Predictable hydrological and ecological responses to Holocene North Atlantic variability.

Climate variations in the North Atlantic region can substantially impact surrounding continents. Notably, the Younger Dryas chronozone was named for the ecosystem effects of abrupt changes in the region at circa (ca.) 12.9-11.7 ka (millennia before 1950 AD). Holocene variations since then, however, have been hard to diagnose, and the responsiveness of terrestrial ecosystems continues to be debated. Here, we show that Holocene climate variations had spatial patterns consistent with changes in Atlantic overturning and repeatedly steepened the temperature gradient between Nova Scotia and Greenland since >8 ka. The multicentury changes correlated with hydrologic and vegetation changes in the northeast United States, including when an enhanced temperature gradient coincided with subregional droughts indicated by water-level changes at multiple coastal lakes at 4.9-4.6, 4.2-3.9, 2.8-2.1, and 1.3-1.2 ka. We assessed the variability and its effects by replicating signals across sites, using converging evidence from multiple methods, and applying forward models of the systems involved. We evaluated forest responses in the northeast United States and found that they tracked the regional climate shifts including the smallest magnitude (∼5% or 50 mm) changes in effective precipitation. Although a long-term increase in effective precipitation of >45% (>400 mm) could have prevented ecological communities from equilibrating to the continuously changing conditions, our comparisons confirm stable vegetation-climate relationships and support the use of fossil pollen records for quantitative paleoclimate reconstruction. Overall, the network of records indicates that centennial climate variability has repeatedly affected the North Atlantic region with predictable consequences.

Opioid prescribing and health outcomes in opioid-naive patients: Analysis of a statewide health information exchange.

BACKGROUND: Widespread use of prescription opioids is associated with adverse outcomes. OBJECTIVE: To identify factors associated with adverse health outcomes and health care use using a statewide health information exchange. METHODS: This is a retrospective cohort study using the Indiana Network for Patient Care. Adult opioid-naive patients who received an opioid prescription between January 2012 and December 2017 were included. The outcomes included (1) a composite outcome of any combination of opioid abuse, dependence, or overdose, (2) all-cause mortality, and (3) health care use. Independent variables included opioid dosage, dispensed amount, days supply, concurrent use of short-acting (SA) and long-acting (LA) opioids, and concurrent use with benzodiazepine or gabapentinoids. Additional variables included patients' age, sex, race, modified Charlson Comorbidity Index score, mental health conditions, and medications for opioid use disorders. Factors associated with composite outcome and mortality were identified using Cox proportional hazards and reported as adjusted hazard ratio (aHR) and 95% CI. Factors associated with health care use were identified using Poisson regression and reported as adjusted incidence rate ratio (aIRR) and 95% CI. RESULTS: 1,328,287 opioid prescriptions were identified for 341,722 patients. Opioid-related factors associated with the composite outcome, mortality, and hospitalizations, respectively, included opioid dosage (aHR 1.003 [95% CI 1.001-1.006]; aHR not applicable; aIRR 1.07 [1.06-1.08]), opioid days supply (aHR 1.03 [1.02-1.03]; aHR 1.009 [1.005-1.014]; aIRR 0.94 [0.92-0.96]), concurrent SA/LA opioids (aHR 2.12 [1.78-2.54]; aHR 1.40 [1.14-1.70]; aIRR 1.40 [1.37-1.42]), and use of benzodiazepines/gabapentinoids (aHR 1.68 [1.38-2.04]; aHR 1.23 [1.01-1.51]; aIRR 1.25 [1.23-1.27]). CONCLUSION: Many factors are associated with poor health outcomes, especially concurrent use of SA and LA opioids and overlapping prescriptions of opioids with benzodiazepines or gabapentinoids. Identification of factors associated with adverse outcomes may help identify patients at risk for poor outcomes and could inform possible interventions.

Widespread sampling biases in herbaria revealed from large-scale digitization.

Nonrandom collecting practices may bias conclusions drawn from analyses of herbarium records. Recent efforts to fully digitize and mobilize regional floras online offer a timely opportunity to assess commonalities and differences in herbarium sampling biases. We determined spatial, temporal, trait, phylogenetic, and collector biases in c. 5 million herbarium records, representing three of the most complete digitized floras of the world: Australia (AU), South Africa (SA), and New England, USA (NE). We identified numerous shared and unique biases among these regions. Shared biases included specimens collected close to roads and herbaria; specimens collected more frequently during biological spring and summer; specimens of threatened species collected less frequently; and specimens of close relatives collected in similar numbers. Regional differences included overrepresentation of graminoids in SA and AU and of annuals in AU; and peak collection during the 1910s in NE, 1980s in SA, and 1990s in AU. Finally, in all regions, a disproportionately large percentage of specimens were collected by very few individuals. We hypothesize that these mega-collectors, with their associated preferences and idiosyncrasies, shaped patterns of collection bias via 'founder effects'. Studies using herbarium collections should account for sampling biases, and future collecting efforts should avoid compounding these biases to the extent possible.

