A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis.

BACKGROUND: Filaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin's barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD). However, not all patients with AD have FLG mutations. OBJECTIVE: We hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease. RESULTS: We describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype. CONCLUSION: Our findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.

Kallikrein-Mediated Cytokeratin 10 Degradation Is Required for Varicella Zoster Virus Propagation in Skin.

Varicella zoster virus (VZV) is a skin-tropic virus that infects epidermal keratinocytes and causes chickenpox. Although common, VZV infection can be life-threatening, particularly in the immunocompromized. Therefore, understanding VZV-keratinocyte interactions is important to find new treatments beyond vaccination and antiviral drugs. In VZV-infected skin, kallikrein 6 and the ubiquitin ligase MDM2 are upregulated concomitant with keratin 10 (KRT10) downregulation. MDM2 binds to KRT10, targeting it for degradation via the ubiquitin-proteasome pathway. Preventing KRT10 degradation reduced VZV propagation in culture and prevented epidermal disruption in skin explants. KRT10 knockdown induced expression of NR4A1 and enhanced viral propagation in culture. NR4A1 knockdown prevented viral propagation in culture, reduced LC3 levels, and increased LAMP2 expression. We therefore describe a drug-able pathway whereby MDM2 ubiquitinates and degrades KRT10, increasing NR4A1 expression and allowing VZV replication and propagation.

Correcting Exorbitism by Monobloc Frontofacial Advancement in Crouzon-Pfeiffer Syndrome: An Age-Specific, Time-Related, Controlled Study.

BACKGROUND: In FGFR2 craniosynostosis, midfacial hypoplasia features oculo-orbital disproportion and symptomatic exorbitism. Clinical consequences may mandate surgery at a young age to prevent globe subluxation, corneal ulceration, and potential loss of vision. Monobloc osteotomy and distraction osteogenesis (monobloc distraction) seek to correct exorbitism. A report of the age-related impact of monobloc osteotomy and distraction osteogenesis on orbital volume, globe volume, and globe protrusion is presented. METHODS: Computed tomographic scan data from 28 Crouzon-Pfeiffer patients were assessed at preoperative, early postoperative, and 1-year follow-up time points. Orbital volumes, globe volumes, and globe protrusions were measured by manual and semiautomatic segmentation techniques, and these were compared to 40 age-matched controls. RESULTS: Crouzon-Pfeiffer syndrome orbital volumes are significantly small, and are significantly overexpanded by distraction to endpoints correcting symptomatic exorbitism. Globe volumes are significantly larger than controls under 5 years, do not independently correlate with globe protrusion, and are unaffected by surgery. Correlation between orbital volume expansion and reduction of globe protrusion is not significant. Age-related variations of postoperative growth potential occur to 1 year postoperatively. The Crouzon-Pfeiffer syndrome FGFR2 orbit exhibits early growth acceleration followed by premature growth arrest at 10 to 14 years. CONCLUSIONS: Orbital volume expansion by monobloc osteotomy and distraction osteogenesis is not the sole determinant of reduced globe protrusion. Mean volume relapse of the orbit at 1 year is insignificant across the series. Derived Crouzon-Pfeiffer growth curves suggest that "early functional monobloc" in infants occurs on a background of dynamic orbital growth, which remains programmed to a Crouzon-Pfeiffer FGFR2 phenotype and aligns with the incidence of delayed clinical regression and later secondary surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Fronto-facial advancement and bipartition in Crouzon-Pfeiffer and Apert syndromes: Impact of fronto-facial surgery upon orbital and airway parameters in FGFR2 syndromes.

A major concern in FGFR2 craniofaciosynostosis is oculo-orbital disproportion, such that orbital malformation provides poor accommodation and support for the orbital contents and peri-orbita, leading to insufficient eyelid closure, corneal exposure and eventually to functional visual impairment. Fronto-facial monobloc osteotomy followed by distraction osteogenesis aims to correct midfacial growth deficiencies in Crouzon-Pfeiffer syndrome patients. Fronto-facial bipartition osteotomy followed by distraction is a procedure of choice in Apert syndrome patients. These procedures modify the shape and volume of the orbit and tend to correct oculo-orbital disproportion. Little is known about the detailed 3D shape of the orbital phenotype in CPS and AS, and about how this is modified by fronto-facial surgery. Twenty-eight patients with CMS, 13 patients with AS and 40 control patients were included. CT scans were performed before and after fronto-facial surgery. Late post-operative scans were available for the Crouzon-Pfeiffer syndrome group. Orbital morphology was investigated using conventional three-dimensional cephalometry and shape analysis after mesh-based segmentation of the orbital contents. We characterized the 3D morphology of CPS and AS orbits and showed how orbital shape is modified by surgery. We showed that monobloc-distraction in CPS and bipartition-distraction in AS specifically address the morphological characteristics of the two syndromes.

