Adipose triglyceride lipase-mediated lipid catabolism is essential for bronchiolar regeneration.

The lung airways are constantly exposed to inhaled toxic substances, resulting in cellular damage that is repaired by local expansion of resident bronchiolar epithelial club cells. Disturbed bronchiolar epithelial damage repair lies at the core of many prevalent lung diseases, including chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, and lung cancer. However, it is still not known how bronchiolar club cell energy metabolism contributes to this process. Here, we show that adipose triglyceride lipase (ATGL), the rate-limiting enzyme for intracellular lipolysis, is critical for normal club cell function in mice. Deletion of the gene encoding ATGL, Pnpla2 (also known as Atgl), induced substantial triglyceride accumulation, decreased mitochondrial numbers, and decreased mitochondrial respiration in club cells. This defect manifested as bronchiolar epithelial thickening and increased airway resistance under baseline conditions. After naphthalene­induced epithelial denudation, a regenerative defect was apparent. Mechanistically, dysfunctional PPARα lipid-signaling underlies this phenotype because (a) ATGL was needed for PPARα lipid-signaling in regenerating bronchioles and (b) administration of the specific PPARα agonist WY14643 restored normal bronchiolar club cell ultrastructure and regenerative potential. Our data emphasize the importance of the cellular energy metabolism for lung epithelial regeneration and highlight the significance of ATGL-mediated lipid catabolism for lung health.

Cholera as a 'sanitary test' of British cities, 1831-1866.

The malign contribution of northern industrial cities to the stagnation of national life expectancy over the period 1820-1870 forms part of one of the most long-running debates in English economic history, regarding the impact of early industrialisation on living standards. The deteriorating quality of urban water supplies often features in these arguments as the key driver of worsening mortality in this period. Here we use mortality reported from cholera in the epidemic years 1831-1832 and 1848-1849 as an indicator of the extent of sewage contamination of water in English and Welsh towns in this period. Surprisingly, the geography of reported mortality did not indicate that northern manufacturing and industrial towns were especially deficient in this respect. However, logistic regression analyses identified a number of risk factors for high cholera mortality, including location on coal-bearing strata, which was a feature of many industrial towns. Notably, however, textile-manufacturing towns, although often located in coal-rich districts, were associated with low levels of cholera mortality, and high population growth rates did not influence the risk of cholera. Reductions in cholera mortality after 1849 raise the possibility of widespread improvements in water quality after mid-century, rather earlier than is often assumed. However, in contrast to cholera, infant and diarrhoeal mortality remained high especially in northern towns until at least 1900. Several lines of evidence suggest that infants were relatively protected from waterborne diseases such as cholera and typhoid, and therefore did not benefit greatly from improvements in water quality. We conclude (1) that any worsening of water quality in urban areas c.1800-1850 was not confined to new͛ or rapidly growing industrial or manufacturing towns; and (2) infants probably rarely drank untreated water, so high infant or diarrhoeal mortality rates should not be read as indicators of poor water quality, in the English context.

A comparison of the antifouling performance of air plasma spray (APS) ceramic and high velocity oxygen fuel (HVOF) coatings for use in marine hydraulic applications.

Maritime hydraulic components are often exposed to harsh environmental conditions which can lead to accelerated deterioration, reduced function, equipment failure and costly repair. Two leading causes of maritime hydraulic failure are biofouling accumulation and corrosion. This study examined the antifouling performance of three candidate replacement high velocity oxygen fuel (HVOF) coatings relative to the performance of the current baseline air plasma spray (APS) ceramic coating for protection of hydraulic actuators. Following 20 weeks immersion at tropical and temperate field exposure sites, the control APS ceramic accumulated significantly greater levels of biofouling compared to the HVOF coatings. More specifically, the magnitude of growth of real-world nuisance hard fouling observed on in-service hydraulic components (eg calcareous tubeworms and encrusting bryozoans) was significantly greater on the APS ceramic relative to HVOF coatings. Possible explanations for the observed patterns include differences in surface topography and roughness, the electrochemical potential of the surfaces and the colour/brightness of the coatings.

The geography of smallpox in England before vaccination: A conundrum resolved.

