanese patients with PPP who had apparent pustules and/or clavicular‐sternocostal arthralgia. Owing to the retrospective design of the study and a small sample size, placebo‐controlled clinical trials with a larger number of patients are warranted to confirm the efficacy of apremilast for treatment of PPP.

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Bee venom (BV) induces skin inflammation, characterized by erythema, blisters, edemas, pain and itching. Although BV has been found to have an inhibitory effect on toll-like receptors (TLRs), we here show that BV enhances keratinocyte responses to polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3. Our results revealed that the enhanced TLR activity was primarily induced by secretory phospholipase A2 (sPLA2), a component of BV (BV-sPLA2). PLA2 mediates the hydrolysis of membrane phospholipids into lysophospholipids and free fatty acids. We demonstrated that BV-sPLA2 increased the intracellular uptake of poly(I:C), phosphorylation of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), and poly(I:C)-mediated interleukin 8 production in human keratinocytes. We further showed that the enzymatic activity of BV-sPLA2 was essential for the increased uptake of poly(I:C). These findings suggest that BV-sPLA2 may induce a modification of the cell membrane structure, leading to enhanced poly(I:C) uptake in keratinocytes. BV-sPLA2 might be able to promote wound healing by enhancing TLR3 responses.

Summary Background/Purpose Topical 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) is an effective treatment for Bowen's disease (BD). In order to compare the efficacy of two different light sources, using either an excimer-dye laser (EDL) (630 nm) or a metal-halide lamp (MHL) (600 to 740 nm) a protocol for topical ALA-PDT for treatment of BD of the extremities was established, and responses during 12 months follow-up were assessed. Methods From 25 patients a total of 26 lesions that had been histopathologically diagnosed as BD from 2005 to 2010 in the Department of Dermatology at the Aichi Medical University Hospital were randomly selected. The light source used for the topical ALA-PDT was EDL in 17 lesions and MHL in 9 lesions. The photosensitizing protoporphyrin IX that is produced within BD lesions 4 h after application of 20% ALA cream was mostly consumed after exposure to 100 J/cm2 irradiation using 630 nm EDL. Each lesion was irradiated once a week for 3 weeks, for a total dosage of 300 J/cm2 (100 mW/cm2). Patients were followed up clinically every 3 months for 12 months, and at 1 month after the final treatment lesions were evaluated histopathologically. Results Histologically, the complete response (CR) rate at 1-month follow-up was 82% (14/17 lesions) in the EDL treatment group and 100% (9/9 lesions) in the MHL treatment group (P > 0.05). The recurrence rate at 12 months after PDT was 46% (6/13 lesions, one patient lost to follow-up) in the EDL group and 0% in the MHL group (P

Components of cherry trees have been used as traditional herbal remedies for various diseases. These components are known to possess antioxidative effects. However, the mechanisms underlying cherry tree component-mediated antioxidative effects remain largely unknown. This study focused on cherry leaves extract (CLE) and examined the mechanism underlying the effect of CLE on tert-butyl hydroperoxide (t-BOOH)-induced melanocytic cell death with DNA damage. Interestingly, CLE prevented t-BOOH-induced cell death with reduction in DNA damage, p38 kinase activation, and reactive oxygen species (ROS) production. CLE-mediated suppression of cell death with reduction of DNA damage, p38 kinase activity and ROS production was prevented by a thioredoxin (Trx) system inhibitor but not by a glutathione (GSH) system inhibitor. Finally, data showed that CLE prevented t-BOOH-induced reduction of Trx2 but not Trx1 and Trx reductases (TrxR1 and TrxR2) protein expression. Thus, our results suggest that CLE prevents t-BOOH-induced reduction in Trx2 expression, promotion of ROS production, activation of p38 kinase, and increase in DNA damage and that it protects against cell death.

