Improvement in Hidradenitis Suppurativa and quality of life in patients treated with adalimumab: Real-world results from the HARMONY Study.

BACKGROUND: Hidradenitis suppurativa (HS), a chronic, recurrent, debilitating skin disease, is characterized by painful, inflammatory, subcutaneous lesions of the axilla, inguinal and anogenital regions. Overall prevalence of HS is ˜1%, and the impact of disease on patient quality of life (QoL) and healthcare resource utilization (HRU) is high. OBJECTIVES: To estimate the real-world effectiveness of adalimumab (Humira®) treatment in patients with moderate-to-severe HS on disease severity, pain, QoL, work productivity and HRU. METHODS: HARMONY (Effectiveness of Adalimumab in Moderate to Severe HidrAdenitis SuppuRativa Patients - a Multi-cOuNtry studY in Real Life Setting) is a multicentre, postmarketing observational study in adult patients with moderate-to-severe HS. Disease severity and QoL parameters were evaluated using validated measures at 12-week intervals over 52 weeks of treatment. The primary endpoint was the proportion of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR: ≥50% reduction in abscess and inflammatory nodule count, with no increase in abscess and draining fistula counts relative to baseline) at 12 weeks. Secondary endpoints were HiSCR at 24, 36 and 52 weeks and changes in QoL parameters and work productivity assessments. Analyses were conducted using as-observed data. RESULTS: The proportion of patients reaching the primary HiSCR endpoint was 70.2% (n = 132/188 enrolled) and remained ≥70% until study completion. There were statistically significant (P < 0.0001) reductions in worst and average skin pain. All of the QoL measures evaluated improved significantly (P < 0.0001) by 12 weeks of adalimumab treatment, as did work productivity assessments (P < 0.05), and there was a ˜50% decrease in HRU between baseline and week 52. Adalimumab was well tolerated. CONCLUSIONS: In this real-world setting, adalimumab treatment of moderate-to-severe HS resulted in decreased disease severity and improvements in QoL and productivity. Response to adalimumab was rapid (within 12 weeks) and sustained (52 weeks). No unexpected safety signals were reported.

European Position Paper on Rhinosinusitis and Nasal Polyps 2020.

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

EPOS2020: development strategy and goals for the latest European Position Paper on Rhinosinusitis.

BACKGROUND: The European Position Papers on Rhinosinusitis from 2005, 2007 and 2012 have had a measurable impact on the way this common condition with high impact on quality of life is managed around the world. EPOS2020 will be the latest iteration of the guideline, addressing new stakeholders and target users, presenting a summary of the latest literature and evolving treatment modalities, and formulating clear recommendations based on all available evidence. METHODOLOGY: Based on the AGREE II framework, this article demonstrates how the EPOS2020 steering group will address six key areas to ensure consistency in quality and presentation of information in the latest rhinosinusitis clinical practice guideline: scope and purpose; stakeholder involvement; rigour of development; clarity of presentation; recommendations and applicability; editorial independence. RESULTS: By analysing the guidance from AGREE II, we formulated a detailed development strategy for EPOS2020. We identify new stakeholders and target users and ratify the importance of patient involvement in the latest EPOS guideline. New and expanded areas of research to be addressed are highlighted. We confirm our intention to use mixed methodologies, combining evidence-based medicine with real life studies; when no evidence can be found, use Delphi rounds to achieve clear, inclusive recommendations. We also introduce new concepts for dissemination of the guideline, using Internet and social media to improve accessibility. CONCLUSION: This article is an introduction to the EPOS2020 project, and presents the key goals, core stakeholders, planned methodology and dissemination strategies for the latest version of this influential guideline.

A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN.

