The biomechanics of amnion rupture: an X-ray diffraction study

Pre-term birth is the leading cause of perinatal and neonatal mortality, 40% of which are attributed to the pre-term premature rupture of amnion. Rupture of amnion is thought to be associated with a corresponding decrease in the extracellular collagen content and/or increase in collagenase activity. However, there is very little information concerning the detailed organisation of fibrillar collagen in amnion and how this might influence rupture. Here we identify a loss of lattice like arrangement in collagen organisation from areas near to the rupture site, and present a 9% increase in fibril spacing and a 50% decrease in fibrillar organisation using quantitative measurements gained by transmission electron microscopy and the novel application of synchrotron X-ray diffraction. These data provide an accurate insight into the biomechanical process of amnion rupture and highlight X-ray diffraction as a new and powerful tool in our understanding of this process.

Optimal growth strategies when mortality and production rates are size-dependent

Pontryagin's maximum principle from optimal control theory is used to find the optimal allocation of energy between growth and reproduction when lifespan may be finite and the trade-off between growth and reproduction is linear. Analyses of the optimal allocation problem to date have generally yielded bang-bang solutions, i.e. determinate growth: life-histories in which growth is followed by reproduction, with no intermediate phase of simultaneous reproduction and growth. Here we show that an intermediate strategy (indeterminate growth) can be selected for if the rates of production and mortality either both increase or both decrease with increasing body size, this arises as a singular solution to the problem. Our conclusion is that indeterminate growth is optimal in more cases than was previously realized. The relevance of our results to natural situations is discussed.

Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction

BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI.

Premature impairment of methylation pathway and cardiac metabolic dysfunction in fa/fa obese Zucker rats

Increasing evidence suggests that obesity is a chronic inflammatory disease, in which adipose tissue is involved in a network of endocrine signals to modulate energy homeostasis. These oxidative-inflammatory pathways, which are associated with cardiovascular complications, are also observed during the aging process. In this study, we investigated the interaction between aging and the development of obesity in a hyperphagic rat model. Metabolic profiles of the liver, white adipose tissue (WAT) and heart from young and adult Zucker lean (fa/+) and obese (fa/fa) rats were characterized using a (1)H NMR-based metabonomics approach. We observed premature metabolic modifications in all studied organs in obese animals, some of which were comparable to those observed in adult lean animals. In the cardiac tissue, young obese rats displayed lower lactate and scyllo-inositol levels associated with higher creatine, choline and phosphocholine levels, indicating an early modulation of energy and membrane metabolism. An early alteration of the hepatic methylation and transsulfuration pathways in both groups of obese rats indicated that these pathways were affected before diabetic onset. These findings therefore support the hypothesis that obesity parallels some metabolic perturbations observed in the aging process and provides new insights into the metabolic modifications occurring in pre-diabetic state.

Sequential variations of phytoplankton growth and mortality in an NPZ model: a remote-sensing-based assessment

Radiometric data in the visible domain acquired by satellite remote sensing have proven to be powerful for monitoring the states of the ocean, both physical and biological. With the help of these data it is possible to understand certain variations in biological responses of marine phytoplankton on ecological time scales. Here, we implement a sequential data-assimilation technique to estimate from a conventional nutrient–phytoplankton–zooplankton (NPZ) model the time variations of observed and unobserved variables. In addition, we estimate the time evolution of two biological parameters, namely, the specific growth rate and specific mortality of phytoplankton. Our study demonstrates that: (i) the series of time-varying estimates of specific growth rate obtained by sequential data assimilation improves the fitting of the NPZ model to the satellite-derived time series: the model trajectories are closer to the observations than those obtained by implementing static values of the parameter; (ii) the estimates of unobserved variables, i.e., nutrient and zooplankton, obtained from an NPZ model by implementation of a pre-defined parameter evolution can be different from those obtained on applying the sequences of parameters estimated by assimilation; and (iii) the maximum estimated specific growth rate of phytoplankton in the study area is more sensitive to the sea-surface temperature than would be predicted by temperature-dependent functions reported previously. The overall results of the study are potentially useful for enhancing our understanding of the biological response of phytoplankton in a changing environment.