Smallpox is regarded as an ancient and lethal disease of humans, however very little is known about the prevalence and impact of smallpox before the advent of vaccination (c.1800). Here we use evidence from English burial records covering the period 1650-1799 to confirm a striking geography to smallpox patterns. Smallpox apparently circulated as a childhood disease in northern England and Sweden, even where population densities were low and settlement patterns dispersed. However, smallpox was a relatively rare epidemic disease in southern England outside the largest cities, despite its commercialised economy and the growing spatial interconnectedness of its settlements. We investigated a number of factors hypothesised to influence the regional circulation of smallpox, including exposure to naturally occurring orthopox viruses, settlement patterns, and deliberate preventative measures. We concluded that transmission was controlled in southern England by local practices of avoidance and mass inoculation that arose in the seventeenth and eighteenth centuries. Avoidance measures included isolation of victims in pest houses and private homes, as well as cancellation of markets and other public gatherings, and pre-dated the widespread use of inoculation. The historical pattern of smallpox in England supports phylogenetic evidence for a relatively recent origin of the variola strains that circulated in the twentieth century, and provides evidence for the efficacy of preventative strategies complementary to immunisation.

Amorphous solid dispersion successfully improved oral exposure of ADX71943 in support of toxicology studies.

ADX71943 is a potent and selective GABA(b) receptor positive allosteric modulator (PAM) which exhibits poor aqueous solubility at all physiologically relevant pHs. The aim of this study was to identify an adequate formulation to improve the solubility of ADX71943 to achieve a sufficiently high plasma exposure after oral administration to support the toxicology program. Considering the overall physicochemical properties and the low solubility of ADX71943 in a variety of solvents, solid dispersion, and particle size reduction have been successfully chosen as potential strategies to improve its oral bioavailability. Both technologies have proven useful in improving the in vitro dissolution profile and as a result of the solubility enhancement, higher bioavailability was obtained in vivo. As the solid dispersion gave better bioavailability (30-fold compared with the neat active pharmaceutical ingredient (API)), this formulation was selected for the toxicology study. Changing the crystalline form of ADX71943 into amorphous state by preparing a solid dispersion has greatly improved its oral bioavailability and has allowed achieving the required plasma concentration needed in toxicology studies.

PAR-2 inhibition reverses experimental pulmonary hypertension.

RATIONALE: A hallmark of the vascular remodeling process underlying pulmonary hypertension (PH) is the aberrant proliferation and migration of pulmonary arterial smooth muscle cells (PASMC). Accumulating evidence suggests that mast cell mediators play a role in the pathogenesis of PH. OBJECTIVE: In the present study we investigated the importance of protease-activated receptor (PAR)-2 and its ligand mast cell tryptase in the development of PH. METHODS AND RESULTS: Our results revealed strong increase in PAR-2 and tryptase expression in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline (MCT)-treated rats. Elevated tryptase levels were also detected in plasma samples from IPAH patients. Hypoxia and platelet-derived growth factor (PDGF)-BB upregulated PAR-2 expression in PASMC. This effect was reversed by HIF (hypoxia inducible factor)-1α depletion, PDGF-BB neutralizing antibody, or the PDGF-BB receptor antagonist Imatinib. Attenuation of PAR-2 expression was also observed in smooth muscle cells of pulmonary vessels of mice exposed to hypoxia and rats challenged with MCT in response to Imatinib treatment. Tryptase induced PASMC proliferation and migration as well as enhanced synthesis of fibronectin and matrix metalloproteinase-2 in a PAR-2- and ERK1/2-dependent manner, suggesting that PAR-2-dependent signaling contributes to vascular remodeling by various mechanisms. Furthermore, PAR-2(-/-) mice were protected against hypoxia-induced PH, and PAR-2 antagonist application reversed established PH in the hypoxia mouse model. CONCLUSIONS: Our study identified a novel role of PAR-2 in vascular remodeling in the lung. Interference with this pathway may offer novel therapeutic options for the treatment of PH.

Maternal signals for progeny prevention against allergy and asthma.

Allergy and asthma are chronic inflammatory diseases which result from complex gene-environment interactions. Recent evidence indicates the importance of prenatal and postnatal developmental processes in terms of maturation of balanced immune responses. According to the current view, gene-environment interactions during a restricted time frame are responsible for programming of the immune system in favor of allergic immune mechanisms later in life. The interaction between genes and environment is complex and only partially understood; however, heritable epigenetic modifications including chemical additions in and alternative packaging of the DNA have been shown to play a crucial role in this context. Novel data indicate that epigenetic mechanisms contribute to the development of T-helper cell function. Environmental factors, including diesel exhaust particles (DEP), vitamins and tobacco smoke, operate through such mechanisms. Furthermore, the role of environmental microbes provides another and maybe even more important group of exogenous exposures which operates in this critical time frame.

