X-linked chronic granulomatous disease secondary to skewed X chromosome inactivation in a female with a novel CYBB mutation and late presentation

Chronic granulomatous disease (CGD) is characterized by defects in the superoxide producing enzyme NADPH oxidase causing phagocytes to improperly clear invading pathogens. Here we report findings of a late presenting 16-year-old female with X-linked CGD. The patient presented with community-acquired pneumonia, but symptoms persisted for 2 weeks during triple antimicrobial coverage. Cultures revealed Aspergillus fumigatus which was resolved through aggressive voriconazole treatment. Neutrophil studies revealed NADPH oxidase activity and flavocytochrome b(558) levels that were 4-8% of controls and suggested carrier status of the mother. We found a null mutation in the CYBB gene (c.252insAG) predicting an aberrant gp91(phox) protein (p.Cys85fsX23) in the heterozygous state. Methylation analysis demonstrated extremely skewed X chromosome inactivation favoring the maternally inherited defective gene. In conclusion, a novel mutation in the CYBB gene and an extremely skewed X-inactivation event resulted in the rare expression of the CGD phenotype in a carrier female.     

Expression of Semaphorin3C in axotomized rodent facial and rubrospinal neurons

Semaphorins are a family of axonal guidance molecules that, by virtue of their chemorepulsive or chemoattractive actions, may be the important factors in determining the success or failure of axonal regeneration in the mature nervous system after injury. Here, we have used two adult mouse models of nervous system injury to evaluate the neuronal expression of Semaphorin3C (Sema3C) in regenerating (facial motoneurons) and non-regenerating (rubrospinal) neurons following axonal injury. Using in situ hybridization (ISH), we observed that uninjured facial motoneurons express Sema3C mRNA and, following axonal injury, there is a transient up-regulation in Sema3C mRNA expression in injured motoneurons. In contrast, Sema3C mRNA was not detected in uninjured rubrospinal neurons; however, following axotomy, injured rubrospinal neurons significantly up-regulate Sema3C mRNA expression. The increase in Sema3C mRNA expression in axotomized rubrospinal neurons was not limited to the mouse nervous system: serial dilution RT-PCR analysis revealed a similar increase in Sema3C mRNA expression in the axotomized rat rubrospinal nucleus, 3 days following a rubrospinal tract lesion. This demonstrates that increased Sema3C mRNA levels in axotomized rubrospinal neurons is common to both mouse and rat injury models.     

Patient preference for falls prevention in hospitals revealed through willingness-to-pay, contingent valuation survey

Rationale, aims and objectives Patient preference for interventions aimed at preventing in‐hospital falls has not previously been investigated. This study aims to contrast the amount patients are willing to pay to prevent falls through six intervention approaches. Methods This was a cross‐sectional willingness‐to‐pay (WTP), contingent valuation survey conducted among hospital inpatients (n = 125) during their first week on a geriatric rehabilitation unit in Queensland, Australia. Contingent valuation scenarios were constructed for six falls prevention interventions: a falls consultation, an exercise programme, a face‐to‐face education programme, a booklet and video education programme, hip protectors and a targeted, multifactorial intervention programme. The benefit to participants in terms of reduction in risk of falls was held constant (30% risk reduction) within each scenario. Results Participants valued the targeted, multifactorial intervention programme the highest [mean WTP (95% CI): $(AUD)268 ($240, $296)], followed by the falls consultation [$215 ($196, $234)], exercise [$174 ($156, $191)], face‐to‐face education [$164 ($146, $182)], hip protector [$74 ($62, $87)] and booklet and video education interventions [$68 ($57, $80)]. A ‘cost of provision’ bias was identified, which adversely affected the valuation of the booklet and video education intervention. Conclusion There may be considerable indirect and intangible costs associated with interventions to prevent falls in hospitals that can substantially affect patient preferences. These costs could substantially influence the ability of these interventions to generate a net benefit in a cost–benefit analysis.     