Early treatment with intranasal neostigmine reduces mortality in a mouse model of Naja naja (Indian Cobra) envenomation

Objective. Most snakebite deaths occur prior to hospital arrival; yet inexpensive, effective, and easy to administer out-of-hospital treatments do not exist. Acetylcholinesterase inhibitors can be therapeutic in neurotoxic envenomations when administered intravenously, but nasally delivered drugs could facilitate prehospital therapy for these patients. We tested the feasibility of this idea in experimentally envenomed mice. Methods. Mice received intraperitoneal injections of Naja naja venom 2.5 to 10 times the estimated LD50 and then received 5

Convergence and accommodation development is pre-programmed in premature infants

Purpose This study investigated whether vergence and accommodation development in pre-term infants is pre-programmed or is driven by experience. Methods 32 healthy infants, born at mean 34 weeks gestation (range 31.2-36 weeks) were compared with 45 healthy full-term infants (mean 40.0 weeks) over a 6 month period, starting at 4-6 weeks post-natally. Simultaneous accommodation and convergence to a detailed target were measured using a Plusoptix PowerRefII infra-red photorefractor as a target moved between 0.33m and 2m. Stimulus/response gains and responses at 0.33m and 2m were compared by both corrected (gestational) age and chronological (post-natal) age. Results When compared by their corrected age, pre-term and full-term infants showed few significant differences in vergence and accommodation responses after 6-7 weeks of age. However, when compared by chronological age, pre-term infants’ responses were more variable, with significantly reduced vergence gains, reduced vergence response at 0.33m, reduced accommodation gain, and increased accommodation at 2m, compared to full-term infants between 8-13 weeks after birth. Conclusions When matched by corrected age, vergence and accommodation in pre-term infants show few differences from full-term infants’ responses. Maturation appears pre-programmed and is not advanced by visual experience. Longer periods of immature visual responses might leave pre-term infants more at risk of development of oculomotor deficits such as strabismus.  

Premature germination of resting spores as a means of Protecting brassica crops from Plasmodiophora brassicae Wor., (clubroot)

Premature germination of resting spores as a means of protecting brassica crops from Plasmodiphora brassicae Wor., (Clubroot). Crop Protection. Clubroot disease causes substantial yield and quality losses in broadacre oil seed and intensive vegetable brassica crops worldwide. The causal microbe Plasmodiophora brassicae Wor., perennates as soil-borne dormant resting spores. Their germination is triggered by exudates from host roots. A valuable addition to sustainable integrated control strategies could be developed by identifying and synthesising the molecules responsible for stimulating resting spore germination. This paper reports experiments in which stimulatory exudates were collected from brassica roots following exposure to infective stages of P. brassicae. Analyses identified a germination signalling molecule of circa 1 kDa formed of glucose sub-units. Mass spectral analyses showed this to be a complex hexasaccharide carbohydrate with structural similarities to the components of plant cell walls. This is the first report of a host generated hexasaccharide which is capable of stimulating the germination of resting spores of P. brassicae. The implications for environmentally benign control of clubroot are discussed briefly.

Improving the health forecasting alert system for cold weather and heat-waves in England: a proof-of-concept using temperature-mortality relationships

Objectives In this study a prototype of a new health forecasting alert system is developed, which is aligned to the approach used in the Met Office’s (MO) National Severe Weather Warning Service (NSWWS). This is in order to improve information available to responders in the health and social care system by linking temperatures more directly to risks of mortality, and developing a system more coherent with other weather alerts. The prototype is compared to the current system in the Cold Weather and Heatwave plans via a case-study approach to verify its potential advantages and shortcomings. Method The prototype health forecasting alert system introduces an “impact vs likelihood matrix” for the health impacts of hot and cold temperatures which is similar to those used operationally for other weather hazards as part of the NSWWS. The impact axis of this matrix is based on existing epidemiological evidence, which shows an increasing relative risk of death at extremes of outdoor temperature beyond a threshold which can be identified epidemiologically. The likelihood axis is based on a probability measure associated with the temperature forecast. The new method is tested for two case studies (one during summer 2013, one during winter 2013), and compared to the performance of the current alert system. Conclusions The prototype shows some clear improvements over the current alert system. It allows for a much greater degree of flexibility, provides more detailed regional information about the health risks associated with periods of extreme temperatures, and is more coherent with other weather alerts which may make it easier for front line responders to use. It will require validation and engagement with stakeholders before it can be considered for use.

