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BACKGROUND Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype-phenotype correlation in some populations. OBJECTIVES We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype-phenotype correlation. METHODS Deep phenotyping was undertaken by history-taking and clinical examination. DNA was screened for mutations using a next-generation sequencing ichthyosis gene panel and Sanger sequencing. RESULTS Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self-improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype. CONCLUSIONS These data refine genotype-phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype-phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.

A fit and well man in his 60s presented to the dermatology urgent assessment clinic with a 4 week history of a worsening pruritic eruption, limited to his elbows and posterior legs. In view of the limited distribution, further questioning was directed towards identifying potential contact factors. In the 1-2 weeks before the rash onset, the patient identified having acquired a new reclining chair made of tanned leather. He reported daily morning episodes of running in his garden to the point of perspiration before lying in T-shirt and shorts upon his new leather recliner for 8 hours a day. Examination revealed a substantial follicular eruption comprising papules and pustules in a strikingly restricted distribution on both legs (fig 1). The distribution and the follicular …

Summary Background Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. Objectives The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. Methods Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. Results The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg−1 per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg−1 vs. 2 mg kg−1 vs. > 2 mg kg−1, the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33–1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04–5·46, P = 0·04, Ptrend < 0·001. Conclusions The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Summary Multifocal capillary malformation (CM) is the cardinal feature of patients with RASA1 mutations. These CMs are ‘red flags’, signalling the possible association with an arteriovenous malformation (AVM) or an arteriovenous fistula (AVF). We report an 8‐year‐old boy who presented with > 20 CMs, who was found to have a novel mutation in the RASA1 gene. Radiological screening of children with RASA1 mutations is not standardized, and we elected to carry out baseline magnetic resonance imaging of the brain and spine in our case, which gave normal results. We discuss the recent literature and our approach in the management of such a case.

This project seeks to advance understanding about how experience of the historic environment creates forms of social value. Value is central to how aspects of the historic environment are designated, managed and conserved as heritage. For much of the twentieth century this was primarily linked to what have been seen as intrinsic historic, aesthetic and scientific values. More recently there has been increasing emphasis on the social values derived from active use of the historic environment. There are considerable difficulties surrounding how these different kinds of value should be weighed up against one another. This is exacerbated by a lack of understanding about social value, which falls largely outside of the kinds of expert knowledge traditionally associated with the heritage sector. Furthermore, social value is not readily captured by quantitative methods or easily subjected to instrumental forms of cost-benefit analysis. Through a critical review of existing research, this report examines current knowledge and understanding of social value. Encompassing the significance of the historic environment to contemporary communities, social value relates to people’s sense of identity, distinctiveness, belonging, and place, as well as forms of memory and spiritual association. Particular attention is focused on the modes of experience, engagement and practice that inform people’s relationships with the historic environment. The report also considers how to deal with the dynamic, iterative, and embodied nature of these relationships. The range of methodologies used in existing research and surveys is critically discussed, along with their application in the spheres of heritage conservation and public policy. Finally, the appropriateness of conceptual frameworks that quantify and fix values is examined. The possibilities for capturing more fluid processes of valuing the historic environment are considered, along with the implications for other spheres of arts and culture.

Maximal static inspiratory pressure (P(IMAX)) generated at the mouth is one of the tests of inspiratory muscle strength in children. In adults, inspiratory muscle strength has also been assessed using sniff nasal inspiratory pressure (SNIP). This test is easier to perform than P(IMAX) and might therefore be applicable to children. To test this hypothesis, we measured P(IMAX) and SNIP in 116 children aged 4 to 11 years (54 girls, 62 boys). P(IMAX) was measured using a tube mouthpiece and SNIP using a tightly fitting plug in one nostril, while a sniff was performed through the other nostril. Both tests were performed from functional residual capacity (FRC). Pressure was measured with a differential pressure transducer and displayed in real time on a computer screen. Weight, standing height, sitting height, gender, and age were recorded. There was a significant difference (P < 0.01) in group mean (SD) data between SNIP (81.3 (27.4) cmH(2)O) and P(IMAX) (67.9 (28.1) cmH(2)O). Bland/Altman analysis demonstrated a mean difference of -13.5 cmH(2)O (SD 21.4) between the techniques. Regression analysis indicated highly significant relations (P < 0.01) between SNIP and P(IMAX), and between weight, standing and sitting height, and age for SNIP, and between weight, standing height, and age for P(IMAX). SNIP and P(IMAX) were greater in boys than girls (83.2 vs. 79.2 cmH(2)O SNIP; 72.9 vs. 62.0 cmH(2)O P(IMAX)), but this difference was only significant for P(IMAX) (P < 0.05). SNIP was significantly greater than P(IMAX) (P < 0.01) in both boys and girls. These data suggest that SNIP provides a simple, noninvasive additional test to P(IMAX) for assessing inspiratory muscle strength in children.