Background: With regards to dyshidrosis in Parkinson’s disease (PD), there is no established and consistent view on the occurrence sites, frequency and etiology, although there have been several reports on hypohidrosis of the limbs and sudoresis on the face/cervical region. Methods: Hydrosis in the forearms of PD patients and healthy individuals were compared by quantitative sudomotor axon reflex test (QSART). The expression of various neuropeptides and α-synuclein was examined with immunohistochemical staining. Results: There was a significant reduction in QSART of PD patients but not of healthy controls. Reduced expression of vasoactive intestinal polypeptide (VIP) was also detected in the sweat glands of PD patients. Conclusion: Reduction in QSART and VIP expression in the sweat glands might be involved in the dyshidrosis of PD patients.

Botulinum toxin A is widely used in Europe and the USA for the treatment of localized hyperhidrosis, and its efficacy has been recognized. In this study, botulinum toxin A (Botox) was locally injected at 30 sites (2 U/injection) on the right palm in 27 patients with palmar hyperhidrosis (14 severe patients, 13 mild patients), and the results confirmed the efficacy of injection. The amount of sweat was then quantified for the left and right hands every month after local injection. The quantity of sweat on the treated hand was approximately one-fifth that on the untreated hand. In addition, the quantity of sweat on the untreated hand decreased slightly. Over time, the quantity of sweat on the treated hand increased slightly, but the quantity of sweat on the treated hand at 6 months after injection was less than half that before injection, and there were significant differences before and after injection. In the present study, severe sweating was defined as 1 mg/cm2/min or more and mild sweating as less than 1 mg/cm2/min, and the therapeutic effects of botulinum toxin A were analyzed in relation to severity. When compared to the mild cases, the quantity of sweat remained higher in the severe cases after botulinum toxin A therapy. Therefore, to achieve satisfactory effects in severe cases, it would be necessary to increase the number of injection sites, as well as injection dose.

Pili torti is an extremely rare hair phenotype characterized by short length of hairs with hair shafts being easily broken. However, the mechanism of fragility in pili torti is unclear. In this study, we examined the underlying morphological features responsible for pili torti formation using transmission electron microscopy (TEM). We used pili torti samples from a patient with Bjornstad syndrome and normal hairs from a healthy subject as a comparison. The macroscopic morphological features of the samples agreed with the results of a previous study showing that pili torti is twisted, flattened, thin and with partial trichorrhexis. Young's modulus of the samples was lower than that of normal hairs. Because the cross-sectional area of the pili torti samples was also smaller than that of normal hairs, it was clarified that the tensile strength of pili torti is 2.1-times lower than that of normal hair. Assessment of morphological features by TEM showed that the cuticle layers of the samples had wavy shapes with different thicknesses. Additionally, the cortex in the samples showed loose keratin intermediate filaments (IF). Our results suggested that these abnormalities in pili torti had already occurred below the infundibulum. Thus, the weakness of pili torti in tensile strength is thought to result from loose IF because of dysformation of disulfide bonds.

There have been several attempts to make granuloma model to clarify the mechanism of granulomatous diseases like sarcoidosis. However, a unique in vitro model that generates multinucleated giant cell (MGC) through epithelioid cells resembled to human granuloma, has not yet been clearly established. In this study, the generation of granuloma model that forms MGC via epithelioid cells from the mouse macrophage cell line was investigated. A RAW 246.7 mouse macrophage cell line was cultured with lipopolysaccharide (LPS) and concanavalin A (Con A) in various concentrations either alone or both. We found that separate treatment of LPS and Con A induced around 35 and 20% MGC respectively whereas cotreatment of these chemicals drastically accelerated granuloma formation rate and it was around 80%. The highest fusion index (MGC formation rate) was observed at days 7. A gradual increase of tumor necrosis factor alpha (TNF-alpha) production in the culture supernatant was analyzed by enzyme-linked immunosorbent assay (ELISA). And the neutralization of the elevated level of TNF-alpha production by its monoclonal antibody leads to significant decrease of MGC formation. Interestingly, we found that the RAW cells were changed into spindle cells, which morphologically resembled to epithelioid cells and eventually MGC was formed from these spindle cells. Our in vitro granuloma model appeared to be similar with in vivo epithelioid cell granulomas like sarcoidosis. Thus, our model would be useful as in vitro epithelioid granuloma model for analyzing the mechanisms and screening the effective drugs of granulomatous diseases in future.

