Proteases and proteomics : cutting to the core of human skin pathologies

Preserving the integrity of the skin's outermost layer (the epidermis) is vital for humans to thrive in hostile surroundings. Covering the entire body, the epidermis forms a thin but impenetrable cellular cordon that repels external assaults and blocks escape of water and electrolytes from within. This structure exists in a perpetual state of regeneration where the production of new cellular subunits at the base of the epidermis is offset by the release of terminally differentiated corneocytes from the surface. It is becoming increasingly clear that proteases hold vital roles in assembling and maintaining the epidermal barrier. More than 30 proteases are expressed by keratinocytes or infiltrating immune cells and the activity of each must be maintained within narrow limits and confined to the correct time and place. Accordingly, over- or under-exertion of proteolytic activity is a common factor in a multitude of skin disorders that range in severity from relatively mild to life-threatening. This review explores the current state of knowledge on the involvement of proteases in skin diseases and the latest findings from proteomic and transcriptomic studies focused on uncovering novel (patho)physiological roles for these enzymes.

Calcitonin receptor plays a physiological role to protect against hypercalcemia in mice

It is well established that calcitonin is a potent inhibitor of bone resorption; however, a physiological role for calcitonin acting through its cognate receptor, the calcitonin receptor (CTR), has not been identified. Data from previous genetically modified animal models have recognized a possible role for calcitonin and the CTR in controlling bone formation; however, interpretation of these data are complicated, in part because of their mixed genetic background. Therefore, to elucidate the physiological role of the CTR in calcium and bone metabolism, we generated a viable global CTR knockout (KO) mouse model using the Cre/loxP system, in which the CTR is globally deleted by >94% but <100%. Global CTRKOs displayed normal serum ultrafiltrable calcium levels and a mild increase in bone formation in males, showing that the CTR plays a modest physiological role in the regulation of bone and calcium homeostasis in the basal state in mice. Furthermore, the peak in serum total calcium after calcitriol [1,25(OH)2D3]-induced hypercalcemia was substantially greater in global CTRKOs compared with controls. These data provide strong evidence for a biological role of the CTR in regulating calcium homeostasis in states of calcium stress.

Interaction of psychosocial risk factors explain increased neck problems among female office workers

This study investigated the relationship between psychosocial risk factors and (1) neck symptoms and (2) neck pain and disability as measured by the neck disability index (NDI). Female office workers employed in local private and public organizations were invited to participate, with 333 completing a questionnaire. Data were collected on various risk factors including age, negative affectivity, history of previous neck trauma, physical work environment, and task demands. Sixty-one percent of the sample reported neck symptoms lasting greater than 8 days in the last 12 months. The mean NDI of the sample was 15.5 out of 100, indicating mild neck pain and disability. In a hierarchical multivariate logistic regression, low supervisor support was the only psychosocial risk factor identified with the presence of neck symptoms. Similarly, low supervisor support was the only factor associated with the score on the NDI. These associations remained after adjustment for potential confounders of age, negative affectivity, and physical risk factors. The interaction of job demands, decision authority, and supervisor support was significantly associated with the NDI in the final model and this association increased when those with previous trauma were excluded. Interestingly, and somewhat contrary to initial expectations, as job demands increased, high decision authority had an increasing effect on the NDI when supervisor support was low.

Quantitative sensory measures distinguish office workers with varying levels of neck pain and disability

This study was undertaken to investigate any relationship between sensory features and neck pain in female office workers using quantitative sensory measures to better understand neck pain in this group. Office workers who used a visual display monitor for more than four hours per day with varying levels of neck pain and disability were eligible for inclusion. There were 85 participants categorized according to their scores on the neck disability index (NDI): 33 with no pain (NDI < 8); 38 with mild levels of pain and disability (NDI 9–29); 14 with moderate levels of pain (NDI ⩾ 30). A fourth group of women without neck pain (n = 22) who did not work formed the control group. Measures included: thermal pain thresholds over the posterior cervical spine; pressure pain thresholds over the posterior neck, trapezius, levator scapulae and tibialis anterior muscles, and the median nerve trunk; sensitivity to vibrotactile stimulus over areas of the hand innervated by the median, ulnar and radial nerves; sympathetic vasoconstrictor response. All tests were conducted bilaterally. ANCOVA models were used to determine group differences between the means for each sensory measure. Office workers with greater self-reported neck pain demonstrated hyperalgesia to thermal stimuli over the neck, hyperalgesia to pressure stimulation over several sites tested; hypoaesthesia to vibration stimulation but no changes in the sympathetic vasoconstrictor response. There is evidence of multiple peripheral nerve dysfunction with widespread sensitivity most likely due to altered central nociceptive processing initiated and sustained by nociceptive input from the periphery.

