Experimental severe Pseudomonas aeruginosa pneumonia and antibiotic therapy in piglets receiving mechanical ventilation

BACKGROUND: Little is known about the general and local consequences of severe pneumonia under mechanical ventilation (SPMV) and how these are resolved with antibiotic therapy (ABT). OBJECTIVES: To investigate the physiologic, biological, microbiological, and pathologic changes produced by experimental SPMV in a porcine model, and to evaluate the effect of ABT. METHODS: Pseudomonas aeruginosa was inoculated in 12 large white-Landrace piglets receiving mechanical that were killed after 72 h if death did not occur before. Vital signs, serum and BAL cytokines, serum C-reactive protein (CRP), and graded postmortem lung pathology and cultures (blood and quantitative BAL and lung) were evaluated. Six piglets received inappropriate ABT (no ABT or ceftriaxone), and six piglets received appropriate ABT (ciprofloxacin). Measurements and main results: Pathologic and microbiological evidence of infection were present in all the animals in both groups. SPMV produced significant oxygenation and lung compliance worsening, increased serum CRP, and reduced BAL fluid tumor necrosis factor (TNF)-alpha. Arterial thrombosis in lung pathology was associated with higher temperature, hypoxemia and low lung compliance, higher initial serum CRP and TNF-alpha concentrations, and increased serum interleukin (IL)-6 and BAL IL-6 and TNF-alpha. Reduced ABT reduced body temperature and culture positivity. CONCLUSIONS: This model resembles VAP and has been used for studying pulmonary infection and inflammation related to mechanical ventilation. ABT reduced fever and bacterial burden in SPMV but had no effect on cytokine or CRP concentrations, oxygenation, or lung mechanics. Pulmonary artery thrombosis was associated with worse response to infection.     

Preclinical modeling of cytosine arabinoside response in Mll-Enl translocator mouse leukemias

Mouse models of human cancer are a potential preclinical setting for drug testing and for development of methods for delivery of macromolecular drugs to tumors. We have assessed a mouse model of leukemia caused by Mll-Enl protein fusion as a preclinical situation in which myeloid-lineage leukemia results from de novo occurrence of chromosomal translocations between Mll and Enl genes. Here, we show that the mouse leukemias respond to cytosine arabinoside, a frontline treatment for human leukemia. The observations show that the myeloid cells are susceptible to the drug and the mice undergo a remission that comprises a reduction of the myeloid population of cells and recovery of the lymphoid population. This translocator model should therefore prove useful for future drug assessments against the recurrent mixed-lineage leukemia-associated translocations.     

Photoacoustic-Ultrasound Tomography: A New Window into Developmental Toxicity

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Worldwide, birth defects affect 3%–6% of infants and account for 20% of all infant deaths.¹ With mounting evidence for links between environmental exposures and birth outcomes,^2,3 there is an need for accurate screening strategies for timely diagnosis and treatment of fetal abnormalities. According to the authors of a recent study published in Environmental Health Perspectives, early detection of developmental defects in mice was achieved using a novel dual-modality imaging technique that can overcome some of the challenges of traditional ultrasound technology.⁴Birth defects arise from unknown causes in roughly half of all cases.^5,6 Congenital heart defects are the most common type of birth defect⁷ and are among the top eight causes of infant mortality.⁸ Mixed evidence associates congenital heart defects with prenatal proximity to landfills and exposures to air pollution, metals, pesticides, solvents, disinfection by-products, and high ambient temperatures.^9,10,11Ultrasound imaging techniques can detect some developmental defects before birth, but despite significant advances, their use is limited to later stages of development. However, even in the second trimester more than 50% of congenital heart abnormalities are not detected by routine fetal ultrasound.¹² In addition, conventional ultrasound cannot measure functional parameters such as tissue oxygen saturation (SaO2) and hemoglobin content (HbT). These two early indicators of alterations in embryo circulation typically precede gross morphological changes.^13,14Open in a separate windowLeft: The heart bulge of this 12-day-old mouse embryo is visible in the center of its body. Scanning electron micrograph, magnification 20× when printed at 10cm wide. Right: A new tomographic technique enabled investigators to pinpoint when heart abnormalities started in embryos that received low (middle) and high (bottom) doses of MMC (the top panel shows the control). Images, left to right: © Steve Gschmeissner/Science Photo Library; Qiu et al.⁴ A newer tool, photoacoustic-ultrasound (PA-US) tomography, combines the specificity, high contrast, and deep-tissue penetration of optical and acoustic imaging technologies to provide details about organ structure and function.¹⁵ In this hybrid technology, optical energy is delivered into biological tissues, resulting in ultrasonic emissions that can be analyzed to produce images.¹⁶ Because optical absorption is directly related to physiological properties such as SaO2 and HbT content, different tissues will produce different photoacoustic signals, which can be translated into extremely detailed three-dimensional pictures of the target area.¹⁷ Although PA-US tomography is a promising clinical tool broadly applied in disease monitoring, functional imaging, and therapy and surgery guidance,¹⁸ this is the first time it was tested for assessing developmental toxicity.In the study, investigators used dual-modality PA-US imaging to examine early embryo morphology and markers of embryonic tissue oxygenation and function in mice, after exposure to methylmercury chloride (MMC), a potential neuro- and cardiotoxicant. Pregnant dams received either a high MMC dose, low MMC dose, or saline control for 6 consecutive days. Exposure occurred during a period equivalent to weeks 2–4 of human gestation, when early organogenesis begins and the risk of developmental abnormalities and miscarriage is highest.^19,20 Embryos from treated and control dams were evaluated for pathological changes using PA-US imaging. That technique enabled detection of differences between the high-dose and control groups in overall embryo size and cardiovascular function, results that were confirmed by ex vivo histopathological analyses. In the low-dose group, quantification of SaO2 and HbT values allowed detection of functional abnormalities that preceded apparent morphological changes and would have eluded diagnosis by conventional ultrasound alone.Fuller Bazer, chair of the Physiology of Reproduction Program at Texas A&M University, notes that the dosages used in the study were high relative to concentrations that are toxic to humans. However, the authors’ main focus was testing the technology’s performance. Given the results, says Bazer, who was not involved in the study, PA-US imaging shows promise as a noninvasive means of detecting developmental abnormalities. With further refinement, he suggests, PA-US imaging could prove instrumental in identifying unique developmental changes during normal gestation, or in mouse models of disease with detrimental effects on fetal and placental development.“Our study provides a new high-resolution, real-time imaging method for in vivo evaluation of embryonic development,” says Qingliang Zhao, senior author of the study. “We believe that dual-modality PA-US imaging has great potential in developmental biology research.” The technology is not yet ready for use in humans, Zhao says. However, he asserts that the application of photoacoustic contrast agents and the optimization of detector bandwidth—both of which are the subject of published studies^21,22—would drastically improve the resolution and imaging depth of the PA-US system. Such an approach could prove useful in preclinical studies and clinical applications.     