Recently, we crossed an original haired RET-transgenic mouse of line 242 with a hairless mouse and established a hairless RET-(HL/RET)-transgenic mouse line (242-hr/hr) with hyperpigmented skin but no tumors. In this study, we examined the effect of hyperpigmented skin in HL/RET-transgenic mice on UV irradiation-mediated cutaneous cancer development. UV irradiation to this mouse line never induced melanoma despite the presence of melanoma-inducible transgenic RET oncogenes. On the contrary, the hyperpigmented skin efficiently protected UV-mediated squamous carcinoma development in the skin. Probably underlying this result, hyperpigmentation protected the skin from damage and blocked the accompanying signal transduction for tyrosine phosphorylation of multiple cellular proteins and activation/phosphorylation of extracellular signal-regulated, c-Jun N-terminal, and p38 kinases. Thus, we demonstrated hyperpigmentation-mediated in vivo protection against UV irradiation-induced skin cancer.

We previously established a RET-transgenic mouse line (304/B6), in which skin melanosis, benign melanocytic tumors and malignant melanoma spontaneously develop. We found that the activities of RET tyrosine kinase, Erk and c-Jun are definitely upregulated in malignant melanoma in the RET-transgenic mice of line 304/B6. We also established another RET-transgenic mouse line (192), in which skin melanosis and benign melanocytic tumors, but not malignant melanoma, spontaneously develop. Ultraviolet irradiation induced malignant melanoma from benign tumors in the RET-transgenic mice of line 192, and promoted RET tyrosine kinase, Erk and c-Jun activities. These results suggest that the ultraviolet irradiation-mediated enhancement of RET and the activity of its downstream molecules play important roles in malignant melanoma development.

The patient was a 73-year-old female. A whitish, flat, protruding tumor of 5×30mm in size was seen in the right corner of her mouth, contiguous with a whitish verrucous tumor of 20×30mm in size in the right buccal mucous membrane. This was diagnosed from biopsy as squamous cell carcinoma. No metastasis to other organs was found with diagnostic imaging. With consideration of the cosmetic and functional prognosis, anticancer agents were injected locally. An anticancer agent sensitivity test (CD-DST) was used in selection of the anticancer agent. A high sensitivity was shown to peplomycin sulfate only. When this agent was used in local injection the tumor shrank and there was a clear clinical effect. Degeneration of the tumor cells was also seen histopathologically, and necrosis was confirmed. Afterward, radiation therapy was also given, but a biopsy revealed remaining tumor cells. Finally the tumor was resected, although the area of the resection was small. The above indicates that CD-DST, which has the capacity to screen in advance the anticancer agents expected to have a clinical effect, will be a useful test in the future. [Skin Cancer (Japan) 2004; 19: 186-189]

Espin is a multifunctional actin-bundling protein with multiple isoforms, and has special connections to hair cell stereocilia and microvillar specializations of sensory cells in the inner ear. However, there have been no reports showing the expression and function of Espin in cancers, including melanoma. Here, it is demonstrated that Espin expression is significantly increased in melanomas that spontaneously developed in RET -transgenic mice (RET-mice). Importantly, the invasion capacity of Espin-depleted Mel-ret melanoma cells derived from a tumor of the RET-mouse was dramatically less than that of control melanoma cells with reductions of lamellipodia, focal adhesion kinase (FAK), and GTP-Rac1 activities. Correspondingly, the ratio of metastatic foci in Espin-depleted Mel-ret melanoma cells was significantly less than that of control melanoma cells in an in vivo melanoma metastasis model. Moreover, Espin could be a novel biomarker of melanoma in humans, because our immunohistochemical analysis data reveal that percentages of Espin-positive cells in human primary and metastatic melanomas were significantly higher than that of cells in melanocytic nevi. Together, these results indicate that Espin is not only a metastatic regulator for melanoma but also a potential biomarker of disease progression. Implications: Actin-binding protein Espin is expressed in melanoma, affects metastasis, and is a potential target for melanoma therapy. Mol Cancer Res; 12(3); 440–6. ©2013 AACR . This article is featured in Highlights of This Issue, [p. 295][1] [1]: /lookup/volpage/12/295?iss=3