Alterations in cervical muscle activity in functional and stressful tasks in female office workers with neck pain

This study determined differences between computer workers with varying levels of neck pain in terms of work stressors, employee strain, electromyography (EMG) amplitude and heart rate response to various tasks. Participants included 85 workers (33, no pain; 38, mild pain; 14, moderate pain) and 22 non-working controls. Work stressors evaluated were job demands, decision authority, and social support. Heart rate was recorded during three tasks: copy-typing, typing with superimposed stress and a colour word task. Measures included electromyography signals from the sternocleidomastoid (SCM), anterior scalene (AS), cervical extensor (CE) and upper trapezius (UT) muscles bilaterally. Results showed no difference between groups in work stressors or employee strain measures. Workers with and without pain had higher measured levels of EMG amplitude in SCM, AS and CE muscles during the tasks than controls (all P < 0.02). In workers with neck pain, the UT had difficulty in switching off on completion of tasks compared with controls and workers without pain. There was an increase in heart rate, perceived tension and pain and decrease in accuracy for all groups during the stressful tasks with symptomatic workers producing more typing errors than controls and workers without pain. These findings suggest an altered muscle recruitment pattern in the neck flexor and extensor muscles. Whether this is a consequence or source of the musculoskeletal disorder cannot be determined from this study. It is possible that workers currently without symptoms may be at risk of developing a musculoskeletal disorder.

Associations between individual and workplace risk factors for self-reported neck pain and disability among female office workers

A cross-sectional survey of female office workers (n=333) was undertaken to determine the level of neck pain and disability (Neck Disability Index—NDI) and to explore the relationship between individual and workplace risk factors with the NDI score and the presence of pain. Workers reported nil (32%), mild (53%), moderate (14%) and severe (1%) neck pain. There were more risk factors associated with the NDI score than the presence of neck pain. The presence of neck pain was associated with a history of neck trauma (OR: 4.8), using a graduated lens (OR: 4.6), and negative affectivity (OR: 2.7) in the multiple regression model. Factors associated with higher NDI score were using the computer mouse for more than 6 h per day, higher negative affectivity, older age and an uncomfortable workstation. These results suggest that measuring the level of neck pain and disability rather than just the presence of neck pain provides more specific directives for the prevention and management of this disorder.

The role of biological extracellular matrix scaffolds in vascularized three-dimensional tissue growth in vivo

An in vivo murine vascularized chamber model has been shown to generate spontaneous angiogenesis and new tissue formation. This experiment aimed to assess the effects of common biological scaffolds on tissue growth in this model. Either laminin-1, type I collagen, fibrin glue, hyaluronan, or sea sponge was inserted into silicone chambers containing the epigastric artery and vein, one end was sealed with adipose tissue and the other with bone wax, then incubated subcutaneously. After 2, 4, or 6 weeks, tissue from chambers containing collagen I, fibrin glue, hyaluronan, or no added scaffold (control) had small amounts of vascularized connective tissue. Chambers containing sea sponge had moderate connective tissue growth together with a mild "foreign body" inflammatory response. Chambers containing laminin-1, at a concentration 10-fold lower than its concentration in Matrigel™, resulted in a moderate adipogenic response. In summary, (1) biological hydrogels are resorbed and gradually replaced by vascularized connective tissue; (2) sponge-like matrices with large pores support connective tissue growth within the pores and become encapsulated with granulation tissue; (3) laminin-containing scaffolds facilitate adipogenesis. It is concluded that the nature and chemical composition of the scaffold exerts a significant influence on the amount and type of tissue generated in this in vivo chamber model.