BACKGROUND: Dowling-Degos disease (DDD), featuring reticulate pigmentation, and familial hidradenitis suppurativa (HS) share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The coexistence of the two disorders was recently found to result from mutations in PSENEN, encoding the γ-secretase subunit protein presenilin enhancer. OBJECTIVES: To investigate PSENEN mutations in a series of four unrelated patients who presented with combined DDD and HS. METHODS: Mutation and haplotype analysis of PSENEN by polymerase chain reaction, and cellular assays investigating the Notch signalling pathway. RESULTS: Here we report four families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Genes associated with DDD, as well as HS, have been shown to encode important regulators of Notch signalling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in a patient's keratinocytes. CONCLUSIONS: The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition.

Industrial applications of nanoparticles.

Research efforts in the past two decades have resulted in thousands of potential application areas for nanoparticles - which materials have become industrially relevant? Where are sustainable applications of nanoparticles replacing traditional processing and materials? This tutorial review starts with a brief analysis on what makes nanoparticles attractive to chemical product design. The article highlights established industrial applications of nanoparticles and then moves to rapidly emerging applications in the chemical industry and discusses future research directions. Contributions from large companies, academia and high-tech start-ups are used to elucidate where academic nanoparticle research has revolutionized industry practice. A nanomaterial-focused analysis discusses new trends, such as particles with an identity, and the influence of modern instrument advances in the development of novel industrial products.

The expanding spectrum of IgA pemphigus: a case report and review of the literature.

IgA pemphigus (IGAP) is a rare, distinct variant of pemphigus, currently classified, depending upon the histological features, immunofluorescence staining pattern and autoantibody profile, into two types: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis. In a patient with a widespread blistering disease of the skin resembling SPD-type IGAP, we demonstrate the coexistence of IgA reactivity to both epidermal (desmocollins 2 and 3) and basement membrane-associated (BP180) proteins, suggesting the coexistence of atypical IGAP and linear IgA bullous dermatosis, respectively. This case, together with 20 previous reports of atypical IGAP, underscores the limitations of current classification schemes. Therefore, we suggest reclassifying these cases under the general term 'IGAP spectrum'.

A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse.

Human cortical malformations, including lissencephaly, polymicrogyria and other diseases of neurodevelopment, have been associated with mutations in microtubule subunits and microtubule-associated proteins. Here we report our cloning of the brain dimple (brdp) mouse mutation, which we recovered from an ENU screen for recessive perinatal phenotypes affecting neurodevelopment. We identify the causal mutation in the tubulin, beta-2b (Tubb2b) gene as a missense mutation at a highly conserved residue (N247S). Brdp/brdp homozygous mutants have significant thinning of the cortical epithelium, which is markedly more severe in the caudo-lateral portion of the telencephalon, and do not survive past birth. The cortical defects are largely due to a major increase in apoptosis and we note abnormal proliferation of the basal progenitors. Adult brdp/+ mice are viable and fertile but exhibit behavioral phenotypes. This allele of Tubb2b represents the most severely affected mouse tubulin phenotype reported to date and this is the first report of a tubulin mutation affecting neuronal proliferation and survival.

Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule.

The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic plasticity.

A nonionic surfactant/chitosan micelle system in an innovative eye drop formulation.

Micelle systems composed of the polyoxyethylated nonionic surfactant Pluronic F127 (F127) and cationic polyelectrolyte chitosan (CH) were prepared with dexamethasone (DEX) as a hydrophobic model drug. The F127/CH micelles were characterised by their hydrodynamic diameter and a zeta-potential ranging between 25.4 and 28.9 nm and +9.3 and +17.6 mV, respectively. The DEX loading was between 0.48% and 0.56%, and no significant influence of CH on DEX loading was observed. All micelle systems were characterised by prolonged release profiles. The addition of CH significantly enhanced the in vitro DEX release rate and transport across Caco-2 cell monolayers, as compared to the CH-free F127 micelle system. This colloidal carrier was well tolerated in rabbit eyes, and no clinically abnormal signs in various ocular structures were observed. The increase in intraocular pressure (IOP) in rabbits was used to evaluate DEX ocular bioavailability. The AUC values showed a 1.7- and 2.4-fold increase in bioavailability with F127 and F127/0.015 (w/v) % CH micelle systems, respectively, as compared to a standard DEX suspension. These data indicate improved intraocular DEX absorption from the micelle systems, which can be ascribed to both F127 and CH corneal permeability enhancement.

