bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytotoxicity of capsaicin on cultured human skin fibroblast
Authors: Kim S. J. , Won Y.‐H. , Kim J.‐K.
Published: August 2010

Capsaicin has been shown the different biologic and toxic effects on the non‐neuronal celIs and serveral transformed cells. The present study aimed at evaluating the cytotoxic mechanism of capsacin on the cultured human skin fibroblast. Normal neonatal human fibroblasts were used for MTT assay to measure the changes of celI survival, while growth factors, receptor antagonist, antioxidants and calcium modulators were pretreated or co‐treated with capsaicin. Fibroblast survival was significantly stimulated with EGF (10 ng/ml), bFGF (10 ng/ml) and capsazepine (10 µm) but inhibited by cycloheximide (1 µg/ml). When 200 µm capsaicin is given to fibroblasts, chromatin condensations were observed at 12 h, and cell survival rate was reduced to 25–50% at 24 h. Vanilloid receptor antagonists, capsazepine and ruthenium red did not prevent the toxic effect of capsaicin, and 10 µm capsazepine rather paradoxically enhanced the cytotoxicity. In contrast to bFGF (10 ng/ml), EGF (10, 100 ng/ml) enhanced the cytotoxicity of capsaicin. Neuropeptides, substance P (1, 10 nm) and CGRP (1, 10 nm), and a structural analogue to capsaicin, tyrosine (0.3–1.2 mm) did not affect the cytotoxicity. However, antioxidants trolox (100 µm) and ascorbic acid (0.1, 0.3 mm) reduced the capsaicin cytotoxicity. Of calcium‐modulating agents, nifedifine, a Ca2+ channel blocker (10, 20 µm) and cyclopiazonic acid, a Ca2+‐ATPase inhibitor in ER (10 µm) did not influence the cytotoxicity, but BAPTA/AM as a chelater for cytoplasmic free calcium ion (10 µm) significantly decreased capsaicin cytotoxicity. Unlike cycloheximide, a protein synthesis inhibitor, z‐VAD‐FMK, a non‐specific caspase inhibitor, prevented the capsaicin cytotoxicity. The DNA ladder and TUNEL‐positive cells were observed from the capsaicin‐treated fibroblasts and Western blot revealed caspase‐3 activity. Thus, capsaicin‐induced cytotoxicity on human skin fibroblasts is more likely to suggest the mechanism of apoptotic pathway where antioxidants may play a role to prevent it.
Neuronal sensitization for itch in patients with chronic pruritus
Authors: Ikoma A. , Handwerker H. , Miyachi Y. , Schmelz M.
Published: August 2010

Itch is one of the major symptoms of various skin diseases. Although specific neuronal pathways for itch were identified both peripherally and centrally, they still fail to explain itchy skin observed in patients with chronic pruritus. In this study, sensitivity to itchy and painful stimuli in patients with atopic dermatitis was investigated. Histamine‐prick evoked enormous itch in their lesional skin, while less itch in their non‐lesional skin than healthy subjects. Flare reaction was not significantly different between their non‐lesional and lesional skin, rather smaller than healthy subjects. Mechanical (pin‐pricks), electrical, heat and chemical (injection of pH3 solution) stimuli evoked intense itch in their lesional skin and partly also in their non‐lesional skin, while only pain in healthy subjects. Itch was also, but not intensely, evoked in healthy subjects by injection of pH3 solution after sufficient histamine stimuli. These results confirm the presence of itchy skin with hyperkinesis (excessive itch by itchy stimuli) and allokinesis (itch by non‐itchy stimuli) in patients with atopic dermatitis, which is so intense that painful stimuli cannot suppress but evoke itch, and suggest that neuronal sensitization is involved in their itch not only peripherally but also centrally.
A comparative study on the effects of naltrexone and loratadine on uremic pruritus
Authors: Legroux‐Crespel E. , Clèdes J. , Misery L.
Published: August 2010

Two recent studies have provided opposite results on the efficacy of naltrexone on uremic pruritus. We have performed a third study. We compared efficacy and tolerance of naltrexone and loratadine on uremic pruritus. Among 296 hemodialysed patients, 65 suffered from uremic pruritus. 52 patients participated in the study. Patients were treated for 2 weeks with naltrexone (50 mg/day; 26 patients) or loratadine (10 mg/day; 26 patients), after a washout of 48 h. Pruritus intensity was scored by a visual analog scale (VAS). Adverse events were carefully searched. The two groups were statistically equivalent. There was no significant difference in the mean VAS scores after treatment, but naltrexone allowed a dramatic decrease of VAS sores (Δ > 3/10) in seven patients. Adverse events (mainly nausea and sleep disturbances) were observed in 10 of 26 patients. We could notice that 22% of hemodialysed patients suffered from uremic pruritus. Naltrexone was effective only in a subset of patients. Adverse events were very frequent. The differences of efficacy and tolerance between patients might be due to metabolism. Naltrexone might be considered as a second‐line treatment.
New chapter in skin biopsy: diagnostic tool for neurodegenerative disorders
Authors: Palotás A. , Penke B. , Kemény L. , Janka Z. , Kálmán J.
Published: August 2010