A low mortality, high morbidity reduced intensity status epilepticus (RISE) model of epilepsy and epileptogenesis in the rat

Animal models of acquired epilepsies aim to provide researchers with tools for use in understanding the processes underlying the acquisition, development and establishment of the disorder. Typically, following a systemic or local insult, vulnerable brain regions undergo a process leading to the development, over time, of spontaneous recurrent seizures. Many such models make use of a period of intense seizure activity or status epilepticus, and this may be associated with high mortality and/or global damage to large areas of the brain. These undesirable elements have driven improvements in the design of chronic epilepsy models, for example the lithium-pilocarpine epileptogenesis model. Here, we present an optimised model of chronic epilepsy that reduces mortality to 1% whilst retaining features of high epileptogenicity and development of spontaneous seizures. Using local field potential recordings from hippocampus in vitro as a probe, we show that the model does not result in significant loss of neuronal network function in area CA3 and, instead, subtle alterations in network dynamics appear during a process of epileptogenesis, which eventually leads to a chronic seizure state. The model’s features of very low mortality and high morbidity in the absence of global neuronal damage offer the chance to explore the processes underlying epileptogenesis in detail, in a population of animals not defined by their resistance to seizures, whilst acknowledging and being driven by the 3Rs (Replacement, Refinement and Reduction of animal use in scientific procedures) principles.

Trends in systemic lupus erythematosus mortality rates in the state of Sao Paulo, Brazil from 1985 to 2004

Objectives To estimate mortality rates and mortality trends from SLE in the state of Sao Paulo, Brazil. Material and methods The official data bank was used to study all deaths occurred from 1985 to 2004 in which SLE was mentioned as the underlying cause of death. Besides the overall mortality rate, the annual gender- and age-specific mortality rates were estimated for each calendar year by age bracket (0-19 years, 20-39 years, 40-59 years and over 60 years) and for the sub-periods 1985-1995 (first) and 1996-2004 (second), by decades. Chi-square test was used to compare the mortality rates between the two periods, as well the mortality rates according to educational level considering years of study. Pearson correlation coefficient test was used to analyse mortality trends. The crude rates were adjusted for age by the direct method, using the standard Brazilian population in 2000. Results A total of 2,601 deaths (90% female) attributed to SLE were analysed. The mean age at death was significantly higher in the second than in the first sub-period (36.6 +/- 15.6 years vs. 33.9 +/- 14.0 years; p<0.001). The overall adjusted mortality rate was 3.8 deaths/million habitants/year for the entire period and 3.4 deaths/million inhabitants/year for the first and 4.0 deaths/million inhabitants/year for the second sub-period (p<0.001). In each calendar year, the mortality rate was significantly lower for the better educated group. Throughout the period, there was a significant increase in mortality rates only among women over 40. Conclusion SLE patients living in the state of Silo Paulo still die at younger ages than those living in developed countries. Our data do not support the theory that there was an improvement in the SLE mortality rate in the last 20 years in the state of Sao Paulo. Socio-economic factors, such as the difficulty to get medical care and adequate treatment, may be the main factors to explain the worst prognosis for our patients.

Chagas disease-related mortality trends, state of Sao Paulo, Brazil, 1985 to 2006: a study using multiple causes of death