PDA-assisted low glycemic index dietary intervention for type II diabetes: a pilot study.

BACKGROUND: Epidemiological and dietary intervention studies suggest that a low-glycemic index (GI) diet is beneficial for blood glucose control; however, long-term clinical utility of the low GI diet has not been fully investigated. OBJECTIVES: To evaluate the feasibility and efficacy of a nutritionist-delivered low-GI dietary intervention, with the support of a personal digital assistant (PDA), for adult patients with poorly controlled type II diabetes. METHOD: The low-GI intervention consisted of six counseling sessions and the use of a PDA-based food database with GI scores for 6 months. Study outcomes included feasibility measures, glycosylated hemoglobin levels (HbA1c), GI and glycemic load (GL) score of self-reported dietary intake, body weight, depression and quality of life (QOL). Measures were obtained at baseline, 3 and 6 months. RESULTS: Of 31 adult patients approached, 15 met study eligibility criteria and were enrolled in the study. Thirteen patients (87%) completed all study assessments. Findings included decreases in average HbA1c (-0.5% P = 0.02), body weight, hip circumference, blood pressure, dietary GI and daily caloric intake. Diabetes impact scores also decreased. All but one participant completed all components of the intervention. There were mixed reports regarding the usefulness of the PDAs; however, participants offered helpful suggestions for further development. CONCLUSIONS: Results of this pilot study support the feasibility of implementing a nutritionist-delivered, PDA-assisted low-GI dietary intervention for patients with poorly controlled type II diabetes. Encouraging initial efficacy data require further testing in the context of a randomized clinical trial.

Seasonal variation in food intake, physical activity, and body weight in a predominantly overweight population.

OBJECTIVE: To describe seasonal variation in food intake, physical activity, and body weight in a predominantly overweight population. DESIGN: A longitudinal observational study. SETTING: Most of the study participants were recruited from a health maintenance organization (HMO) in central Massachusetts, USA. Additional individuals of Hispanic descent were recruited from outside of the HMO population to increase the ethnic diversity of this sample. SUBJECTS: Data from 593 participants, aged 20-70, were used for this investigation. Each participant was followed quarterly (five sampling points: baseline and four consecutive quarters) for 1-year period. Body weight measurements and three 24-h dietary and physical activity recalls were obtained on randomly selected days (including 2 weekdays and 1 weekend day) per quarter. Sinusoidal regression models were used to estimate peak-to-trough amplitude and phase of the peaks. RESULTS: Daily caloric intake was higher by 86 kcal/day during the fall compared to the spring. Percentage of calories from carbohydrate, fat and saturated fat showed slight seasonal variation, with a peak in the spring for carbohydrate and in the fall for total fat and saturated fat intake. The lowest physical activity level was observed in the winter and the highest in the spring. Body weight varied by about 1/2 kg throughout the year, with a peak in the winter (P<0.001 winter versus summer). Greater seasonal variation was observed in subjects who were male, middle aged, nonwhite, and less educated. CONCLUSIONS: Although there is seasonal variation in diet, physical activity and body weight, the magnitude of the change is generally small in this population. SPONSORSHIP: US National Heart, Lung and Blood Institute.

Bilateral orbital tumour as the presentation of mammographically occult breast cancer.

We report a rare case of bilateral orbital metastases as the presentation in a 63-year-old woman. Biopsy of a diffusely infiltrated medial rectus muscle suggested metastatic adenocarcinoma. Investigation revealed a palpable mass of the right breast not shown on mammography or sonography. Invasive lobular carcinoma was found at core-needle biopsy with histological features identical to those of the orbital lesion. Metastases to the extraocular muscles are uncommon, particularly as the initial abnormality in the absence of disseminated disease.

