Activation of the kynurenine pathway and mitochondrial respiration to face allostatic load in a double-hit model of stress.

Allostasis is the process by which the body's physiological systems adapt to environmental changes. Chronic stress increases the allostatic load to the body, producing wear and tear that could, over time, become pathological. In this study, young adult male Wistar Kyoto rats were exposed to an unpredictable chronic mild stress (uCMS) protocol to increase allostatic load. First, physiological systems which may be affected by extended uCMS exposure were assessed. Secondly, 5 weeks of uCMS were used to investigate early adaptations in the previously selected systems. Adverse experiences during developmentally sensitive periods like adolescence are known to severely alter the individual stress vulnerability with long-lasting effects. To elucidate how early life adversity impacts stress reactivity in adulthood, an additional group with juvenile single-housing (JSH) prior to uCMS was included in the second cohort. The aim of this work was to assess the impact of chronic stress with or without adversity during adolescence on two domains known to be impacted in numerous stress-related disorders: mitochondrial energy metabolism and the immune system. Both, uCMS and adolescence stress increased kynurenine and kynurenic acid in plasma, suggesting a protective, anti-oxidant response from the kynurenine pathway. Furthermore, uCMS resulted in a down-regulation of immediate early gene expression in the prefrontal cortex and hippocampus, while only rats with the double-hit of adolescent stress and uCMS demonstrated increased mitochondrial activity in the hippocampus. These results suggest that early life adversity may impact on allostatic load by increasing energetic requirements in the brain.

Calcifying fibrous pseudotumor of pleura. A report of three cases of a newly described entity involving the pleura.

A newly recognized distinctive fibrous soft tissue lesion called "calcifying fibrous pseudotumor" (CFPT) was recently described in the soft tissues of the extremities, trunk, scrotum, groin, neck, or axilla. To date, CFPT has not been described in the pleura. The authors reviewed the clinical, radiologic, and pathologic features of three cases. A 23-year old woman and 34-year old man who presented with chest pain, and a 28-year old woman without chest symptoms were found to have a pleural mass on chest radiographs. Computed tomography (CT) scans of each patient revealed pleural-based nodular masses with central areas of increased attenuation due to calcifications. Each lesions consisted of circumscribed, but unencapsulated masses of hyalinized collagenous fibrotic tissue interspersed with lymphoplasmacytic infiltrates and calcifications, many of which had psammomatous features. The lesions were limited to the pleura and did not involve the underlying lung parenchyma. Electron microscopy in one case showed fibroblasts scattered in dense collagenous tissue. Calcifying fibrous pseudotumor is distinct from other pleural lesions such as fibrous tumor of pleura, calcified granulomas, calcified pleural plaques, and chronic fibrous pleuritis as well as intrapulmonary lesions such as hyalinizing granuloma, inflammatory pseudotumor, and amyloid. As in the soft tissues, local excision appears adequate therapy for CFPT of the pleura. If these lesions behave in a similar fashion to CFPT of soft tissues, one might expect a low frequency of local recurrence.

Improvement in hypoxemia at 4600 meters of simulated altitude with carbohydrate ingestion.

BACKGROUND: Carbohydrate ingestion increases the relative production of carbon dioxide which results in an increase in ventilation in normal individuals. An increase in ventilation at altitude can result in improvement of altitude-induced hypoxemia. HYPOTHESIS: Carbohydrate ingestion will increase the arterial blood oxygen tension and oxyhemoglobin saturation during acute high altitude simulation. METHODS: There were 15 healthy volunteers, aged 18-33 yr, who were given a 4 kcal x kg(-1) oral carbohydrate beverage administered 2.5 h into an exposure to 15,000 ft (4600 m) of simulated altitude (5.5 h after the last meal). Altitude was simulated by having subjects breath a 12% oxygen/balance nitrogen mixture while remaining at sea level. Arterial blood gas samples were drawn at baseline and at regular intervals up to 210 min after carbohydrate ingestion. Subjects were evaluated for AMS by use of the Environmental Symptoms Questionnaire (ESQ) and a weighted average of cerebral symptom score (AMS-C). RESULTS: Baseline PaO2 increased significantly (p < 0.01) from 43.0 +/- 3.0 mmHg at 4600 m before carbohydrate ingestion to 46.8 +/- 6.2 mmHg at 60 min after carbohydrate ingestion. Arterial oxygen saturation rose significantly (p < 0.01) from a baseline of 79.5% +/- 5.1 to 83.8% +/- 6.42 at 60 min. CONCLUSIONS: Carbohydrate consumption significantly increased oxygen tension and oxyhemoglobin saturation in arterial blood of normal subjects during simulated altitude. Effects reached statistical significance across all subjects at 60 min. There was no significant difference in arterial oxygen levels or arterial oxygen saturation in subjects who developed AMS vs. those who did not develop AMS.

Lung function during moderate hypobaric hypoxia in normal subjects and patients with chronic obstructive pulmonary disease.