The accumulation of the ubiquitous amyloid peptide in the brain is a defining feature of Alzheimer's disease. Consistent with studies demonstrating alterations of various biochemical processes of cells of peripheral tissues and the importance of skin biopsy in the diagnosis of neurodegenerative disorders, we investigated whether differences in the basal intracellular free calcium levels of lymphocytes and cultured cutaneous fibroblasts derived from sporadic Alzheimer patients and from age‐matched control individuals might be present. Calcium levels were measured in Fura‐2AM‐loaded human fibroblasts by dual‐wavelength spectrofluorimetry. Basal calcium levels appeared to be higher in Alzheimer lymphocytes when compared with control ones. Resting calcium concentration of Alzheimer fibroblasts, however, has proved to be lower than that seen with control cells. Exposure of cells to amyloid resulted in the elevation in the Ca2+ level of both control cell types, however, that of Alzheimer lymphocytes and fibroblasts did not differ considerably. Our test could prove useful in supporting the diagnosis of (sporadic) AD in patients suspected of suffering from the disease. Also, this simple finding may serve as a springboard to monitoring Alzheimer pathology in the peripheral systems of the body.
Electrode design for skin electroporation with minimal nerve stimulation
Authors: Pliquett U.
Published: August 2010

Electroporation is an efficient tool for transdermal delivery of water‐soluble molecules sizing up to several kDa. The main barrier to these agents is the stratum corneum, a 15 mm thin layer of dead keratinized cells. Once this layer is charged (approximately 50 V) by an outer electric field, structural rearrangements of the lipids create aqueous pathways (electroporation). Due to the high electric field within the stratum corneum, (E = 50 V/15 µm = 33 kV/cm) electrophoresis can drive charged molecules into the deeper skin layers. A major concern is the high electric field required, because nerve stimulation is inconvenient for the patient. Taking advantage of the fact that up to a depth of 50 µm no nervous receptors appear, a confinement of the field within the upper 15 µm would circumvent sensation. Field confinement within the stratum corneum is arranged by a special electrode geometry, an array of 300 µm holes within a 0.5 mm thick dielectric. The bottom, facing the stratum corneum, is metalized with a gap to the holes. The size of this gap (3–10 µm) is critical for the penetration depth of the electric field between the metalized bottom and a distant electrode at the other side of the holes. A drug reservoir is implemented below the distant electrode and the dielectric.
Evidence for a proinflammatory role of proteinase‐activated receptor‐2 during cutaneous inflammation in vivo
Authors: Steinhoff M. , Seeliger S. , Derian C. , Nawroth R. , Sunderkötter C. , Metze D. , Vestweber D. , Andrade‐Gordon P. , Luger T. A.
Published: August 2010

Contact dermatitis (CD) is a frequent dermatological disease with a high socioeconomical impact characterized by acute to chronic inflammation of the skin, often leading to therapy‐resistent eczema. Proteinase‐activated receptor‐2 (PAR‐2), a G‐protein‐coupled receptor for certain serine proteases, is localized on keratinocytes, endothelial cells, and nerve fibers and has been demonstrated to play a role during inflammation of several tissues. However, the precise role of PAR‐2 and the underlying mechanism of PAR‐2‐induced regulation of inflammation are still fragmentary. Therefore, we were interested in whether or not PAR‐2 is involved in cutaneous inflammation using a model of experimentally induced allergic (ACD) and irritant (ICD) contact dermatitis. In wild‐type (PAR‐2+/+) mice, PAR‐2 agonists induced an increased intradermal edema and enhanced plasma extravasation with a maximum between 3 and 24 h. These inflammatory responses were significantly diminished in PAR‐2‐deficient (PAR2–/–) mice and controls (vehicle). Morphological analysis revealed a dramatic increase of spongiosis and intradermal edema along with enhanced infiltration of neutrophils and monocytes in PAR‐2+/+ mice as compared with PAR‐2–/– mice. Interestingly, nitric oxide (NOS) inhibitors significantly diminished these effects, indicating a role of NO in PAR‐2‐induced inflammatory responses of the skin. Functional studies at the RNA and protein level further revealed PAR‐2‐induced upregulation of the cell adhesion molecules ICAM‐1 and E‐selectin by dermal microvascular endothelial cells during inflammation, suggesting that PAR‐2 directly regulates cell adhesion molecule function during skin inflammation. PAR‐2 agonists also stimulated upregulation of mediators involved in cutaneous inflammatory responses such as IL‐6 and NO in murine and human (dermal) endothelial cells. Together, these results strongly suggest a proinflammatory role of PAR‐2 during CD and probably other inflammatory dermatoses, especially during the early phase characterized by edema, plasma extravasation, and recruitment of inflammatory cells to the site of inflammation. Thus, PAR‐2 antagonists may be therapeutic tools for the treatment of inflammatory skin disorders such as contact dermatitis and atopic eczema.
Expression and regulation of pro‐opiomelanocortin‐derived peptides in human hair growth and pigmentation
Authors: Tobin D. J.
Published: August 2010

Human skin provides for the local cleavage of pro‐opiomelanocortin (POMC) to yield multiple peptide products, e.g. α‐MSH, ACTH and β‐endorphin (β‐end). α‐MSH and ACTH are well documented to regulate human skin pigmentation. We have recently shown that human epidermal melanocytes express a fully functioning β‐end/µ‐opiate receptor system, and that β‐end has potent melanogenic, mitogenic and dendritogenic effects in cultured epidermal melanocytes. However, little is known about their role in human hair follicle (HF) biology. We have characterized the expression and regulation of β‐end, ACTH, α‐MSH and their receptors in human haired scalp and in cultured HF melanocytes, keratinocytes and fibroblasts by immunochemistry, detection of mRNA transcripts and by assessment of potential melanogenic, dendritogenic and mitogenic effects of these peptides in vitro. These studies show that the POMC peptide system is expressed in HF cells as a function of their anatomic location and differentiation status during the hair growth cycle. All three peptides exhibit similar melanogenic, mitogenic and dendritogenic effects in cultured HF melanocytes. Moreover, while the in situ expression profiles of ACTH and α‐MSH are similar, they differ strikingly from β‐end for all follicular cell populations. One such example is the persistent expression of the former in the hair inductive follicular papilla (FP) throughout the entire hair cycle (but are expressed variably in HF keratinocytes and melanocytes). However, β‐end expression is low to undetectable in the FP during hair growth. In toto, these results indicate that POMC peptides are involved in regulating human HF growth and pigmentation and that alterations in POMC homeostasis may be contribute to pathology.
The role of neurotrophins in brain metastasis of malignant melanoma cells
Authors: Nicolson G. L.
Published: August 2010