A novel lobule rotation flap for the reconstruction of middle third auricular defects.

BACKGROUND: There are numerous techniques for the reconstruction of cutaneous defects of the pinna. Many of these distort the auricle, and several are challenging and time-consuming to perform. METHODS: An illustrative case is presented to demonstrate a novel lobule rotational flap, which can be used to cover cutaneous defects of the middle third of the pinna. RESULTS: Postoperative photography illustrates that this simple one-stage technique causes minimal anatomical distortion and allows the final scar to be concealed within the inner helical rim. CONCLUSIONS: Small local flaps can be raised from the lobule to cover challenging defects of the middle third of the pinna. In selected patients, with abundant lobular tissue, this technique can be as effective as more complex reconstructive options.

Descriptive and inferential statistical methods used in burns research.

BACKGROUND: Burns research articles utilise a variety of descriptive and inferential methods to present and analyse data. The aim of this study was to determine the descriptive methods (e.g. mean, median, SD, range, etc.) and survey the use of inferential methods (statistical tests) used in articles in the journal Burns. METHODS: This study defined its population as all original articles published in the journal Burns in 2007. Letters to the editor, brief reports, reviews, and case reports were excluded. Study characteristics, use of descriptive statistics and the number and types of statistical methods employed were evaluated. RESULTS: Of the 51 articles analysed, 11(22%) were randomised controlled trials, 18(35%) were cohort studies, 11(22%) were case control studies and 11(22%) were case series. The study design and objectives were defined in all articles. All articles made use of continuous and descriptive data. Inferential statistics were used in 49(96%) articles. Data dispersion was calculated by standard deviation in 30(59%). Standard error of the mean was quoted in 19(37%). The statistical software product was named in 33(65%). Of the 49 articles that used inferential statistics, the tests were named in 47(96%). The 6 most common tests used (Student's t-test (53%), analysis of variance/co-variance (33%), chi(2) test (27%), Wilcoxon & Mann-Whitney tests (22%), Fisher's exact test (12%)) accounted for the majority (72%) of statistical methods employed. A specified significance level was named in 43(88%) and the exact significance levels were reported in 28(57%). CONCLUSION: Descriptive analysis and basic statistical techniques account for most of the statistical tests reported. This information should prove useful in deciding which tests should be emphasised in educating burn care professionals. These results highlight the need for burn care professionals to have a sound understanding of basic statistics, which is crucial in interpreting and reporting data. Advice should be sought from professionals in the fields of biostatistics and epidemiology when using more advanced statistical techniques.

A 10-year review of benign and malignant peripheral nerve sheath tumors in a single center: clinical and radiographic features can help to differentiate benign from malignant lesions.

BACKGROUND: Malignant peripheral nerve sheath tumors are rare, and their aggressive nature mandates treatment in specialist centers. In contrast, benign peripheral nerve sheath tumors are common and are treated by a variety of specialist surgeons, including plastic surgeons. The authors aimed to detect features in the clinical presentation of peripheral nerve sheath tumors that point toward a diagnosis of malignant peripheral nerve sheath tumor and therefore prompt referral to a specialist center. METHODS: All histologically diagnosed primary peripheral nerve sheath tumors from January of 1995 to December of 2004 were identified from histopathology records. Notes were reviewed and analyzed with regard to symptoms, signs, radiology, electrophysiology, surgery, and pathology. Statistical comparisons used Fisher's exact test and the Mann-Whitney test. RESULTS: During the study period, 32 cases of malignant peripheral nerve sheath tumor in 30 patients were treated. Factors in the clinical evaluation that significantly predicted the presence of malignant peripheral nerve sheath tumor included site, large size, depth in relation to the deep fascia, short duration of symptoms, and pain. Magnetic resonance imaging and computed tomography were sensitive and specific ways of confirming the clinical diagnosis. Interestingly, schwannomata were harder to distinguish from malignant peripheral nerve sheath tumors both clinically and radiologically. CONCLUSIONS: The authors have reviewed their institutional experience of peripheral nerve sheath tumors over a 10-year period. Their results will help to focus clinical and radiologic investigation of patients presenting with these tumors.