BACKGROUND: We sought to describe changes in spirometric variables and lung volume subdivisions in healthy subjects and patients with chronic obstructive pulmonary disease (COPD) during moderate acute hypobaric hypoxia as occurs during air travel. We further questioned whether changes in lung function may associate with reduced maximum ventilation or worsened arterial blood gases. METHODS: Ambulatory patients with COPD and healthy adults comprised the study populations (n = 27). We obtained baseline measurements of spirometry, lung volumes and arterial blood gases from each subject at sea level and repeated measurements during altitude exposure to 8000 ft (2438 m) above sea level in a man-rated hypobaric chamber. RESULTS: Six COPD patients and three healthy subjects had declines in FVC during altitude exposure greater than the 95% confidence interval (CI) for expected within day variability (p < 0.05). Average forced vital capacity (FVC) declined by 0.123 +/- 0.254 L (mean +/- SD; 95% CI = -0.255, -0.020; p < 0.05) for all subjects combined. The magnitude of decline in FVC did not differ between groups (p > 0.05) and correlated with increasing residual volume (r = -0.455; <0.05). Change in maximum voluntary ventilation (MVV) in the COPD patients equaled -1.244 +/- 4.797 L x min(-1) (95% CI = -3.71, 1.22; p = 0.301). Decline in maximum voluntary ventilation (MVV) in the COPD patients correlated with decreased FVC (r = 0.630) and increased RV (r = -0.546; p < 0.05). Changes in spirometric variables for patients and controls did not explain significant variability in the arterial blood gas variables PaO2, PaCO2 or pH at altitude. CONCLUSIONS: We observed a decline in forced vital capacity in some COPD patients and normal subjects greater than expected for within day variability. Spirometric changes correlated with changes in reduced maximum voluntary ventilation in the patients but not with changes in resting arterial blood gases.

The impact of computerized provider order entry on medication errors in a multispecialty group practice.

OBJECTIVE: Computerized provider order entry (CPOE) has been shown to improve patient safety by reducing medication errors and subsequent adverse drug events (ADEs). Studies demonstrating these benefits have been conducted primarily in the inpatient setting, with fewer in the ambulatory setting. The objective was to evaluate the effect of a basic, ambulatory CPOE system on medication errors and associated ADEs. DESIGN: This quasiexperimental, pretest-post-test study was conducted in a community-based, multispecialty health system not affiliated with an academic medical center. The intervention was a basic CPOE system with limited clinical decision support capabilities. MEASUREMENT: Comparison of prescriptions written before (n=5016 handwritten) to after (n=5153 electronically prescribed) implementation of the CPOE system. The primary outcome was the occurrence of error(s); secondary outcomes were types and severity of errors. RESULTS: Frequency of errors declined from 18.2% to 8.2%-a reduction in adjusted odds of 70% (OR: 0.30; 95% CI 0.23 to 0.40). The largest reductions were seen in adjusted odds of errors of illegibility (97%), use of inappropriate abbreviations (94%) and missing information (85%). There was a 57% reduction in adjusted odds of errors that did not cause harm (potential ADEs) (OR 0.43; 95% CI 0.38 to 0.49). The reduction in the number of errors that caused harm (preventable ADEs) was not statistically significant, perhaps due to few errors in this category. CONCLUSIONS: A basic CPOE system in a community setting was associated with a significant reduction in medication errors of most types and severity levels.

The impact of an ambulatory CPOE system on medication errors.

Few studies have evaluated the impact of an ambulatory computerized physician order entry (CPOE) system on medication errors. We conducted a retrospective analysis of 10,172 prescriptions to evaluate the impact of a basic CPOE system on prescribing-related medication errors, and found a significant decrease in the occurrence of errors.

FiO2 and positive end-expiratory pressure as compensation for altitude-induced hypoxemia in an acute respiratory distress syndrome model: implications for air transportation of critically ill patients.

OBJECTIVES: To determine whether increases in FiO2 or positive end-expiratory pressure will compensate for hypoxemia resulting from exposure to 8000 feet (2440 m) of altitude in a model of acute respiratory distress syndrome. DESIGN: Intervention and crossover design. SETTING: Military research altitude chamber. SUBJECTS: Sixteen Yucatan miniature swine (Sus scrofa). INTERVENTIONS: Swine initially were placed on mechanical ventilation (zero positive end-expiratory pressure, 21% FiO2). Twelve animals had moderate to severe acute respiratory distress syndrome (50% to 70% FiO2 at sea level to maintain PaO2 of 50-70 torr [6.65-9.31kPa]) induced by intravenous oleic acid. Four animals were controls (no lung injury). The animals were taken to 8000 feet (2440 m) in an altitude chamber, and then stepwise increases of either 5% FiO2 (six animals) or 2.5 cm H2O positive end-expiratory pressure (six animals) were made until PaO2 values exceeded 75 torr (10.0 kPa). If PaO2 did not reach 75 torr (10.0 kPa), and time permitted, the animal was crossed over to the other group. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were drawn at baseline (sea level and at altitude) and after every change in ventilator settings. Positive end-expiratory pressure increases from 5 to 12.5 cm H2O were required to bring the PaO2 in the injured pigs to 75 torr (10.0 kPa). FiO2 increases did not achieve a PaO2 of 75 torr (10.0 kPa) for three of six animals despite reaching 100% FiO2. One animal crossed over from Fio2 to positive end-expiratory pressure and achieved a PaO2 of 75 torr (10.0 kPa) with 5 cm H2O of positive end-expiratory pressure. CONCLUSIONS: Fifty percent of the animals with lung injury had altitude-induced hypoxia that was resistant to increases in FiO2. Increases in positive end-expiratory pressure are more reliable than increases in FiO2 for correcting altitude-induced hypoxia in this model of acute respiratory distress syndrome.