Summary Aquagenic palmar wrinkling (APW) is characterized by the rapid and transient oedematous wrinkling of the palms after brief immersion in water. APW has been associated with cystic fibrosis (CF). Since the discovery of the CF gene, the clinical spectrum of CF has broadened from classic severe CF to include milder ‘atypical CF’ and ‘CF-related disorders’. We report an unusual case in which APW occurred in a patient with no lung disease, and in whom investigations showed evidence of CF gene dysfunction. APW may be a presenting feature of a CF-related disorder and should prompt investigation of CF gene dysfunction.

Summary Background There is only retrospective evidence for the efficacy of narrowband ultraviolet B (NB-UVB) in children with eczema. Objectives To measure the difference in means for objective scores [Six Area Six Sign Atopic Dermatitis score (SASSAD), percentage surface area] and quality-of-life scores, between patients treated with NB-UVB and unexposed cohorts at the end of treatment, and 3 and 6 months post-treatment. Methods Twenty-nine children aged 3–16 years for whom NB-UVB was indicated, were scored prospectively using SASSAD and percentage surface area involvement at baseline, at 12 weeks (end of treatment) and 3 and 6 months post-NB-UVB. Their scores were compared with those of unexposed children (n = 26) for whom NB-UVB phototherapy was indicated and offered, but who chose not to undertake treatment. Results There was a 61% reduction in mean SASSAD score in the NB-UVB cohort compared with an increase of 6% in the unexposed cohort. Mean SASSAD score for the NB-UVB cohort at the end of treatment was 11·6 vs. 24·8 for the unexposed; difference in means −13·2 [95% confidence interval (CI) −18·7 to −7·7, P

Bat rabies cases in Europe are principally attributed to two lyssaviruses, namely European bat lyssavirus type 1 (EBLV-1) and European bat lyssavirus type 2 (EBLV-2). Between 1977 and 2011, 961 cases of bat rabies were reported to Rabies Bulletin Europe, with the vast majority (97%) being attributed to EBLV-1. There have been 25 suspected cases of EBLV-2, of which 22 have been confirmed. In addition, two single isolations of unique lyssaviruses from European insectivorous bats were reported in south-west Russia in 2002 (West Caucasian bat virus) and in Germany in 2010 (Bokeloh bat lyssavirus). In this review, we present phylogenetic analyses of the EBLV-1 and EBLV-2 using partial nucleoprotein (N) gene sequences. In particular, we have analysed all EBLV-2 cases for which viral sequences (N gene, 400 nucleotides) are available (n = 21). Oropharyngeal swabs collected from two healthy Myotis daubentonii during active surveillance programmes in Scotland and Switzerland also yielded viral RNA (EBLV-2). Despite the relatively low number of EBLV-2 cases, a surprisingly large amount of anomalous data has been published in the scientific literature and Genbank, which we have collated and clarified. For both viruses, geographical relationships are clearly defined on the phylogenetic analysis. Whilst there is no clear chronological clustering for either virus, there is some evidence for host specific relationships, particularly for EBLV-1 where more host variation has been observed. Further genomic regions must be studied, in particular for EBLV-1 isolates from Spain and the EBLV-2 isolates to provide support for the existence of sublineages.

Blister formation and eccrine sweat gland necrosis have been recognized to occur in states of impaired consciousness and were first reported following barbiturate intoxication. Their etiology is complex and cannot simply be explained by pressure effects. Now that barbiturates are less frequently used, clinicians are likely to be less aware of the phenomenon of coma blister formation; however, newer drugs have also been associated with the occurrence of coma blisters. We describe 2 new associations of coma blisters and anticonvulsants in children. In the first child, blisters recurred on multiple occasions along with obtundation and edema. Our aims are to alert clinicians to the occurrence of coma blisters in children sedated on anticonvulsant medications and to report the new finding of recurrent coma blisters.

Publisher Summary This chapter outlines the results and conclusions of the preceding chapters. This project has resulted in numerous rich insights that are critical for understanding the way the role of management accountants in an ERP environment differs from their role. Time, scope, and budget control are very important to successful projects, none more so than when ERP implementations are involved. It was found to be critical in our study that management accountants be involved in ERP implementations from the start, that they are recognized as key members of the project team and that they champion the change process and management. When an organization moves to a complex ERP environment, changes in staff relationships generally occur and employees will likely need to acquire new skills, assume additional responsibilities, create new working relationships, and share information among departments. It is clear that the role of management accountants in an ERP environment is more like a business advisor to top management than that of a traditional management accountant. This chapter further stresses on the importance of ERP implementation with a concluding remark that it will not be too far into the future before an ERP approach is the norm across all organizations.