"Too much of that stuff can't be good": Canadian teens, morality, and fast food consumption

Recently, public health agents and the popular media have argued that rising levels of obesity are due, in part, to "obesogenic" environments, and in particular to the clustering of fast food establishments in Western urban centers that are poor and working class. Our findings from a multi-site, cross-national qualitative study of teenaged Canadians' eating practices in urban and rural areas offer another perspective on this topic, showing that fast food consumption is not simply a function of the location of fast food outlets, and that Canadian teens engage in complex ways with the varied dimensions of choosing (or rejecting) fast foods. Drawing on evidence gleaned from semi-structured interviews with 132 teenagers (77 girls and 55 boys, ages 13-19 years) carried out between 2007 and 2009, we maintain that no easy relationship exists between the geographical availability of fast food and teen eating behaviors. We use critical obesity literature that challenges widely accepted understandings about obesity prevalence and etiology, as well as Lamont's (1992, 2000) concept of "moral boundary work," to argue that teen fast food consumption and avoidance is multifaceted and does not stem exclusively nor directly from spatial proximity or social class. Through moral boundary work, in which teens negotiated with moralistic notions of healthy eating, participants made and re-made themselves as "good" and successful subjects by Othering those who were "bad" in references to socially derived discourses of healthy eating.     

Immunophenotypic features by multiparameter flow cytometry can help distinguish low grade B‐cell lymphomas with plasmacytic differentiation from plasma cell proliferative disorders with an unrelated clonal B‐cell process

Highly sensitive flow cytometry studies may incidentally identify B cell clones when used to assess plasma cell clonality in bone marrows. Clinical history, which can help differentiate related clones (low grade B cell lymphoma with plasmacytic differentiation/LBCL‐PD) from unrelated ones (plasma cell proliferative disorder (PCPD) with an unrelated B cell clone), is often unavailable in referred specimens. We sought to identify morphologic or phenotypic features that would help predict the significance of these clones in the absence of history. We included only cases with identical light chain B and plasma cell clones, as determined by 6‐color flow cytometry with additional DNA ploidy analysis, in which the relationship between clones could be established by review of medical records. There were 26 cases; 18 were related (14 were Waldenstrom macroglobulinemia) and eight were unrelated (seven multiple myeloma). Features seen exclusively in LBCL‐PD include CD19+/CD45+ clonal plasma cell phenotype (66·7%, P = 0·0022) and morphologic features such as paratrabecular bone marrow involvement, increased mast cells, and plasma cells surrounding B‐cell nodules. Aneuploidy was identified exclusively in PCPD cases (75%, P = 0·000028). We conclude that CD19+/CD45+ clonal plasma cell phenotype and aneuploidy are useful in distinguishing related clones (LBCL‐PD) from unrelated clones (PCPD).     

Oxidative metabolism of the human eosinophil

We have compared the oxidative metabolism of human eosinophils (80%-90% purity) to that of neutrophils. Hexose monophosphate (HMP) shunt activity of eosinophils was higher than that of neutrophils under either resting or phagocytizing conditions. Eosinophil HMP shunt activity also was stimulated by phorbol myristate acetate, a membrane- active agent. Eosinophils showed a marked incorporation of 125I into trichloroacetic acid-insoluble material under resting conditions, which increased markedly during phagocytosis. Eosinophils likewise showed a greater reduction of nitroblue tetrazolium dye during phagocytosis than did neutrophils. Measurement of other parameters of oxidative metabolism indicated that eosinophils generated superoxide anion following phagocytosis and also elicited a burst of chemiluminescence similar to that observed during phagocytosis by neutrophils. Measurement of NADPH oxidase activity demonstrated that this enzyme was 3-6 times more active in fractions isolated from eosinophils than in corresponding fractions isolated from neutrophils; this was observed over a range of substrate concentrations. The eosinophil enzyme sedimented differently than the neutrophil enzyme with differential centrifugation; neither showed sedimentation characteristics of peroxidase. These data indicate that eosinophils possess a similar, although in some ways more potent, oxidative burst than neutrophils and are consistent with a role for NADPH oxidase in the initiation of that burst.     

