Clinical investigation of an outbreak of alveolitis and asthma in a car engine manufacturing plant

Background Exposure to metal working fluid (MWF) has been associated with outbreaks of EAA in the US, with bacterial contamination of MWF being a possible cause, but was uncommon in the UK. Twelve workers developed extrinsic allergic alveolitis (EAA) in a car engine manufacturing plant in the UK, presenting clinically between December 2003 and May 2004. This paper reports the subsequent epidemiological investigation of the whole workforce. This had three aims:- • To measure the extent of the outbreak by identifying other workers who may have developed EAA or other work-related respiratory diseases. • To provide case-detection so that those affected can be treated. • To provide epidemiological data to identify the cause of the outbreak. Methods The outbreak was investigated in a three-phase cross-sectional survey of the workforce. Phase I A respiratory screening questionnaire was completed by 808/836 workers (96.7%) in May 2004. Phase II 481 employees with at least one respiratory symptom on screening and 50 asymptomatic controls were invited for investigation at the factory in June 2004. This included a questionnaire, spirometry and clinical opinion. 454/481(94.4%) responded along with 48/50(96%) controls. Workers were identified who needed further investigation and serial measurements of peak expiratory flow (PEF). Phase III 162 employees were seen at the Birmingham Occupational Lung Disease clinic. 198 employees returned PEF records, including 141 of the 162 who attended for clinical investigation. Case definitions for diagnoses were agreed. Results 87 workers (10.4% of workforce) met case definitions for occupational lung disease, comprising EAA(19), occupational asthma(74) and humidifier fever(7). 12 workers had more than one diagnosis. The peak onset of work-related breathlessness was Spring 2003. The proportion of workers affected was higher for those using metal working fluid (MWF) from a large sump(27.3%) compared with working all over the manufacturing area (7.9%) (OR=4.39,p<0.001). Two workers had positive specific provocation tests to the used but not the unused MWF solution. Conclusions Extensive investigation of the outbreak of EAA detected a large number of affected workers, not only with EAA but also occupational asthma. This is the largest reported outbreak in Europe. Mist from used MWF is the likely cause. In workplaces using MWF, there is a need to carry out risk assessments, to monitor and maintain fluid quality, to control mist and to carry out respiratory health surveillance

Thin film notch filters as platforms for biological image processing

Many image processing operations involve the modification of the spatial frequency content of images. Here we demonstrate object-plane spatial frequency filtering utilizing the angular sensitivity of a commercial spectral bandstop filter. This approach to all-optical image processing is shown to generate real-time pseudo-3D images of transparent biological and other samples, such as human cervical cancer cells. This work demonstrates the potential of non-local, non-interferometric approaches to image processing for uses in label-free biological cell imaging and dynamical monitoring.Comment: manuscript 14 pages, 5 figures, supplementary material 7 pages, 4 supplementary figure

Self-injurious behaviours are associated with alterations in the somatosensory system in children with autism spectrum disorder.

Children with autism spectrum disorder (ASD) frequently engage in self-injurious behaviours, often in the absence of reporting pain. Previous research suggests that altered pain sensitivity and repeated exposure to noxious stimuli are associated with morphological changes in somatosensory and limbic cortices. Further evidence from postmortem studies with self-injurious adults has indicated alterations in the structure and organization of the temporal lobes; however, the effect of self-injurious behaviour on cortical development in children with ASD has not yet been determined. Thirty children and adolescents (mean age = 10.6 ± 2.5 years; range 7-15 years; 29 males) with a clinical diagnosis of ASD and 30 typically developing children (N = 30, mean age = 10.7 ± 2.5 years; range 7-15 years, 26 males) underwent T1-weighted magnetic resonance and diffusion tensor imaging. No between-group differences were seen in cerebral volume, surface area or cortical thickness. Within the ASD group, self-injury scores negatively correlated with thickness in the right superior parietal lobule t = 6.3, p \u3c 0.0001, bilateral primary somatosensory cortices (SI) (right: t = 4.4, p = 0.02; left: t = 4.48, p = 0.004) and the volume of the left ventroposterior (VP) nucleus of the thalamus (r = -0.52, p = 0.008). Based on these findings, we performed an atlas-based region-of-interest diffusion tensor imaging analysis between SI and the VP nucleus and found that children who engaged in self-injury had significantly lower fractional anisotropy (r = -0.4, p = 0.04) and higher mean diffusivity (r = 0.5, p = 0.03) values in the territory of the left posterior limb of the internal capsule. Additionally, greater incidence of self-injury was associated with increased radial diffusivity values in bilateral posterior limbs of the internal capsule (left: r = 0.5, p = 0.02; right: r = 0.5, p = 0.009) and corona radiata (left: r = 0.6, p = 0.005; right: r = 0.5, p = 0.009). Results indicate that self-injury is related to alterations in somatosensory cortical and subcortical regions and their supporting white-matter pathways. Findings could reflect use-dependent plasticity in the somatosensory system or disrupted brain development that could serve as a risk marker for self-injury

A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.

Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers

Physician-Industry Collaboration: Organizational Considerations for the Future of Innovation and Growth in Dermatology

The U.S. medical environment continues to evolve with issues from Privacy to EMR, Insurance regulations, Physician Access and Healthcare Reform, and MACRA (Medicare Access and CHIP Reauthorization Act) on the discussion table. Not since the advent of Medicare and Medicaid in the mid 1960’s, have we seen such widespread changes in the medical healthcare environment (Centers for Medicare and Medicaid Services). Physicians, industry, patients and consumers are affected by the changes. These four groups have historically worked as separate entities, but are now key stakeholders in the future of dermatology. As stakeholders collaborating in building a future together, the dermatologists/physicians will help to ensure and preserve the quality of patient care and best patient outcomes. In the Executive Forum, leaders from the Women’s Dermatologic Society and Industry, explored five important areas: 1) A five-year outlook of Dermatology and Medicine; 2) Access of Industry to Dermatologists and Trainees; 3) The New Practice Environment; 4) Doing Things Differently; and 5) Unmet Specialty Needs. The collaborative group explored solutions for our specialty and the patients we serve

Systems Analysis Implicates WAVE2&nbsp;Complex in the Pathogenesis of&nbsp;Developmental Left-Sided Obstructive&nbsp;Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

Applying laboratory thermal desorption data in an interstellar context: sublimation of methanol thin films

Methods by which experimental measurements of thermal desorption can be applied in astrophysical environments have been developed, using the sublimation of solid methanol as an example. The temperature programmed desorption of methanol from graphitic, amorphous silica and polycrystalline gold substrates was compared, with the kinetic parameters of desorption extracted by either a leading edge analysis or by fitting using a stochastic integration method. At low coverages, the desorption shows a substrate-dependent fractional order. However, at higher coverages methanol desorption is zeroth order with kinetic parameters independent of substrate. Using a kinetic model based on the stochastic integration analyses, desorption under astrophysically relevant conditions can be simulated. We find that the chemical and morphological nature of the substrate has relatively little impact on the desorption temperature of solid methanol, and that the substrate independent zeroth-order kinetics can provide a satisfactory model for desorption in astrophysical environments. Uncertainties in the heating rate and the distribution of grain sizes will have the largest influence on the range of desorption temperature. These conclusions are likely to be generally applicable to all species in dust grain ice mantles

Opposing brain differences in 16p11.2 deletion and duplication carriers

Deletions and duplications of the recurrent ∼600 kb chromosomal BP4–BP5 region of 16p11.2 are associated with a broad variety of neurodevelopmental outcomes including autism spectrum disorder. A clue to the pathogenesis of the copy number variant (CNV)'s effect on the brain is that the deletion is associated with a head size increase, whereas the duplication is associated with a decrease. Here we analyzed brain structure in a clinically ascertained group of human deletion (N = 25) and duplication (N = 17) carriers from the Simons Variation in Individuals Project compared with age-matched controls (N = 29 and 33, respectively). Multiple brain measures showed increased size in deletion carriers and reduced size in duplication carriers. The effects spanned global measures of intracranial volume, brain size, compartmental measures of gray matter and white matter, subcortical structures, and the cerebellum. Quantitatively, the largest effect was on the thalamus, but the collective results suggest a pervasive rather than a selective effect on the brain. Detailed analysis of cortical gray matter revealed that cortical surface area displays a strong dose-dependent effect of CNV (deletion > control > duplication), whereas average cortical thickness is less affected. These results suggest that the CNV may exert its opposing influences through mechanisms that influence early stages of embryonic brain development

Plasma cytokine levels during acute HIV-1 infection predict HIV disease progression

BACKGROUND: Both T-cell activation during early HIV-1 infection and soluble markers of immune activation during chronic infection are predictive of HIV disease progression. Although the acute phase of HIV infection is associated with increased pro-inflammatory cytokine production, the relationship between cytokine concentrations and HIV pathogenesis is unknown. OBJECTIVES: To identify cytokine biomarkers measurable in plasma during acute HIV-1 infection that predict HIV disease progression. DESIGN: Study including 40 South African women who became infected with HIV-1 and were followed longitudinally from the time of infection. METHODS: The concentrations of 30 cytokines in plasma from women with acute HIV-1 infection were measured and associations between cytokine levels and both viral load set point 12 months postinfection and time taken for CD4 cell counts to fall below 350 cells/microl were determined using multivariate and Cox proportional hazards regression. RESULTS: We found that the concentrations of five plasma cytokines, IL-12p40, IL-12p70, IFN-gamma, IL-7 and IL-15 in women with acute infection predicted 66% of the variation in viral load set point 12 months postinfection. IL-12p40, IL-12p70 and IFN-gamma were significantly associated with lower viral load, whereas IL-7 and IL-15 were associated with higher viral load. Plasma concentrations of IL-12p40 and granulocyte-macrophage colony-stimulating factor during acute infection were associated with maintenance of CD4 cell counts above 350 cells/microl, whereas IL-1alpha, eotaxin and IL-7 were associated with more rapid CD4 loss. CONCLUSION: A small panel of plasma cytokines during acute HIV-1 infection was predictive of long-term HIV disease prognosis in this group of South African women