Clinical dermatologists have great difficulty keeping abreast of research in genetic skin disease. This is because there is too much information, in too many places, and in an unfamiliar language. In this review we have simplified and tabulated our current knowledge of the genodermatoses. We hope this 'at a glance' online guide will help dermatologists apply research findings to clinical practice and give informed advice to patients.

Naevoid basal cell carcinoma syndrome (NBCCS) or Gorlin syndrome is a rare autosomal dominant cancer disorder. The Gorlin's gene, Patched 1 (PTCH1), maps to Chromosome 9q. Germline mutations of PTCH1 occur in patients with NBCCS. The subsequent loss of the remaining allele results in cancer formation. We present a patient with NBCCS and additional phenotypic features including severe developmental delay, short stature and hypotelorism who was found to have an interstitial chromosome 9q deletion. The NBCCS phenotype in our patient occurred as a result of PTCH1 deletion in contrast with an inherited mutation of this gene.

Maximal static inspiratory pressure (P(IMAX)) generated at the mouth is one of the tests of inspiratory muscle strength in children. In adults, inspiratory muscle strength has also been assessed using sniff nasal inspiratory pressure (SNIP). This test is easier to perform than P(IMAX) and might therefore be applicable to children. To test this hypothesis, we measured P(IMAX) and SNIP in 116 children aged 4 to 11 years (54 girls, 62 boys). P(IMAX) was measured using a tube mouthpiece and SNIP using a tightly fitting plug in one nostril, while a sniff was performed through the other nostril. Both tests were performed from functional residual capacity (FRC). Pressure was measured with a differential pressure transducer and displayed in real time on a computer screen. Weight, standing height, sitting height, gender, and age were recorded. There was a significant difference (P0.01) in group mean (SD) data between SNIP (81.3 (27.4) cmH(2)O) and P(IMAX) (67.9 (28.1) cmH(2)O). Bland/Altman analysis demonstrated a mean difference of -13.5 cmH(2)O (SD 21.4) between the techniques. Regression analysis indicated highly significant relations (P0.01) between SNIP and P(IMAX), and between weight, standing and sitting height, and age for SNIP, and between weight, standing height, and age for P(IMAX). SNIP and P(IMAX) were greater in boys than girls (83.2 vs. 79.2 cmH(2)O SNIP; 72.9 vs. 62.0 cmH(2)O P(IMAX)), but this difference was only significant for P(IMAX) (P0.05). SNIP was significantly greater than P(IMAX) (P0.01) in both boys and girls. These data suggest that SNIP provides a simple, noninvasive additional test to P(IMAX) for assessing inspiratory muscle strength in children.

A longitudinal study of the CD8+ TCR variable (Vbeta) chain repertoire was performed in rhesus macaques experimentally infected with simian immunodeficiency virus (SIV) using both TCR Vbeta chain-specific monoclonal antibodies and TCR beta chain CDR3 length analysis. Expansions of subpopulations of CD8+ T cells were detected during the acute phase of SIV infection. In all monkeys studied, monoclonal expansions persisted for at least 18 months and increasingly dominated the repertoire of CD8+ T cells expressing the relevant Vbeta chain. This study shows that persistent CD8+ T cell expansions develop in response to a virus infection. This is important not only for our understanding of the T cell response to viruses but also for understanding the factors that determine the normal CD8+ TCR repertoire.

Previously we identified an acid protease activity which was located in the endosomes of rabbit alveolar macrophages (Diment, S., and Stahl, P.D. (1985) J. Biol. Chem. 260, 15311-15317). In this study, the endosomal protease is identified as cathepsin D by immunoprecipitation with polyclonal antibodies raised against rabbit cathepsin D and by NH2-terminal sequence. In order to elucidate the mechanism for targeting of cathepsin D to endosomes, we first examined the membrane association of cathepsin D with light (rho = 1.05 g/ml) and heavy density (rho = 1.1 g/ml) vesicles from Percoll density gradients. After sequential washes, 8.4 and 21.9% of cathepsin D activity remained associated with heavy and light density vesicles, respectively. This membrane-associated cathepsin D could not be solubilized in either buffer at pH 5.0 containing mannose 6-phosphate and EDTA or in buffer at pH 10.6. Solubilization required the detergent Triton X-100. To determine whether membrane-associated cathepsin D was found in endosomes, the enzyme was radioiodinated within endosomes and lysosomes with internalized lactoperoxidase. The membrane-associated form was detected in endosomes, but much less in lysosomes. Biosynthetic studies combined with the same extraction procedure revealed that macrophage cathepsin D is first synthesized as an inactive membrane-associated precursor. The precursor is processed to an active, membrane-associated form and then to the active soluble form found in lysosomes. Our studies provide evidence that 1) cathepsin D is in endosomes of macrophages; 2) cathepsin D is transported to endosomes as a membrane-associated form; and 3) the membrane-associated form is a biosynthetic precursor for the soluble form found in endosomes and lysosomes.