Genomic expression changes induced by topical N-acetyl glucosamine in skin equivalent cultures in vitro

N-acetyl glucosamine (NAG) has been shown to be effective in reducing the appearance of hyperpigmented spots. From published in vitro mechanistic testing, glucosamine inhibits enzymatic glycosylation, a required processing step in converting inactive human pro-tyrosinase to the active tyrosinase, a key enzyme in the production of melanin. There is also published literature discussing the anti-inflammatory and antioxidant properties of glucosamine compounds. To identify additional mechanisms by which NAG might affect melanin production, an in vitro genomics experiment was conducted in SkinEthic skin equivalent cultures, which were topically dosed with NAG vs. a vehicle control. Relative to vehicle, NAG reduced melanin production, and the expression of several pigmentation-relevant genes were affected (down-regulated or up-regulated) by NAG treatment. Thus, there are several mechanisms that may be operative in the observed pigmentation effects.     

A prospective observational cohort study examining the development of head and neck lymphedema from the time of diagnosis

Introduction

Head and neck lymphedema can occur in the internal or external structures of the head and neck region. Little is known about the development of this condition over the course of treatment for head and neck cancer. This study aimed to observe the development of internal and external lymphedema from diagnosis to 12 weeks postacute treatment.

Methods

A single center, prospective observational cohort study assessed participants for external lymphedema, internal lymphedema, quality of life, and symptom burden. Assessments were conducted prior to starting radiotherapy (RT), at the end of RT, 6 and 12 weeks after RT.

Results

Forty-six participants were recruited. External lymphedema as measured by percentage water content, increased from 41.9 at baseline (95% CI: 39.3–44.4) to 50.4 (95% CI: 46.0–54.8) at 12 weeks following RT (p-value < .001). After adjusting for changes in weight and participant age at baseline, a general increase in tape measurements was observed over time with significant increases from baseline to 12 weeks post-RT for all measurement points. By 12 weeks post-RT, all participants had lymphedema present in eight of 13 internal sites assessed.

Conclusions

Internal and external head and neck lymphedema was observed to increase from baseline to 12 weeks after completion of RT without abatement. People with head and neck cancer should be educated about the potentially extended duration of this treatment side effect. Further research is required to determine the point at which swelling symptoms recede.     

Pregnant women’s awareness,knowledge and beliefs about pelvic floor muscles: a cross-sectional survey

Introduction and hypothesis

Pregnant women benefit from completing pelvic floor muscle exercises (PFMEs). The aims of the study were to evaluate pregnant women’s levels of awareness, knowledge, and beliefs about the pelvic floor muscles (PFMs) and PFMEs.

Methods

A cross-sectional survey was conducted. Respondents were pregnant women over the age of 18 years who attended antenatal clinics in Western Australia (WA). Questionnaire items measured awareness and knowledge about PFMs, confidence and beliefs about engaging in PFMEs, and attendance at antenatal education (ANE) classes. Chi-squared tests examined potential associations between questionnaire items and respondent characteristics.

Results

Mean gestation of respondents (n?=?633 out of 850; 74% response rate) was 28.7 (+7.8) weeks and 50% were giving birth for the first time. Although 76% of respondents knew that PFMs can prevent urinary incontinence, only 27% knew that they prevented faecal incontinence and 41% thought it was normal to leak urine when pregnant. Only n?=?72 (11%) were practicing PFMEs. Respondents who had attended ANE (28%) were significantly more knowledgeable about pelvic floor function (p?<?.001) and significantly less likely to believe that leaking urine during pregnancy was normal (p?=?0.02), compared with those who had not attended ANE. Respondents who did not speak English at home (18%) were significantly less knowledgeable about PFMs and PFMEs, and significantly less likely to have attended, or planned to attend, ANE classes.

Conclusion

Pregnant women require more health education regarding PFMs. Education should be provided using diverse modes, especially for women from migrant backgrounds and women who do not plan to attend formal ANE classes.