We have examined the role of neurotrophin receptors and neurotrophins in brain invasion and colonization of malignant melanoma cells. Using mouse and human melanoma variant cell sublines that have the capacity to form brain tumor colonies in nude mice, we studied the effects of neurotrophins and growth factors on malignant properties. The high brain‐colonizing melanoma lines were characterized by high expression of the low‐affinity nerve growth factor (NGF) receptor p75NTR, which forms transmembrane complexes containing the neurotrophin and its receptors, but they expressed very low amounts if any of the high‐affinity neurotrophin receptor trkA. In the presence of brain endothelial cell‐derived motility factors, NGF and other neurotrophins, such as neurotrophin‐3 (NT‐3), stimulate release of basement membrane degradative enzymes and significantly increase the invasion of endothelial cell extracellular matrix and Matigel‐coated filters. Enzymes such as the collagenase‐degrading enzyme MMP‐2 and heparan sulfate‐degrading enzyme heparanase are increased in their synthesis and release from the high brain‐colonizing but not by other melanoma variant lines by NGF or NT‐3. The increase in heparanase can be blocked by antisense resulting in decreased invasion and capacity to colonize brain. Neurotrophins also stimulate the synthesis and release of autocrine growth factors by brain‐colonizing melanoma cells. Brain‐colonizing melanoma cells also respond to paracrine growth factors in the brain, and one of the important paracrine growth factors in brain metastasis has been identified as a transferrin. Examination of the invasion front in brains colonized by the brain‐colonizing melanoma cells revealed high concentrations of NGF and other neurotrophins (NT‐3) at the interface between melanoma cells and adjoining normal brain tissue (with extensive gliosis) that gradually diminished with distance from the invasion front. Using immunohistochemical techniques to detect neurotrophins, uninvolved brain tissue (adult animals) possessed very low or undetectable concentrations of these neurotrophins. Trophic factors, autocrine factors, paracrine growth factors and other factors may determine whether metastatic melanoma cells can successfully invade, colonize and grow in the CNS.
Agonist‐independent, high constitutive activity of the human mela‐nocortin 1 receptor
Authors: Sánchez‐Más J. , Gerritsen I. , García‐Borrón J. C. , Jiménez‐Cervantes C.
Published: August 2010

The melanocortin hormones act on epidermal melanocytes to increase eumelanogenesis, melanocyte dendricity and likely melanosome transfer to keratinocytes. These actions are mediated by the melanocortin 1 receptor (MC1R), positively coupled to adenylyl cyclase. Gain‐of‐function Mc1r alleles are associated with dark, eumelanic skin. Conversely, loss‐of‐function variants or overexpression of agouti, the natural antagonist, yield yellow, pheomelanic furs. In humans, loss‐of‐function MC1R variants are associated with fair skin, poor tanning and increased skin cancer risk. Therefore, MC1R is a key regulator of mammalian pigmentation. An induction of constitutive pigmentation in amelanotic mouse melanoma cells following the expression of MC1R has been reported, suggesting that this receptor might display agonist‐independent activity, although this aspect has not yet been comparatively studied for MC1R and Mc1r. We show that the expression of MC1R in heterologous systems leads to high agonist‐independent increases in intracellular cAMP. This basal signalling is a function of the quantity of receptor expressed, is considerably higher for MC1R than Mc1r and is also observed in human melanoma cells overexpressing MC1R. Moreover, MC1R basal signalling is abolished or reduced by point mutations impairing the response to agonists. Lastly, the expression of wild‐type MC1R, but not of loss‐of‐function mutants potently stimulates forskolin activation of adenylyl cyclase, a feature characteristic of constitutively active G‐coupled receptors. Therefore, we conclude that MC1R displays a strong agonist‐independent constitutive activity.
A ‘hot’ new twist to hair biology – involvement of vanilloid receptor‐1 signaling in human hair growth control
Authors: Bodó E. , Bíró T. , Telek A. , Czifra G. , Griger Z. , Tóth I. B. , Lázár J. , Meschalchin A. , Ito T. , Bettermann A. , Pertile P. , Kovács L. , Paus R.
Published: August 2010