Background: Sezary syndrome and mycosis fungoides are forms of cutaneous T-cell lymphoma, and in the early stage of these diseases psoralen plus ultraviolet A (PUVA) is one of the treatments of choice. Photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) is an effective, non-invasive, and safe treatment for most superficial skin cancers. In order to obtain greater efficacy of PUVA, we investigated the synergistic anti-tumor effects of ALA-PDT and PUVA using 8-methoxypsoralen (8-MOP) and a UVA lamp. Methods: The in vitro effects of PUVA and ALA-PDT and their combination in HUT-78 cell line from human SS were determined by MTT assay. Results: In our results, cell proliferation compared with controls was inhibited to 53.2% with UVA alone, 52.3% with 1 μM 8-MOP, 43.8% with 100 μM ALA, and 19.2% with combined 8-MOP and ALA. Conclusion: Combined use of ALA and PUVA using 8-MOP and UVA lamps, which are widespread in Japan, had a strong anti-tumor effect in vitro. Combined treatment with ALA-PDT and PUVA using a UVA lamp appears to have a strong treatment effect.

Topical 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) is an effective treatment for Bowen's disease (BD). In order to compare the efficacy of two different light sources, using either an excimer-dye laser (EDL) (630 nm) or a metal-halide lamp (MHL) (600 to 740 nm) a protocol for topical ALA-PDT for treatment of BD of the extremities was established, and responses during 12 months follow-up were assessed.From 25 patients a total of 26 lesions that had been histopathologically diagnosed as BD from 2005 to 2010 in the Department of Dermatology at the Aichi Medical University Hospital were randomly selected. The light source used for the topical ALA-PDT was EDL in 17 lesions and MHL in 9 lesions. The photosensitizing protoporphyrin IX that is produced within BD lesions 4 h after application of 20% ALA cream was mostly consumed after exposure to 100 J/cm(2) irradiation using 630 nm EDL. Each lesion was irradiated once a week for 3 weeks, for a total dosage of 300 J/cm(2) (100 mW/cm(2)). Patients were followed up clinically every 3 months for 12 months, and at 1 month after the final treatment lesions were evaluated histopathologically.Histologically, the complete response (CR) rate at 1-month follow-up was 82% (14/17 lesions) in the EDL treatment group and 100% (9/9 lesions) in the MHL treatment group (P0.05). The recurrence rate at 12 months after PDT was 46% (6/13 lesions, one patient lost to follow-up) in the EDL group and 0% in the MHL group (P0.05) (χ(2) test with Fisher's exact test). The average period before recurrence after EDL treatment was 6.5 months.A novel protocol for topical ALA-PDT in Japanese in Asian patients with BD was developed and implemented. The protocol improved the CR rate compared with previous studies. Moreover, the present results indicate that the efficacy of topical ALA-PDT using MHL was superior to that using EDL for BD patients.