High SBS-threshold single-mode single-frequency monolithic pulsed fiber laser in the C-band.

We report a high SBS-threshold, single-frequency, single-mode, polarization maintaining (PM) monolithic pulsed fiber laser source in master oscillator and power amplifier (MOPA) configuration that can operate over the C-band. In order to achieve a narrow transform-limited linewidth for pulses longer than 100 ns, we use a single-frequency Q-switched fiber laser seed, which itself can be seamlessly tuned up to 1.24 micros. The Q-switched pulses are amplified in the power amplifier stage of MOPA using a high SBS threshold single-mode PM large core highly Er/Yb co-doped phosphate glass fiber (LC-EYPhF). This seed and amplifier combination represents the first monolithic, all-fiber implementation of a single-frequency pulsed laser with the highest pulse energy of 54 microJ and peak power of 332 W for 153-ns pulses at 1538 nm.

Effect of body posture on pharyngeal shape and size in adults with and without obstructive sleep apnea.

STUDY OBJECTIVES: In patients with obstructive sleep apnea (OSA), the severity and frequency of respiratory events is increased in the supine body posture compared with the lateral recumbent posture. The mechanism responsible is not clear but may relate to the effect of posture on upper airway shape and size. This study compared the effect of body posture on upper airway shape and size in individuals with OSA with control subjects matched for age, BMI, and gender. PARTICIPANTS: 11 males with OSA and 11 age- and BMI-matched male control subjects. RESULTS: Anatomical optical coherence tomography was used to scan the upper airway of all subjects while awake and breathing quietly, initially when supine, and then in the lateral recumbent posture. A standard head, neck, and tongue position was maintained during scanning. Airway cross-sectional area (CSA) and anteroposterior (A-P) and lateral diameters were obtained in the oropharyngeal and velopharyngeal regions in both postures. A-P to lateral diameter ratios provided an index of regional airway shape. In equivalent postures, the ratio of A-P to lateral diameter in the velopharynx was similar in OSA and control subjects. In both groups, this ratio was significantly less for the supine than for the lateral recumbent posture. CSA was smaller in OSA subjects than in controls but was unaffected by posture. CONCLUSIONS: The upper airway changes from a more transversely oriented elliptical shape when supine to a more circular shape when in the lateral recumbent posture but without altering CSA. Increased circularity decreases propensity to tube collapse and may account for the postural dependency of OSA.

Anatomical optical coherence tomography for long-term, portable, quantitative endoscopy.

In this paper, we report on anatomical optical coherence tomography, a catheter-based optical modality designed to provide quantitative sectional images of internal hollow organ anatomy over extended observational periods. We consider the design and performance of an instrument and its initial intended application in the human upper airway for the characterization of obstructive sleep apnea (OSA). Compared with current modalities, the technique uniquely combines quantitative imaging, bedside operation, and safety for use over extended periods of time with no cumulative dose limit. Our experiments show that the instrument is capable of imaging subjects during sleep, and that it can record dynamic changes in airway size and shape.

Evaluation of pharyngeal shape and size using anatomical optical coherence tomography in individuals with and without obstructive sleep apnoea.

This study compared shape, size and length of the pharyngeal airway in individuals with and without obstructive sleep apnoea (OSA) using a novel endoscopic imaging technique, anatomical optical coherence tomography (aOCT). The study population comprised a preliminary study group of 20 OSA patients and a subsequent controlled study group of 10 OSA patients and 10 body mass index (BMI)-, gender- and age-matched control subjects without OSA. All subjects were scanned using aOCT while awake, supine and breathing quietly. Measurements of airway cross-sectional area (CSA) and anteroposterior (A-P) and lateral diameters were obtained from the hypo-, oro- and velopharyngeal regions. A-P : lateral diameter ratios were calculated to provide an index of regional airway shape. In all subjects, pharyngeal CSA was lowest in the velopharynx. Patients with OSA had a smaller velopharyngeal CSA than controls (maximum CSA 91 +/- 40 versus 153 +/- 84 mm(2); P < 0.05) but comparable oro- (318 +/- 80 versus 279 +/- 129 mm(2); P = 0.48) and hypopharyngeal CSA (250 +/- 105 versus 303 +/- 112 mm(2); P = 0.36). In each pharyngeal region, the long axis of the airway was oriented in the lateral diameter. Airway shape was not different between the groups. Pharyngeal airway length was similar in both groups, although the OSA group had longer uvulae than the control group (16.8 +/- 6.2 versus 11.2 +/- 5.2 mm; P < 0.05). This study has shown that individuals with OSA have a smaller velopharyngeal CSA than BMI-, gender- and age-matched control volunteers, but comparable shape: a laterally oriented ellipse. These findings suggest that it is an abnormality in size rather than shape that is the more important anatomical predictor of OSA.