[Phototherapeutic keratectomy (o-PTK) with 193 nm excimer laser for superficial corneal scars. Prospective long-term results of 31 consecutive operations]. / Phototherapeutische Keratektomie (o-PTK) mittels 193-nm-Excimerlaser bei oberflächlichen HornhautnarbenProspektive Langzeitergebnisse von 31 konsekutiven Eingriffen.

PURPOSE: To investigate the functional and morphological long-term outcome of phototherapeutic keratectomy (PTK) for superficial corneal scars of varying origin. PATIENTS AND METHODS: Between 1989 and 11/2002, 317 PTKs were performed in Erlangen, of which 31 consecutive procedures were assessed in this prospective study. The intended laser ablation depth after epithelial debridement and pannectomy varied from 12 to 150 microm. We used the slit-scanning-mode (Carl Zeiss Meditec AG) with a repetition rate of 20/s or 25/s, a pulse energy of 14.5 mJ (median) and a pulse rate of 2565+/-2036 (222-6962). In most cases a 6.0 mm metal mask was used to protect peripheral Bowman's layer. RESULTS: After a mean follow-up of 2.0+/-1.9 (maximum 6.9) years, best-corrected visual acuity increased from preoperatively 0.3+/-0.2 to 0.5+/-0.3 (increase 87%, no change 10%, decrease 3%). Corneal surface topography regularized significantly (p=0.02). The spherical equivalent increased only slightly from -0.4+/-2.5 D preoperatively to 0.2+/-2.9 D postoperatively. Likewise, mean keratometric central power did not change significantly. In 10 eyes the maximum postoperative haze was mild, in 4 eyes moderate, and there was only one recurrent scar after delayed epithelial healing following epidemic keratoconjunctivitis. CONCLUSIONS: In superficial corneal scars of varying origin an o-PTK using the 193 nm excimer laser can moderately increase visual acuity in most cases. Therefore, a lamellar or penetrating keratoplasty might be avoided.

[Phototherapeutic keratectomy for recurrent corneal erosion syndrome (e-PTK). Report on 116 consecutive interventions]. / Phototherapeutische Kera-tektomie bei rezidivierender Erosio corneae (e-PTK). Bericht über 116 konsekutive Eingriffe.

BACKGROUND AND AIMS: Patients with recurrent corneal erosion syndrome can suffer both psychologically and socially due to excessive pain. After the failure of conservative treatment, conventional surgical interventions, such as anterior stromal puncture have been suggested. The purpose of this study was to assess the morphological and functional results of minimally invasive excimer laser phototherapeutic keratectomy (e-PTK) for treatment of recurrent corneal erosion syndrome and in particular, to evaluate the cumulative recurrence rate. PATIENTS AND METHODS: Between July 1990 and January 2001, 116 e-PTKs have been performed mostly in the acute stage of the disease in this single center study. In 15 eyes an unsuccessful PTK had previously been performed elsewhere. Reasons for the erosion included trauma ( n=80), Cogan's epithelial dystrophy ( n=14), bullous keratopathy ( n=2), and in 20 cases no cause could be detected. A manually guided spot profile was applied in 99 cases (pulse energy 10 mJ, repetition rate 2/s or 3/s, 66-330 pulses). In 17 cases a scanning slit procedure was applied (intended ablation per scan 1 microm, repetition rate 20/s, 447-1,017 pulses). The broad deepithelialisation of Bowman's layer was treated with defocussed overlapping laser pulses. RESULTS: Complete epithelial closure was achieved after an average of 2.3+/-1.3 (median 2) days, the mean follow-up was 2.2+/-1.6 years with a maximum of 5.6 years. Best corrected visual acuity increased from 0.6+/-0.4 preoperatively to 0.9+/-0.3 postoperatively. The keratometric central power remained constant (preoperative 43.0+/-2.2 D (diopters), postoperative 43.3+/-1.9 D). The median keratometric astigmatism remained constant at 1.0 D. Only in 2 patients was an iatrogenic, not completely reversible irregular astigmatism of more than 2 D induced during the learning curve. The spherical equivalent did not change significantly (-1.0+/-3.3 D preop., -1.1+/-3.4 D postop.). In 9 eyes (7.8%) a recurrent epithelial defect occurred after 2-24 (average 8+/-6) months. The cumulative 1-year recurrence rate was 6.5%, the 2-year recurrence rate was 11.5%, the 3-, 4-, and 5-year recurrence rates were all 13.6%. CONCLUSIONS: For recurrent corneal erosion syndrome, e-PTK performed with low pulse energy and low number of pulses can be considered an effective treatment modality to achieve a fast and mostly durable epithelial closure. Even after broad removal of the loose epithelium, change of refraction or induction of an irregular astigmatism with visual loss seems to be the exception.