Promoting resilience in children with intellectual disability : a randomized controlled trial in Australian schools

Children with intellectual disability are more vulnerable to adverse developmental outcomes because of the lifelong risks associated with cognitive impairment. Difficulties with learning and adaptive behaviour inevitably produce considerable personal, social and economic disadvantage. Of concern is consistent evidence that psychiatric disorders affect a substantial proportion of people with intellectual disability. The estimated prevalence rate of between 35 and 49 % is three times that found in the general population (Wallander, Dekker, & Koot, 2006). Until recently, mental illness has been relatively neglected for people with intellectual disability, especially in relation to prevention or early detection (Kolaitis, 2008) and most research to date has been descriptive rather than focused on intervention (Bouras, 2013). Yet a considerable body of evidence demonstrates that efficacious interventions do exist for preventing psychopathology and enhancing resilience in typically developing children and adolescents (see Mallin, Walker, & Levin, 2013 for a review). In order to prevent the high comorbidity of intellectual disability and psychopathology, there is a compelling need for evidence-based practices that promote the resilience of individuals with intellectual disability (Matson, Terlonge, & Minshawi, 2008). In this chapter, we describe a randomized controlled trial of an intervention that was designed to enhance the resilience of a group of children with mild intellectual disability as they prepared to make the transition to high school. We report results from our evaluation of this intervention, and reflect on the difficulties of providing successful interventions for children whose lives are complicated not only by intellectual disability, but also by a range of contextual disadvantages.

Should we tailor standardize exercise interventions to suit differing menopausal status?

The article by Kretzschmar et al in this issue of Menopause details a study investigating the effect of a mild-intensity aerobic exercise training program on markers of mortality risk in both pre- and post-menopausal African American women. The findings of this study showed that aerobic exercise training was successful in improving some markers of cardiovascular disease and mortality in post-menopausal women. The premise of this study, however, does suggest that increased exercise intensity may be required in post-menopausal women as opposed to pre menopausal women to achieve the same decreased changes in CVD markers. The outcome of the study is thus of interest to the readers of Menopause and to all those who provide health care to postmenopausal women, as they suggest that higher levels of exercise intensity or perhaps additional interventions may need to be considered in this population to further decrease mortality risk. The study therefore, has greater implications than simply the suggesting of tailoring exercise interventions generally, rather, the publication highlights the importance of prescribing exercise as medicine in a tailored fashion for women depending on their menopausal status.

Assessment of revised recruitment standards for asthma in the Australian Defence Force

Objective To assess the impact of relaxed asthma recruitment standards adopted by the Australian Defence Force (ADF) in 2007. Methods A retrospective audit was conducted on clinical and administrative data for recruits, with and without mild asthma, in their first year of service. Results There was no evidence that mild asthmatics experienced worse outcomes than nonasthmatic recruits. Mild asthmatics had fewer illnesses and restricted duty days and were less costly compared to other recruits. There was no difference in the rate of discharge (attrition) between those with and without mild asthma. Conclusions The revised recruitment standards for asthma in the ADF have not resulted in unanticipated medical or administrative costs to the organisation. Health and administrative outcomes differed little between mild asthmatics and non-asthmatic recruits in their first twelve months of service.

An investigation of goethite-seeded Al(OH)3 precipitation using in situ X-ray diffraction and Rietveld-based quantitative phase analysis

An in situ X-ray diffraction investigation of goethite-seeded Al(OH)3 precipitation from synthetic Bayer liquor at 343 K has been performed. The presence of iron oxides and oxyhydroxides in the Bayer process has implications for alumina reversion, which causes significant process losses through unwanted gibbsite precipitation, and is also relevant for the nucleation and growth of scale on mild steel process equipment. The gibbsite, bayerite and nordstrandite polymorphs of Al(OH)3 precipitated from the liquor; gibbsite appeared to precipitate first, with subsequent formation of bayerite and nordstrandite. A Rietveld-based approach to quantitative phase analysis was implemented for the determination of absolute phase abundances as a function of time, from which kinetic information for the formation of the Al(OH)3 phases was determined.