Objectives. To study mortality trends related to Chagas disease taking into account all mentions of this cause listed on any line or part of the death certificate. Methods. Mortality data for 1985-2006 were obtained from the multiple cause-of-death database maintained by the Sao Paulo State Data Analysis System (SEADE). Chagas disease was classified as the underlying cause-of-death or as an associated cause-of-death (non-underlying). The total number of times Chagas disease was mentioned on the death certificates was also considered. Results. During this 22-year period, there were 40 002 deaths related to Chagas disease: 34 917 (87.29%) classified as the underlying cause-of-death and 5 085 (12.71%) as an associated cause-of-death. The results show a 56.07% decline in the death rate due to Chagas disease as the underlying cause and a stabilized rate as associated cause. The number of deaths was 44.5% higher among men. The fact that 83.5% of the deaths occurred after 45 years of age reflects a cohort effect. The main causes associated with Chagas disease as the underlying cause-of-death were direct complications due to cardiac involvement, such as conduction disorders, arrhythmias and heart failure. Ischemic heart disease, cerebrovascular disorders and neoplasms were the main underlying causes when Chagas was an associated cause-of-death. Conclusions. For the total mentions to Chagas disease, a 51.34% decline in the death rate was observed, whereas the decline in the number of deaths was only 5.91%, being lower among women and showing a shift of deaths to older age brackets. Using the multiple cause-of-death method contributed to the understanding of the natural history of Chagas disease.

Sex and socioeconomic inequalities of lung cancer mortality in Barcelona, Spain and Sao Paulo, Brazil

The objective of this paper was to assess sex and socioeconomic inequalities in lung cancer mortality in two major cities of Europe and South America. Official information on mortality and population allowed the estimation of sex- and age-specific death rates for Barcelona, Spain and Sao Paulo, Brazil (1995-2003). Mortality trends and levels were independently assessed for each city and subsequently compared. Rate ratios assessed by Poisson regression analysis addressed hypotheses of association between the outcome and socioeconomic covariates (human development index, unemployment and schooling) at the inner-city area level. Barcelona had a higher mortality in men (76.9/100000 inhabitants) than Sao Paulo (38.2/100 000 inhabitants); although rates were decreasing for the former (-2%/year) and levelled-off for the [after. Mortality in women ranked similarly (9.1 for Barcelona, 11.5 for Sao Paulo); with an increasing trend for women aged 35-64 years (+ 7.7%/year in Barcelona and + 2.4%/year in Sao Paulo). The socioeconomic gradient of mortality in men was negative for Barcelona and positive for Sao Paulo; for women, the socioeconomic gradient was positive in both cities. Negative gradients indicate that deprived areas suffer a higher burden of disease; positive gradients suggest that prosmoking lifestyles may have been more prevalent in more affluent areas during the last decades. Sex and socioeconomic inequalities of lung cancer mortality reinforce the hypothesis that the epidemiologic profile of cancer can be improved by an expanded access to existing technology of healthcare and prevention. The continuous monitoring of inequalities in health may contribute to the concurrent promotion of well-being and social justice.

Paracoccidioidomycosis-related mortality trend, state of Sao Paulo, Brazil: a study using multiple causes of death

Objective. To investigate mortality in which paracoccidioidomycosis appears on any line or part of the death certificate. Method. Mortality data for 1985-2005 were obtained from the multiple cause-of-death database maintained by the Sao Paulo State Data Analysis System (SEADE). Standardized mortality coefficients were calculated for paracoccidioidomycosis as the underlying cause-of-death and as an associated cause-of-death, as well as for the total number of times paracoccidioidomycosis was mentioned on the death certificates. Results. During this 21-year period, there were 1950 deaths related to paracoccidioidomycosis; the disease was the underlying cause-of-death in 1 164 cases (59.69%) and an associated cause-of-death in 786 (40.31%). Between 1985 and 2005 records show a 59.8% decline in the mortality coefficient due to paracoccidioidomycosis as the underlying cause and a 53.0% decline in the mortality as associated cause. The largest number of deaths occurred among men, in the older age groups, and among rural workers, with an upward trend in winter months. The main causes associated with paracoccidioidomycosis as the underlying cause-of-death were pulmonary fibrosis, chronic lower respiratory tract diseases, and pneumonias. Malignant neoplasms and AIDS were the main underlying causes when paracoccidioidomycosis was an associated cause-of-death. The decision tables had to be adapted for the automated processing of causes of death in death certificates where paracoccidioidomycosis was mentioned. Conclusions. Using the multiple cause-of-death method together with the traditional underlying cause-of-death approach provides a new angle on research aimed at broadening our understanding of the natural history of paracoccidioidomycosis.