The functional role of VR1, which we and others have recently identified on several epithelial and mesenchymal human skin cell populations, was investigated in the human hair follicle (HF), as a prototypic epithelial–mesenchymal interaction system. VR1 immunoreactivity was confined to distinct epithelial compartments of HFs in anagen and catagen, while dermal papilla fibroblasts and HF melanocytes were VR1 negative. In organ culture, VR1 activation by capsaicin resulted in a dose‐dependent and VR1‐specific inhibition of hair shaft elongation, suppression of proliferation, promotion of apoptosis, and induction of catagen transformation, possibly due to upregulation of a potent hair growth inhibitor TGFβ2. Cultured outer root sheath (ORS), as well as HaCaT, keratinocytes also expressed functional VR1, whose stimulation inhibited proliferation, induced apoptosis, and elevated intracellular calcium concentration. Finally, VR1 stimulation of cultured ORS keratinocytes upregulated the expression of recognized endogenous hair growth inhibitors (IL‐1β and TGFβ2) and downregulated the expression of stimulators (HGF, IGF‐1, and SCF), while key differentiation markers (CK17, CK14, filaggrin, and involucrin) remained unaffected. In conclusion, VR1 is a significant novel player in human hair growth control underscoring that its physiological functions in human skin far extend beyond sensory neuron‐coupled nociception.
Defective hair formation in calcitonin‐like receptor transgenic mice
Authors: Ittner L. M. , Husmann K. , Muff R. , Götz J. , Bonneick S. , Suter U. , Born W. , Fischer J. A.
Published: August 2010

The heterodimeric calcitonin‐like receptor (CLR)/receptor‐activity‐modifying protein 2 (RAMP2) complex is an adrenomedullin (AM) receptor. Here, transgenic mice expressing a V5‐CLR in hair follicles have been generated. Skin sections of the transgenic mice and of control littermates have been investigated. The hair diameter of the mice was measured during hair morphogenesis and first hair cycle. Size and weight of V5‐CLR transgenic and control mice were indistinguishable. But after day 12, the coat of the transgenic mice is waved. The number of hairs with a small diameter was significantly higher in transgenic mice as compared with control littermates (P < 0.001). There skin sections revealed immunoreactive V5‐CLR in the bulb of cycling hair follicles. On in situ hybridization, RAMP2 encoding mRNA colocalized with the V5‐CLR protein. Autoradiographic examination showed specific 125I‐AM binding in the same place. In conclusion, CLR/RAMP2‐overexpressing mice reveal a defined phenotype with thinning of the hairs during postnatal development.
CRH peptides modulate human hair follicle growth in vitro– a preliminary study
Authors: Kauser S. , Slominski A. , Wei E. T. , Tobin D. J.
Published: August 2010

Mammalian skin may contain an equivalent of the hypothalamic‐pituitary‐adrenal axis (HPA), composed of locally produced corticotropin‐releasing hormone (CRH) that, together with signalling via CRH receptor 1 (CRH‐R1) and CRH‐R2, may regulate local homeostasis. Studies in murine skin have demonstrated significant hair cycle‐dependent fluctuations in the expression of CRH and urocortin peptides and CRH‐Rs genes, suggesting a modulatory role for this signalling system in hair growth/cycling. This study was designed to investigate the effects of ligands showing increased selectivity for CRH‐R1 [(D‐Glu20)‐CRH (10−7 and 10−8 m)] and CRH‐R2 [(D‐Pro5)‐CRH (10−8 and 10−9 m)] and (D‐Pro4)‐urocortin (10−7 and 10−8 m) on human hair growth in ex vivo culture. (D‐Pro5)‐CRH can also activate CRH‐R1, while (D‐Pro4)‐urocortin is highly selective for CRH‐R2. Anagen hair follicles (HFs) were isolated from human scalp and stimulated for 9 days, with 10 HFs tested per CRH peptide concentration. Preliminary findings indicate that (D‐Pro4)‐urocortin (10−8 m) stimulated a 79% mean hair fibre elongation compared to the initial HF length over the 9‐day study period. (D‐Glu20)‐CRH (10−8 m) also stimulated hair fibre elongation of 63% of initial length, while (D‐Pro5)‐CRH (10−9 m), which inhibited hair fibre elongation, compared to unstimulated controls. In agreement with our previous detection of CRH‐R1 and CRH‐R2 in human HFs, the above data suggest the existence of a functionally active CRH peptide/receptor system in cultured human HFs and suggest that signalling via these receptors may participate in the regulation of human hair growth/cycling in vivo.
Induction of neuropeptides in skin innervating sensory neurons by stress and nerve growth factor as a possible reason for hair growth alteration
Authors: Kuhlmei A. , Dinh Q. T. , Peters E. M. J. , Kandil J. , Paus R. , Arck P. C.
Published: August 2010

Recently, we introduced a mouse model launching experimental evidence for stress‐induced hair growth inhibition (HGI), pointing to the existence of a brain‐hair follicle axis (BFA). We suggested that nerve growth factor (NGF), besides neuropeptide substance P (SP), is a candidate mediator along the BFA. Published data further indicate that stress‐related neuropeptides, e.g. calcitonin gene‐related peptide (CGRP) and SP may be involved in HGI. SP and CGRP are synthesized in dorsal root ganglia (DRG) and released after axonal transport in the skin. Thus, aim of the present study was to investigate the effect of stress or subcutaneous injection of NGF, which mimics stress and regulates neuropeptide genes in sensory neurons, on the expression of SP and CGRP in DRG. Anagen was induced in C57BL/6 mice by depilation and retrograde tracing was employed on day 9 post‐depilation (PD). On day 14 PD, mice were either exposed to sound stress (n = 4) injected subcutaneously with NGF (n = 4) or served as control (n = 4). On day 16 PD, DRG (mean of 30/mouse) were harvested and SP and CGRP in skin‐specific sensory neurons, as identified by the tracer dye, were labelled by immunohistochemistry and counted. Stress exposure as well as NGF injection leads to a significant induction of SP and CGRP in retrograde‐labelled neurons. This allows us to conclude that sensitive dermal nerve fibres are likely to originate from the presently identified neuropeptide‐positive neurons. Peripheral activation of SP‐expressing afferent nerve fibres via NGF‐dependent pathways may cause neurogenic inflammation, eventually resulting in HGI.
Mapping of two genetic loci for autosomal dominant hidradenitis suppurativa
Authors: Irwin McLean W. H. , Wood Pam , Irvine Alan D. , Von Der Werth Jan
Published: August 2010

Hidradenitis suppurativa (HS) is a severe and debilitating skin condition that is relatively common in the population. In many cases, there is a strong family history showing autosomal dominant inheritance with incomplete penetrance. We identified several large kindreds from the United Kingdom and Ireland showing dominant transmission and carried out two genome‐wide scans by genetic linkage analysis with 400 closely spaced microsatellite markers.