[Primary open angle glaucoma in cornea plana masked by false normal applanation tonometry (Goldman) - a case report]. / Durch falsch normale Applanationstonometrie nach Goldmann maskiertes primär chronisches Offenwinkelglaukom bei extremer Cornea plana.

BACKGROUND: Cornea plana is a rare syndrome, which leads to a flat corneal curvature due to a reduced sclero-corneal angle. Depending on the regularity of the corneal astigmatism the frequently resulting hyperopia may be difficult to compensate for. Because of the flatness of the cornea the anterior chamber is also flat, the anterior chamber angle can be restricted, and the applanatory intraocular pressures (IOPs) are measured too low. A primary open angle glaucoma is therefore not diagnosed for a long time, until changes of the optic nerve head occur. Patient and methods We report on a 66-year-old male with cornea plana. Although his intraocular pressure (IOP), measured with an applanation tonometer (Goldmann), had always been normal (< 21 mm Hg), he suffered from an increasing glaucomatous atrophy of the optic disc. We carried out a complete ophthalmological investigation, including keratometry and corneal topography analysis (TMS-1, Tomey). Furthermore, visual field was determined (G1, Octopus) and the optic nerve heads were documented and analysed by papillometry. A 48-hour tension profile was worked out for both eyes including applanation and Schiötz tonometry. Results The central refractive power of the cornea was 31 diopters and the cornea seemed to be flattened on slit lamp evaluation. The glaucomatous atrophy of the optic disc was more pronounced in the OD than in the OS (OD=neuroretinal rim loss in the upper part, at the bottom and in the lateral part of the optic disc, OS=laterally distinct neuroretinal rim loss). While the anterior parts of the eye were shortened (depth of the anterior chamber was OD/OS=1.9 mm), a macrophthalmus posterior was stated (axial length OD=25.78 mm, OS=25.72 mm). However, the IOPs were measured below 21 mm Hg by applanation during the entire tension analysis, comparable values measured with the Schiötz tonometer showed values above 21 mm Hg. We converted the applanatory IOP values according to the flat corneal power, as described in literature (addition of 1 mm Hg to the applanatory values per 3 diopters decreased corneal power). The tension analysis now showed increased values, as expected after observation of the glaucomatous excavated optic nerve head. Conclusion In patients with cornea plana applanatory IOPs are measured too low. Therefore in case of very flat corneas a mathematical correction of the applanatory IOP should be carried out, in order to diagnose a primary open angle glaucoma early enough.

Role of hysteroscopy in detection and extraction of endometrial polyps: results of a prospective study.