Explosive increases in skin cancers have been reported in more than 36 million patients with arsenicosis caused by drinking arsenic-polluted well water. This study and previous studies showed high levels of barium as well as arsenic in the well water. However, there have been no reports showing a correlation between barium and cancer. In this study, we examined whether barium (BaCl(2)) may independently have cancer-related effects on human precancerous keratinocytes (HaCaT). Barium (5-50 µM) biologically promoted anchorage-independent growth and invasion of HaCaT cells in vitro. Barium (5 µM) biochemically enhanced activities of c-SRC, FAK, ERK and MT1-MMP molecules, which regulate anchorage-independent growth and/or invasion. A SRC kinase specific inhibitor, protein phosphatase 2 (PP2), blocked barium-mediated promotion of anchorage-independent growth and invasion with decreased c-SRC kinase activity. Barium (2.5-5 µM) also promoted anchorage-independent growth and invasion of fibroblasts (NIH3T3) and immortalized nontumorigenic melanocytes (melan-a), but not transformed cutaneous squamous cell carcinoma (HSC5 and A431) and malignant melanoma (Mel-ret) cells, with activation of c-SRC kinase. Taken together, our biological and biochemical findings newly suggest that the levels of barium shown in drinking well water independently has the cancer-promoting effects on precancerous keratinocytes, fibroblast and melanocytes in vitro.

A dose of 60 units (U) of botulinum toxin type A (BT-A) has been confirmed to have efficacy for patients with palmoplantar hyperhidrosis. However, the effectiveness of this dose is limited in severe cases defined as sweat production of 2 mg/cm(2) per min or more (measured by the ventilated capsule method) and a Hyperhidrosis Disease Severity Scale (HDSS) grade of 3 or 4. An increased dose of 90 U of BT-A was found to reduce sweating for approximately 7 months. In a comparison of patients with sweat production of more than 2.5 mg/cm(2) per min and an HDSS grade of 4 and patients with sweat production of 2.5 mg/cm(2) per min or less and an HDSS grade of 3, there was no difference in the reduction of sweat production at 5 months, but the duration of the reduced sweating was shorter for the former group. This suggests that there are limits to the efficacy of BT-A for severe forms of the disease with sweat production of more than 2.5 mg/cm(2) per mL.

A dose of 60 units (U) of botulinum toxin type A (BT-A) has been confirmed to have efficacy for patients with palmoplantar hyperhidrosis. However, the effectiveness of this dose is limited in severe cases defined as sweat production of 2 mg/cm(2) per min or more (measured by the ventilated capsule method) and a Hyperhidrosis Disease Severity Scale (HDSS) grade of 3 or 4. An increased dose of 90 U of BT-A was found to reduce sweating for approximately 7 months. In a comparison of patients with sweat production of more than 2.5 mg/cm(2) per min and an HDSS grade of 4 and patients with sweat production of 2.5 mg/cm(2) per min or less and an HDSS grade of 3, there was no difference in the reduction of sweat production at 5 months, but the duration of the reduced sweating was shorter for the former group. This suggests that there are limits to the efficacy of BT-A for severe forms of the disease with sweat production of more than 2.5 mg/cm(2) per mL.

Although methane sulfonate compounds are widely used for the protein modification for their selectivity of thiol groups in proteins, their intracellular signaling events have not yet been clearly documented. This study demonstrated the methane sulfonate chemical 1,4-butanediyl-bismethanethiosulfonate (BMTS)-induced cascades of signals that ultimately led to apoptosis of Jurkat cells. BMTS induced apoptosis through fragmentation of DNA, activation of caspase-9 and caspase-3, and downregulation of Bcl-2 protein with reduction of mitochondrial membrane potential. Moreover, BMTS intensely and transiently induced intracellular reactive oxygen species (ROS) production and ROS produced by BMTS was mediated through mitochondria. We also found that a reducing agent dithiothreitol (DTT) and an anti-oxidant N-acetyl cysteine (NAC) inhibited BMTS-mediated caspase-9 and -3 activation, ROS production and induction of Annexin V/propidium iodide double positive cells, suggesting the involvement of ROS in the apoptosis process. Therefore, this study further extends our understanding on the basic mechanism of redox-linked apoptosis induced by sulfhydryl-reactive chemicals. J. Cell. Biochem. 108: 1059–1065, 2009. © 2009 Wiley-Liss, Inc.