This resulted in the identification of two separate genetic loci that show statistically significant linkage with HS. Marker D19S414 gave a significant log‐of‐the‐odds (LOD) score of 3.66 in a single kindred and represents robust genetic linkage. Recombination with markers D19S911 and D19S1170 limited the interval to a 16.5‐Mb region on chromosome 19, containing at least 35 known or strongly predicted genes. Many of these are transcription factors thought to be involved in modulation of the immune system, which may be consistent with HS. Two additional kindreds did not map to this locus but instead showed linkage to marker D6S290, giving a maximum combined 2‐point LOD score of 4.0 with no recombination. Visible recombinants narrowed this disease interval to a 1.48‐Mb region between D6S440 and D6S441 on chromosome 6q25.1‐25.2 containing six genes. We have already screened a large number of exons in both loci for mutations without identifying any obvious mutations.

The eventual identification of genes causing HS will shed light on the pathomechanisms underlying inherited forms of the disease and, ultimately, will set the scene for rational design of therapies aimed at treating the root causes of this disorder.
Genetic analysis of three large Indian pedigrees with autosomal dominant hidradenitis suppurativa
Authors: Radhakrishna Uppala , Mehta Timir Y. , Solanki Jitendra V. , Nath Swapan K.
Published: August 2010

Hidradenitis suppurativa (HS: OMIM 142690) is an aggravating chronic inflammatory skin condition characterized by swollen, painful, inflamed lesions in the axillae, groin, and other parts of the body that contain apocrine glands. Incidence ranges from 0.1/100 to 4/100 in adults. It affects more females than males. The risk of developing non‐melanoma skin cancer is very high among patients with HS (Arch Dermatol 2001: 137: 730–734). This chronic condition is familial, which supports its genetic basis. However the causative gene(s) is not yet identified.

We have studied three large Indian hidradenitis suppurativa families with an apparent autosomal dominant mode of inheritance and 100% penetrance. No skipping of generations was observed. Pedigrees consist of 149 individuals, including 48 affecteds (20 males/28 females). The age of onset is 25–35 years. Histopathological studies were conducted in selected affecteds. The expression of the phenotype was quite variable within these families, and the majority was severely affected. All affecteds had typical characteristics of HS. Clinical findings included folliculitis, gastrointesinal (GI) polyps, sinuses axillae, cutaneous scars, retinal haemorrhage, epidermoid carcinoma, and polymorph function defects. Six of the affected females had hirsutism. Affected body parts included tops of inner thighs, genitals, groin, buttocks, and under the breasts in women. Skin grafting was performed in some of the affecteds. A few deaths due to squamous cell carcinoma were reported in these families. Cytogenetic analysis of two affecteds from each family did not show any abnormality.

Genomewide linkage analysis is in progress to map the elusive locus and provide a target for positional cloning.
A DNA array project for hidradenitis suppurativa/acne inversa
Authors: Fimmel Sabine , Makrantonaki Evgenia , Zouboulis Christos C.
Published: August 2010

Hidradenitis suppurativa (HS)/acne inversa (AI) is a chronic skin disorder involving the apocrine glandular zones, where inflammation of sebaceous glands and terminal hair follicles can be identified. The exact aetiology of HS/AI is unclear. The reported incidence is 1:300 with a female‐to‐male predominance of 4:1. There is an apparent strong influence of sex hormones on HS/AI and association with acne vulgaris and hirsutism. The disease occurs at post puberty and disease activity declines at the climacteric, whereas improvement is seen during pregnancy. Most HS/AI patients have normal androgen profiles and apocrine glands, nevertheless, there have been reports of symptomatic improvement with the use of anti‐androgen therapy. This DNA array project studies differences in gene expression of axillary apocrine secretory cells in vivo, between HS/AI patients and controls. Additionally, the gene expression pattern in axillary apocrine secretory cells of age‐matched men and pre‐ vs. post‐menopausal women is evaluated to identify those genes, whose expression is linked to circulating androgen levels, and highlights any gender/age differences in apocrine gland function. These experiments will further identify genes and biochemical pathways that could act as new targets for classical drugs and also targets for siRNA molecules in the treatment of HS/AI.
Finding models for skin diseases: successes and failures
Authors: Sundberg John P. , King Lloyd E.
Published: August 2010