Assessment of the temperature effect on childhood diarrhea using satellite imagery

A quasi-Poisson generalized linear model combined with a distributed lag non-linear model was used to quantify the main effect of temperature on emergency department visits (EDVs) for childhood diarrhea in Brisbane from 2001 to 2010. Residual of the model was checked to examine whether there was an added effect due to heat waves. The change over time in temperature-diarrhea relation was also assessed. Both low and high temperatures had significant impact on childhood diarrhea. Heat waves had an added effect on childhood diarrhea, and this effect increased with intensity and duration of heat waves. There was a decreasing trend in the main effect of heat on childhood diarrhea in Brisbane across the study period. Brisbane children appeared to have gradually adapted to mild heat, but they are still very sensitive to persistent extreme heat. Development of future heat alert systems should take the change in temperature-diarrhea relation over time into account.

Correlation between BRAF mutation and the clinicopathological parameters in papillary thyroid carcinoma with particular reference to follicular variant

Mutation of the BRAF gene is common in thyroid cancer. Follicular variant of papillary thyroid carcinoma is a variant of papillary thyroid carcinoma that has created continuous diagnostic controversies among pathologists. The aims of this study are to (1) investigate whether follicular variant of papillary thyroid carcinoma has a different pattern of BRAF mutation than conventional papillary thyroid carcinoma in a large cohort of patients with typical features of follicular variant of papillary thyroid carcinoma and (2) to study the relationship of clinicopathological features of papillary thyroid carcinomas with BRAF mutation. Tissue blocks from 76 patients with diagnostic features of papillary thyroid carcinomas (40 with conventional type and 36 with follicular variant) were included in the study. From these, DNA was extracted and BRAF V600E mutations were detected by polymerase chain reaction followed by restriction enzyme digestion and sequencing of exon 15. Analysis of the data indicated that BRAF V600E mutation is significantly more common in conventional papillary thyroid carcinoma (58% versus 31%, P = .022). Furthermore, the mutation was often noted in female patients (P = .017), in high-stage cancers (P = .034), and in tumors with mild lymphocytic thyroiditis (P = .006). We concluded that follicular variant of papillary thyroid carcinoma differs from conventional papillary thyroid carcinoma in the rate of BRAF mutation. The results of this study add further information indicating that mutations in BRAF play a role in thyroid cancer development and progression.

Vulnerability : an issue for law and policy in pandemic planning?

The 2009 H!Nl 'swine flu' pandemic was the first influenza pandemic of the twenty-first centmy. Unlike the first influenza pandemic of the twentieth century, the so-called 'Spanish flu' which killed millions of people worldwide, the 2009 pandemic was relatively mild. While the mildness of the 2009 pandemic meant that the 'Yorld was spared from the impact of a high-mortality event that would cause widespread social and economic disruption, the 2009 pandemic did provide an opportunity to road-test pandemic readiness. In other work we have assessed Australia's pandemic plans and emergency management legislation, finding that both provide flexible and adaptive forms of regulation that are capable of adapting to the scale and severity of a pandemic or other public health emergency. 1 In this chapter we consider whether pandemic planning adequately addresses the needs of vulnerable individuals and groups, both within countries and between them. Central to this is the question of whether vulnerability is itself a useful concept for both law and policy, and if so, the implications of expressly incorporating the concept of vulnerability into pandemic planning.

Annealing-free high-mobility diketopyrrolopyrrole-quaterthiophene copolymer for solution-processed organic thin film transistors

A donor-acceptor polymer semiconductor, PDQT, comprising diketopyrrolopyrrole (DPP) and β-unsubstituted quaterthiophene (QT) for organic thin film transistors (OTFTs) is reported. This polymer forms ordered layer-by-layer lamellar packing with an edge-on orientation in thin films even without thermal annealing. The strong intermolecular interactions arising from the fused aromatic DPP moiety and the DPP-QT donor-acceptor interaction facilitate the spontaneous self-assembly of the polymer chains into close proximity and form a large π-π overlap, which are favorable for intermolecular charge hopping. The well-interconnected crystalline grains form efficient intergranular charge transport pathways. The desirable chemical, electronic, and morphological structures of PDQT bring about high hole mobility of up to 0.97 cm2/(V·s) in OTFTs with polymer thin films annealed at a mild temperature of 100 °C and similarly high mobility of 0.89 cm2/(V·s) for polymer thin films even without thermal annealing.