Pancreaticoduodenectomy for islet cell tumors of the head of the pancreas: long-term survival analysis

Pancreaticoduodenectomy (PD) has been performed infrequently for islet cell tumors of the pancreas because of the perceived perioperative morbidity and the relatively protracted natural history of those tumors. To determine whether the improved safety of PD affects long-term outcome of patients with islet cell tumors, we reviewed our experience. All consecutive patients who underwent PD or total pancreatectomy for islet cell tumors between 1980 and 1995 were analyzed. Diagnoses were based on histologic findings and endocrine (biochemical) manifestations of the tumors. Patients were followed by outpatient clinic visits and mail correspondence. Clinical and pathologic factors were analyzed for prognostic risk. Survival and recurrence curves were generated using the Kaplan-Meier method, and the log-rank test was used for comparison (p <0.05 was significant). We identified 29 patients who fulfilled the inclusion criteria with an even distribution by gender (14M:15F). Mean age of patients was 56 years (SD +/- 14 years); mean tumor size was 4.4 cm (SD +/- 2.6 cm). Most tumors were nonfunctioning (n = 20); there were 4 somatostatinomas, 3 insulinomas, and 2 gastrinomas. Operating time was 316 minutes (SD +/- 75 minutes), median transfusion requirement was 0 units (mean 1.5 units). Standard Whipple resection was performed in 20 patients; the pylorus-preserving Whipple procedure, in 7; and total pancreatectomy, in 2. Regional lymph nodes were involved by tumor in 16 patients. The complication rate was 31%, and operative mortality was 10% (n = 3). Length of hospital stay was 17 days (SD +/- 8.8 days). Overall survival was 81% and 70% at 5 and 10 years. Recurrence-free survival was 76% at 5 and 10 years. There was a trend toward greater recurrence-free survival for node-negative patients (88% vs 65% at 5 years, p = 0.13), and overall survival was greater for node-negative patients (100% vs 67% at 5 years, p = 0.04). Mean follow-up was 8.8 years. PD is an appropriate strategy for selected malignant islet cell tumors of the pancreas, which offers extended survival with a low recurrence rate and control of endocrine symptoms.     

Cadmium, mercury and lead in the blood of urban women in Croatia, the Czech Republic, Poland, Slovakia, Slovenia, Sweden, China, Ecuador and Morocco

Objectives

The aim of the study was to make an international comparison of blood levels of cadmium (B-Cd), lead (B-Pb) and mercury (B-Hg) of women in seven European, and three non-European cities, and to identify determinants.

Materials and Methods

About 50 women (age: 46–62) from each city were recruited (totally 480) in 2006–2009. Interview and questionnaire data were obtained. Blood samples were analysed in one laboratory to avoid interlaboratory variation.

Results

Between the European cities, the B-Pb and B-Cd results vary little (range of geometric means: 13.5–27.0 μg/l and 0.25–0.65 μg/l, respectively); the variation of B-Hg was larger (0.40–1.38 μg/l). Between the non-European cities the results for B-Pb, B-Cd and B-Hg were 19.2–68.0, 0.39–0.99 and 1.01–2.73 μg/l, respectively. Smoking was a statistically significant determinant for B-Cd, while fish and shellfish intakes contributed to B-Hg and B-Pb, amalgam fillings also contributed to B-Hg.

Conclusions

The present results confirm the previous results from children; the exposure to lead and cadmium varies only little between different European cities suggesting that other factors than the living area are more important. The study also confirms the previous findings of higher cadmium and lead levels in some non-European cities. The geographical variation for mercury is significant.