Hidradenitis suppurativa (HS) is a disfiguring and debilitating, relatively rare disease in humans. Reports of similar diseases in domestic animals are also very rare. A clinically similar disease was reported in dogs, particularly in Collies and Shelties, but this was later re‐evaluated and determined to be a form of vesicular cutaneous lupus erythematosus. The alternative term for HS, acne inversa, suggests forms of acne in domestic animals might provide an alternative approach to finding a model. Mice, unlike dogs and cats, do not generally develop acne. However, the icthyosis mutation (Lbric) does develop bacterial infections within the infundibulum that may result in furunculosis. If combined with various immunodeficiencies, through the creation of double mutant mice, then this might provide a useful model. However, finding spontaneous or genetically engineered mouse models usually result in obtaining the best tools. The success obtained by developing or finding simple single gene mutation or complex polygenic disease models for pseudoxanthoma elasticum and alopecia areata, respectively, through support from their respective foundations, provide a road map on how such models can be found, defined, and provide unique tools to unravel the complex mechanisms of HS and, more importantly, provide preclinical tools for drug efficacy testing approaches.
Cytokeratin expression in hidradenitis suppurativa and pilonidal sinus
Authors: Kurokawa Ichiro , Hakamada Arata , Isoda Ken‐ichi , Yamanaka Kei‐ichi , Mizutani Hitoshi , Tsubura Airo
Published: August 2010

Purpose: The aim of our study was to elucidate the pathogenesis of hidradenitis suppurativa (HS) and pilonidal sinus (PS) by evaluating their cytokeratin (CK) expression.

Methods: CK expression in HS (n = 15) and PS (n = 9) was studied immunohistochemically using six anti‐keratin antibodies.

Results: In HS and PS, three types of epithelia were identified: infundibular‐like keratinized epithelium (type A), non‐infundibular keratinized epithelium (type B), and non‐keratinized epithelium (type C). Type A contained CK1, 10, and 14 similar to normal infundibulum, but it did not contain CK17. In types B and C, CK14, 16, and 17 were detected similar to that in normal outer root sheath. In tumor nests of squamous cell carcinoma derived from HS, CK 14, 17, and 19 were detected.

Conclusions: Based on CK expression in HS and PS, sinus epithelium in HS and PS may possess characteristics of fragility, hyperproliferation, and undifferentiation.
Clinical characteristics and outcome measures in hidradenitis suppurativa research
Authors: Revuz Jean
Published: August 2010

Introduction: Outcome measures for medical treatment of HS are needed.

Patients and methods: One hundred and sixty‐four consecutive patients were prospectively evaluated. A new score was evaluated: HSPAIN = pain intensity on a visual analog scale (VAS 1‐10) × number of painful days/month.

Results: Mean age was 34 years (± 11), sex ratio F/M 2.8:1. Forty‐two per cent were over weighted; 82% were smokers, 30% had a family history of HS. Age at onset was 23 years. Hurley's class was I = 72%; II = 25 %; III = 3%. Mean Sartorius' score (1) was 22 (range: 3–72). Pain on VAS was 4.1 for lower localizations, and its duration was >15 days/month for 25% of patients. Patients with a Sartorius' score > median were older (P = 0.003), more frequently overweighted (0.02). The mean HSPAIN scored 7.9 (0–30). It was highly correlated to Sartorius' score (P < 10‐3). This new score has been used in therapeutic trials of dalacine – rifadin combination and of zinc gluconate. Quality of life study of 61 patients emphasizes the strong impact of HS compared with other dermatological diseases; patients with an early onset, long duration and continuous evolution are particularly affected.

Conclusion: Surgery is not the only treatment for HS; we need outcome measures that are more adapted to medical treatment, i.e. integrating pain which is the major burden of this disease.
Surgical treatment options for hidradenitis suppurativa and critical review of own experience†
Authors: Mandal Anirban , Watson J.
Published: August 2010

Background: Hidradenitis suppurativa has always been a challenging area to the plastic and reconstructive surgeon. The aetiology is idiopathic, and medical treatment offers temporary relief only. Radical surgical excision, therefore, is the mainstay of active management.

Aim: To present and evaluate a series of 106 patients of hidradenitis suppurativa treated in the regional plastic surgery unit of southeast Scotland between January 1990 and December 2000.

Patients: Median age at onset was 36 years (range 17–70 years). The patients were predominantly females (88.78%) and heavy smokers (98.1%). Median age before active surgical intervention was six years (range 1–30 years). The patients were divided into a mild group (n = 64) and a severe group (n = 42). All patients had broad‐spectrum antibiotics and multiple incision and drainage procedures before referral from general practitioners, dermatologists or general surgeons. One hundred sites were managed by primary closure (mostly in the ‘mild’ group); 29 resurfaced with split skin grafts and 14 with local, fasciocutaneous or musculocutaneous flaps (mostly in the ‘severe’ group). Median postoperative follow‐up period was 3 years (range 1–7 years).

Results: In the ‘primary closure’ series, recurrence rate requiring at least one secondary operation was 69.88%. There was no recurrence, no serious complications and no revision operations in the ‘graft’ and the ‘flap’ series.

Conclusion: A high index of suspicion is required before contemplating primary closure in hidradenitis suppurativa, even in the ‘mild’ variety. This condition should always be treated aggressively by radical excision of all hair‐bearing areas and reconstructed with a graft or a flap.
Surgical treatment of acne inversa (hidradenitis suppurativa): a 20‐year experience
Authors: Hartschuh Wolfgang
Published: August 2010

Acne inversa (AI) is caused by follicular hyperkeratosis in intertriginous areas rich in apocrine glands followed by occlusion and rupture of the follicle and inflammation. Sinus tracts, scarring and often contraction with limitation in mobility may occur. There is a world‐wide consensus that in chronic disease surgical removal of all involved tissue as early as possible is the most effective treatment modality. The aim of this study is to demonstrate our operative strategy, including postoperative wound care and prevention, the results and pitfalls in the treatment of AI.