The incidence of slope water intrusions at a coastal monitoring station near Sydney was examined in relation to movements of particular eddies and meanders of the East Australian Current (EAC) from 1979 to 1984. Intrusions occurred when an eddy of EAC meander came within 90 km of the shelf break, driving waters from the continental slope onto the shelf, enriching the coastal water column and initiating plankton blooms. However, these slope water intrusions were rare from May to July when the EAC is weak and the prevailing winds are from the west. The mechanisms responsible for these episodic pulses of enrichment along the central coast of New South Wales appear to be analogous to those that operate in the South Atlantic Bight under the influence of the Florida Current.

Deep convective overturn has an important role1 in enhancing the productivity of warm-core ocean eddies. An eddy (F) formed from the East Australian Current in early 1978 overwintered further to the south and developed a significant phytoplankton bloom the following spring. We describe here another process which tends to terminate such blooms by submerging winter water, relatively rich in nutrients, beneath poorer water of more recent origin.

Personal interviews concerning health beliefs and behaviors were conducted with a parent and child in each of 250 households. Index scores were constructed for parental and child health beliefs, and these scores were entered, along with demographic variables, in a series of multiple regression analyses predicting child health beliefs and behaviors. The age of the child was the variable most highly associated with three of four child health behaviors and four of six child health beliefs. The children's snacking between meals and cigarette smoking were related to several parental behaviors and, to a lesser extent, parental health beliefs. The children's health beliefs were less predictable than were their health behaviors, and the observed significant relationships were with parental health beliefs and demographics. The implications for the design of health education programs are discussed.

There is good correlation between the specific gravity and osmolality of urine obtained from neonates and adults, if specimens contain neither protein nor glucose. The regression equations between specific gravity and osmolality, however, differ considerably between the two age groups, maturation to the adult regression occurring within the first 5 years of life. Specifically derived regression equations should therefore be used when predicting urine osmolality from measurement of specific gravity in neonates.

Previously we identified an acid protease activity which was located in the endosomes of rabbit alveolar macrophages (Diment, S., and Stahl, P.D. (1985) J. Biol. Chem. 260, 15311-15317). In this study, the endosomal protease is identified as cathepsin D by immunoprecipitation with polyclonal antibodies raised against rabbit cathepsin D and by NH2-terminal sequence. In order to elucidate the mechanism for targeting of cathepsin D to endosomes, we first examined the membrane association of cathepsin D with light (rho = 1.05 g/ml) and heavy density (rho = 1.1 g/ml) vesicles from Percoll density gradients. After sequential washes, 8.4 and 21.9% of cathepsin D activity remained associated with heavy and light density vesicles, respectively. This membrane-associated cathepsin D could not be solubilized in either buffer at pH 5.0 containing mannose 6-phosphate and EDTA or in buffer at pH 10.6. Solubilization required the detergent Triton X-100. To determine whether membrane-associated cathepsin D was found in endosomes, the enzyme was radioiodinated within endosomes and lysosomes with internalized lactoperoxidase. The membrane-associated form was detected in endosomes, but much less in lysosomes. Biosynthetic studies combined with the same extraction procedure revealed that macrophage cathepsin D is first synthesized as an inactive membrane-associated precursor. The precursor is processed to an active, membrane-associated form and then to the active soluble form found in lysosomes. Our studies provide evidence that 1) cathepsin D is in endosomes of macrophages; 2) cathepsin D is transported to endosomes as a membrane-associated form; and 3) the membrane-associated form is a biosynthetic precursor for the soluble form found in endosomes and lysosomes.

Mannose receptors are expressed only in primary macrophages. Established macrophage-derived cell lines, although apparently possessing the potential to synthesize mannose receptors, do not express them on their plasma membranes. Using the drug 5-Azacytidine, mannose receptor expression was induced in the macrophage-derived mouse cell line J774. Receptor positive cells were sorted through a fluorescent activated cell sorter (FACS) prior to cloning. Clones were isolated which continuously express mannose receptors in culture. These macrophages were able to endocytose β-glucuronidase and phagocytose yeast particles via mannose receptors. Secretion of the lysosomal enzyme β-hexosaminidase was also reduced in proportion to the degree of mannose receptor expression.