Needle-based refractive index measurement using low-coherence interferometry.

We present a novel needle-based device for the measurement of refractive index and scattering using low-coherence interferometry. Coupled to the sample arm of an optical coherence tomography system, the device detects the scattering response of, and optical path length through, a sample residing in a fixed-width channel. We report use of the device to make near-infrared measurements of tissues and materials with known optical properties. The device could be used to exploit the refractive index variations of tissue for medical and biological diagnostics accessible by needle insertion.

Compact, single-frequency all-fiber Q-switched laser at 1 microm.

We demonstrate a unique, all-fiber, actively Q-switched laser operating in the 1 microm region. The laser is compact, single mode, single frequency, highly polarized, and exhibits high peak power. The laser cavity is constructed without external coupling, utilizing fiber Bragg gratings that permit feedback at only a single polarization. By using a piezoelectric to press the fiber and modulate the fiber birefringence, the cavity is switched between high and low loss states, permitting Q-switching. We demonstrate this Q-switching at repetition rates up to 700 KHz.

Single-frequency terahertz source pumped by Q-switched fiber lasers based on difference-frequency generation in GaSe crystal.

We demonstrate a unique terahertz (THz) source that is compact, utilizes recently developed all-fiber Q-switched lasers, and is based on difference-frequency generation in a GaSe crystal. A single piezo simultaneously Q switched the two fiber lasers by using stress-induced birefringence, to achieve the temporal overlap of pulses from the two fiber lasers. These correlated pulses then combine in the GaSe crystal to produce coherent and highly monochromatic THz pulses. The peak power for this THz source can reach 0.53 mW, corresponding to an average power of 0.43 microW and a conversion efficiency of 4.75 x 10(-7). The estimated linewidth of this THz source can be as narrow as approximately 35 MHz or 1.17 x 10(-3) cm(-1).

Quantitative upper airway imaging with anatomic optical coherence tomography.

BACKGROUND: Measurements of upper airway size and shape are important in investigating the pathophysiology of obstructive sleep apnea (OSA) and in devising, applying, and determining the effectiveness of treatment modalities. We describe an endoscopic optical technique (anatomic optical coherence tomography, aOCT) that provides quantitative real-time imaging of the internal anatomy of the human upper airway. METHODS: Validation studies were performed by comparing aOCT- and computed tomography (CT)-derived measurements of cross-sectional area (CSA) in (1) conduits in a wax phantom and (2) the velo-, oro-, and hypopharynx during wakefulness in five volunteers. aOCT scanning was performed during sleep in one subject with OSA. RESULTS: aOCT generated images of pharyngeal shape and measurements of CSA and internal dimensions that were comparable to radiographic CT images. The mean difference between aOCT- and CT-derived measurements of CSA in (1) the wax phantom was 2.1 mm(2) with limits of agreement (2 SD) from -13.2 to 17.4 mm(2) and intraclass correlation coefficient of 0.99 (p < 0.001) and (2) the pharyngeal airway was 14.1 mm(2) with limits of agreement from -43.7 to 57.8 mm(2) and intraclass correlation coefficient of 0.89 (p < 0.001). aOCT generated quantitative images of changes in upper airway size and shape before, during, and after an apneic event in an individual with OSA. CONCLUSIONS: aOCT generates quantitative, real-time measurements of upper airway size and shape with minimal invasiveness, allowing study over lengthy periods during both sleep and wakefulness. These features should make it useful for study of upper airway behavior to investigate OSA pathophysiology and aid clinical management.

In vivo size and shape measurement of the human upper airway using endoscopic longrange optical coherence tomography.

We describe a long-range optical coherence tomography system for size and shape measurement of large hollow organs in the human body. The system employs a frequency-domain optical delay line of a configuration that enables the combination of high-speed operation with long scan range. We compare the achievable maximum delay of several delay line configurations, and identify the configurations with the greatest delay range. We demonstrate the use of one such long-range delay line in a catheter-based optical coherence tomography system and present profiles of the human upper airway and esophagus in vivo with a radial scan range of 26 millimeters. Such quantitative upper airway profiling should prove valuable in investigating the pathophysiology of airway collapse during sleep (obstructive sleep apnea).