The operations are increasingly performed in tumescence anaesthesia, followed by secondary healing. Only removal of extended skin areas in the inguino‐genital and ano‐perineal regions demand general anaesthesia. In axillary regions, all hair‐bearing skin including the sweat glands is removed to obtain a hair‐free, dry skin area. In the other regions with ill‐defined hair and apocrine gland areas, only involved indurated skin is excised. For early limited disease with fluctuant abscesses, unroofing instead of mere incision and drainage is a good first option. Professional wound care with shaving and stretching of the wound margins is very important to avoid premature wound closure. Locally applied disinfectant soaps and 2% triclosane ointments are effective in pre‐ and postoperative skin care.

Follow‐up evaluation and collaboration among surgeons and dermatologists and an improved insight in the pathogenesis of AI are mandatory for the successful long‐term management of patients afflicted with this complex and debilitating disease.
Infliximab for hidradenitis suppurativa: report of seven consecutive patients
Authors: Dupuy Alain , Fardet Laurence , Kerob Delphine , Levy Annabelle , Bachelez Hervé , Morel Patrice , Lebbe Celeste
Published: August 2010

Purpose: To evaluate all consecutive patients treated with infliximab for hidradenitis suppurativa (HS).

Patients and methods: Within 1 year, all consecutive patients seen in our department for HS (1) resistant to usual medical therapies (2) which could not be easily cured by surgery (3) not treated with new medication within 2 months before inclusion were treated intravenously with infliximab (5 mg/kg) without corticosteroids premedication. Four infusions were planned (week 0, week 2, week 6 and week 10) before the interruption of therapy and follow‐up. Clinical activity of HS and quality of life of the patients were assessed immediately before the first, the third and the fourth infusions of infliximab.

Results: Seven patients were included. Five completed the four infusions. Two patients received only three infusions because of severe side effects. The Sartorius score moderately improved with infliximab (mean score at week 0: 94 ± 39, at week 6: 71 ± 38 and at week 10: 83 ± 48). At week 6, patients judged the efficacy of therapy as marked (n = 1), moderate (n = 4) or null (n = 2). At week 10, five patients were evaluated and judged this efficacy as marked (n = 2), moderate (n = 2) or null (n = 1). The mean Skindex‐29 score varied from 22 ± 11 (E: 25 ± 9, S: 13 ± 5, F: 28 ± 12) at week 0 to 18 ± 10 (E: 22 ± 8, S: 12 ± 8, F: 22 ± 12) at week 10.

Conclusion: The efficacy of infliximab in severe HS is partial. More experience is needed before finding a place for infliximab in the therapeutic armamentarium for HS.
Case of dystrophic calcinosis cutis in epidermal cyst arising from verrucous epidermal nevus
Authors: LEE Ji Hyun , PARK Hyun Jeong , LEE Jun Young , CHO Baik Kee
Published: August 2010

Dystrophic calcinosis cutis is diagnosed when calcium is deposited into previously damaged tissue by connective tissue disease, panniculitis, pseudoxanthoma elasticum or trauma. We report a case of dystrophic calcinosis cutis arising from the lesion of an epidermal cyst on the verrucous epidermal nevus. A 20‐year‐old woman presented with a polypoid pinkish tumor on a brownish, verrucous plaque. Histopathological findings of the pinkish tumor showed calcium deposits as amorphous, basophilic material lining the true epidermis in the upper dermis, which were compatible with dystrophic calcinosis cutis and the plaque was diagnosed as a verrucous epidermal nevus.
Catecholaminergic neurotransmission: flagship of all neurobiology
Authors: Stjärne L.
Published: August 2010

The paper describes, with focus on the first half of the century, the roles played by study of the sympathoadrenal system for developing modern neurobiology. Adrenaline isolated from extracts of adrenal medulla was the first intercellular messenger to be chemically identified and synthesized. Similarities between effects of adrenaline and sympathetic nerve stimulation led to the first concrete proposal of chemical neurotransmission. That effluent from a sympathetically or parasympathetically stimulated frog heart induced acceleration or slowing of an unstimulated recipient heart was the first conclusive proof of chemical neurotransmission. Acetylcholine (in parasympathetic or somatomotor) and noradrenaline (in sympathetic nerves) are the first identified mammalian neurotransmitters. The existence of a `receptive substance for adrenaline' represents the first proposal that target cells recognize and react to the released transmitter. Deviations from the `‐ergic' concept, in which sympathetic and parasympathetic nerves are termed `adrenergic' and `cholinergic', led to discovery of `non‐adrenergic, non‐cholinergic' nerves and a range of other transmitters. That some effects of e.g. sympathetic nerve stimulation are not blocked by any noradrenaline antagonist led to the recognition that some nerves utilize more than one transmitter. Noradrenaline in sympathetic nerves was the first neurotransmitter to be visualized in the light microscope. Catecholamines in adrenal medulla and sympathetic nerves were the first messengers to be shown to be stored in vesicles.
The use of caged adenine nucleotides and caged phosphate in intact skeletal muscle fibres of the mouse
Authors: Allen D. G. , Lännergren J. , Westerblad H.
Published: August 2010