OBJECTIVE: The aim of this study was to determine whether hysteroscopy improves the detection and extraction of endometrial polyps in postmenopausal women. This method was compared with curettage complemented by Randall polyp forceps. STUDY DESIGN: In a prospective study hysteroscopy was performed before and after curettage in postmenopausal women. In addition to curettage, the Randall polyp forceps was used to extract endometrial polyps. Curettage and polyp extraction by Randall forceps were performed by a second surgical team that did not know the results of hysteroscopy. RESULTS: A total of 83 patients were included in the study because of either postmenopausal bleeding (n = 40) or ultrasonographic abnormal endometrium (n = 37), or both (n = 6). Thirty-two patients received either hormone replacement therapy or tamoxifen. Hysteroscopy revealed endometrial polyps in 51 patients. Polyps were diagnosed by curettage alone in 22 (43%) cases. In 18 of these 22 cases remnants of polyps were extracted by Randall forceps, and in another 23 cases polyps were only found by use of the Randall forceps. Thus in 45 (88%) of 51 patients the detection of endometrial polyps by curettage and Randall forceps was possible. A second hysteroscopy procedure revealed remnants of polyps or polyps in 31 cases. These patients with incomplete curettage predominantly had a preoperative endometrial thickness of > or =10mm. CONCLUSIONS: Curettage alone in postmenopausal patients is not sufficient for detection and extraction of endometrial polyps. Additional use of Randall forceps improves detection of polyps considerably. However, with both procedures complete extraction of polyps was not achieved in a considerable number of patients. Hysteroscopy-controlled extraction was superior, especially in those patients with an endometrial thickness of >10 mm.

Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling.

Lysosomal cysteine proteinases of the papain family are involved in lysosomal bulk proteolysis, major histocompatibility complex class II mediated antigen presentation, prohormone processing, and extracellular matrix remodeling. Cathepsin L (CTSL) is a ubiquitously expressed major representative of the papain-like family of cysteine proteinases. To investigate CTSL in vivo functions, the gene was inactivated by gene targeting in embryonic stem cells. CTSL-deficient mice develop periodic hair loss and epidermal hyperplasia, acanthosis, and hyperkeratosis. The hair loss is due to alterations of hair follicle morphogenesis and cycling, dilatation of hair follicle canals, and disturbed club hair formation. Hyperproliferation of hair follicle epithelial cells and basal epidermal keratinocytes-both of ectodermal origin-are the primary characteristics underlying the mutant phenotype. Pathological inflammatory responses have been excluded as a putative cause of the skin and hair disorder. The phenotype of CTSL-deficient mice is reminiscent of the spontaneous mouse mutant furless (fs). Analyses of the ctsl gene of fs mice revealed a G149R mutation inactivating the proteinase activity. CTSL is the first lysosomal proteinase shown to be essential for epidermal homeostasis and regular hair follicle morphogenesis and cycling.

Dual epitope recognition by the VASP EVH1 domain modulates polyproline ligand specificity and binding affinity.

The Ena-VASP family of proteins act as molecular adaptors linking the cytoskeletal system to signal transduction pathways. Their N-terminal EVH1 domains use groups of exposed aromatic residues to specifically recognize 'FPPPP' motifs found in the mammalian zyxin and vinculin proteins, and ActA protein of the intracellular bacterium Listeria monocytogenes. Here, evidence is provided that the affinities of these EVH1-peptide interactions are strongly dependent on the recognition of residues flanking the core FPPPP motifs. Determination of the VASP EVH1 domain solution structure, together with peptide library screening, measurement of individual K(d)s by fluorescence titration, and NMR chemical shift mapping, revealed a second affinity-determining epitope present in all four ActA EVH1-binding motifs. The epitope was shown to interact with a complementary hydrophobic site on the EVH1 surface and to increase strongly the affinity of ActA for EVH1 domains. We propose that this epitope, which is absent in the sequences of the native EVH1-interaction partners zyxin and vinculin, may provide the pathogen with an advantage when competing for the recruitment of the host VASP and Mena proteins in the infected cell.

Synthesis of periphery-functionalized dendritic molecules using polylithiated dendrimers as starting material

A general method for the functionalization of Si-Cl terminated carbosilane dendritic molecules via organolithium or organomagnesium reagents is described. Quantitative exchange of the bromine atoms of 4-bromophenyl-functionalized dendrimers affords polylithiated species that are valuable starting materials for further functionalization, e.g., into pyridyl alcohols. The latter were successfully applied as catalyst precursors in a ruthenium-mediated ring-closure metathesis reaction.