The effects of 1‐(2‐nitrophenyl)ethyl ester of ATP (NPE‐caged ATP), NPE‐caged ADP, NPE‐caged phosphate (Pi) and desoxybenzoinyl phosphate (desyl‐caged Pi) on mouse skeletal muscle function were studied. All these caged compounds, when microinjected into intact single mouse muscle fibres, reduced the myoplasmic calcium during a tetanus (tetanic [Ca2+]i) and reduced force. Flash photolysis partially reversed this reduction of tetanic [Ca2+]i and force. In fibres fatigued by repeated tetani, flash photolysis of NPE‐caged ATP, ADP and Pi also caused a transient recovery of tetanic [Ca2+]i and force. Because photolytic release of ATP, ADP and Pi produced comparable effects it seems that the mechanism of action is the reduction in concentration of the caged compound rather than the release of the biologically active molecule. Experiments on mechanically skinned rat skeletal muscle fibres with intact T‐tubular/sarcoplasmic reticulum coupling showed that 1 mM NPE‐caged ATP had no effect on depolarization‐induced force. This result suggests that the depressant effects of the NPE‐caged compounds are neither on voltage‐activated Ca2+ release from the sarcoplasmic reticulum nor on myofibrillar function. Thus all the caged compounds tested inhibit excitation–contraction coupling in muscle by an unknown mechanism and this limits their value as sources of biologically important molecules. This inhibitory effect was smallest for desyl‐caged Pi and under conditions of maximal activation photolytic release of Pi caused a direct inhibition of the contractile proteins. This inhibition amounted to a 1% reduction of maximum force with an increase of [Pi] of about 0.3 mM. The mean rate of force decline under these conditions was 55 s–1, which reflects the rate of cross‐bridge cycling during a maximal tetanus.
Comparison on plasma caesium kinetics in goats and horses with special emphasis on exercising horses
Authors: Kaikkonen M. , Hyyppä S.
Published: August 2010

Aims:  Like potassium (K+), caesium (Cs+) tends to concentrate intracellularly. The aim here was to determine how moderate exercise affects the uptake of Cs+ from blood plasma.

Methods:  After an intravenous Cs+ dose of 5 μmol kg−1, plasma Cs+ concentration was followed for 100 min in goats and for 60 min in horses. The latter were divided into two groups, one resting and the other trotting on a treadmill (inclination 3°, speed 5 m s−1).

Results:  The plasma Cs+ concentration follows a multiphase exponential decay curve, which initially could be approximated with a two‐phase curve. The initially high rate constant (∼10 h−1) decreased to around 1 h−1 in 40 min. Exercise more than doubled the rate of removal of Cs+ from plasma between 20 and 40 min after the start of exercise. After exercise, the rate returned to resting levels within 10 min. Plasma K+, on the contrary, declined for at least 20 min after exercise had ended.

Conclusions:  Moderate exercise significantly increases the rate of removal of Cs+ from the bloodstream. After exercise, the rate returns to the resting levels within 10 min. The increased rate of Cs+ removal during exercise is likely due to increased activity of Na+, K+‐ATPase in working skeletal muscles.
Neuromuscular function during prolonged pedalling exercise at different cadences
Authors: Sarre G. , Lepers R.
Published: August 2010

Aim:  The purpose of the present work was to assess the strategies set by the central nervous system in order to provide the power output required throughout a prolonged (1‐h) pedalling exercise performed at different cadences (50 rpm, 110 rpm and the freely chosen cadence).

Methods:  Neuromuscular (NM) activity of vastus lateralis, rectus femoris, biceps femoris and gastrocnemius lateralis muscles was studied quantitatively [root‐mean square (RMS) and mean power frequency (MPF)] and qualitatively (timing of onset and offset of muscle bursts during crank cycle).

Results:  The present results showed that increased cadence resulted in earlier muscle activation in crank cycle. The influence of cadence on RMS and MPF depended on the considered muscle and its functional role during pedalling. Timing of onset and offset of muscle bursts was not altered by fatigue throughout the prolonged exercise. In contrast, RMS and MPF of some muscles was found to increase during prolonged exercise.

Conclusion:  In summary, the present study revealed that tonic aspects of the NM activity (RMS, MPF) are altered during prolonged pedalling exercise, while phasic aspects are remained unchanged. These results suggest that the strategies set by the central nervous system in order to provide the power output required by the exercise are held constant throughout the exercise, but that quantitative aspects of the central drive are increased in order to adapt to the progressive occurrence of the NM fatigue.
Protein kinases A and C stimulate the Na+ active transport in frog skeletal muscle without an appreciable change in the number of sarcolemmal Na+ pumps
Authors: Venosa R. A.
Published: August 2010

Aim:  The activation of both protein kinases A (PKA) and protein kinases C (PKC) in some cell types increases and in others reduces active Na+ efflux. These effects have been ascribed to either a change in the rate of ionic translocation by a fixed number of Na+ pumps or, a change in the number of plasma membrane pumps. The purpose of the present experiments was to study the effect of activating PKA and PKC on the Na+ extrusion by the Na+ pump in frog skeletal muscle.

Methods:  Na+ (22Na+) fluxes and ouabain (3H‐ouabain) binding were measured in frog sartorius muscles.

Results:  Both activation of PKA and PKC increased the active Na+ extrusion by a factor of two; these effects were not additive. Ouabain binding experiments indicated that the pump stimulation by activation of these kinases is not associated with any significant increase in the number of plasma membrane pumps. Stimulation of the active Na+ efflux by protein kinase activation (no change in the number of sarcolemmal pumps) and by hypotonicity (increase in the number of pumps) could be elicited in the same preparation and they were additive.

Conclusion:  It is concluded that in frog skeletal muscle fibres, (1) activation of both PKA and PKC stimulate the Na+ pump by increasing its rate of ionic translocation; and (2) two modes of Na+ active transport (with and without an increase in the number of pumps) are operative, and can be at work simultaneously, a phenomenon to be reckoned with.