Long-term structural and biomass dynamics of virgin Tsuga canadensis-Pinus strobus forests after hurricane disturbance.

The development of old-growth forests in northeastern North America has largely been within the context of gap-scale disturbances given the rarity of stand-replacing disturbances. Using the 10-ha old-growth Harvard Tract and its associated 90-year history of measurements, including detailed surveys in 1989 and 2009, we document the long-term structural and biomass development of an old-growth Tsuga canadensis-Pinus strobus forest in southern New Hampshire, USA following a stand-replacing hurricane in 1938. Measurements of aboveground biomass pools were integrated with data from second- and old-growth T. canadensis forests to evaluate long-term patterns in biomass development following this disturbance. Ecosystem structure across the Tract prior to the hurricane exhibited a high degree of spatial heterogeneity with the greatest levels of live tree basal area (70-129 m2 /ha) on upper west-facing slopes where P. strobus was dominant and intermixed with T. canadensis. Live-tree biomass estimates for these stratified mixtures ranged from 159 to 503 Mg/ha at the localized, plot scale (100 m2 ) and averaged 367 Mg/ha across these portions of the landscape approaching the upper bounds for eastern forests. Live-tree biomass 71 years after the hurricane is more uniform and lower in magnitude, with T. canadensis currently the dominant overstory tree species throughout much of the landscape. Despite only one living P. strobus stem in the 2009 plots (and fewer than five stems known across the entire 10-ha area), the detrital legacy of this species is pronounced with localized accumulations of coarse woody debris exceeding 237.7-404.2 m3 /ha where this species once dominated the canopy. These patterns underscore the great sizes P. strobus attained in pre-European landscapes and its great decay resistance relative to its forest associates. Total aboveground biomass pools in this 71-year-old forest (255 Mg/ha) are comparable to those in modern old-growth ecosystems in the region that also lack abundant white pine. Results highlight the importance of disturbance legacies in affecting forest structural conditions over extended periods following stand-replacing events and underscore that post-disturbance salvage logging can alter ecosystem development for decades. Moreover, the dominant role of old-growth P. strobus in live and detrital biomass pools before and after the hurricane, respectively, demonstrate the disproportionate influence this species likely had on carbon storage at localized scales prior to the widespread, selective harvesting of large P. strobus across the region in the 18th and 19th centuries.

Nonnative forest insects and pathogens in the United States: Impacts and policy options.

We review and synthesize information on invasions of nonnative forest insects and diseases in the United States, including their ecological and economic impacts, pathways of arrival, distribution within the United States, and policy options for reducing future invasions. Nonnative insects have accumulated in United States forests at a rate of ~2.5 per yr over the last 150 yr. Currently the two major pathways of introduction are importation of live plants and wood packing material such as pallets and crates. Introduced insects and diseases occur in forests and cities throughout the United States, and the problem is particularly severe in the Northeast and Upper Midwest. Nonnative forest pests are the only disturbance agent that has effectively eliminated entire tree species or genera from United States forests within decades. The resulting shift in forest structure and species composition alters ecosystem functions such as productivity, nutrient cycling, and wildlife habitat. In urban and suburban areas, loss of trees from streets, yards, and parks affects aesthetics, property values, shading, stormwater runoff, and human health. The economic damage from nonnative pests is not yet fully known, but is likely in the billions of dollars per year, with the majority of this economic burden borne by municipalities and residential property owners. Current policies for preventing introductions are having positive effects but are insufficient to reduce the influx of pests in the face of burgeoning global trade. Options are available to strengthen the defenses against pest arrival and establishment, including measures taken in the exporting country prior to shipment, measures to ensure clean shipments of plants and wood products, inspections at ports of entry, and post-entry measures such as quarantines, surveillance, and eradication programs. Improved data collection procedures for inspections, greater data accessibility, and better reporting would support better evaluation of policy effectiveness. Lack of additional action places the nation, local municipalities, and property owners at high risk of further damaging and costly invasions. Adopting stronger policies to reduce establishments of new forest insects and diseases would shift the major costs of control to the source and alleviate the economic burden now borne by homeowners and municipalities.

A postglacial paleoenvironmental dataset from New England.

This paleoenvironmental database features postglacial lake-sediment records from 31 study sites located across New England. The study sites span an environmental gradient from the cooler, northern and inland part of the region to the warmer, southern and coastal areas of New England. Sediment-core chronologies were determined using 14C dating, 210Pb analysis, and pollen evidence. Detailed analyses of sediment lithology, pollen, and charcoal were used to reconstruct changes in climate, vegetation, and fire at centennial temporal scales and subregional spatial scales for the last 14,000 years. Analyses of paleoenvironmental data provide insights into the rates, patterns, and drivers of ecosystem change, helping us anticipate future ecosystem dynamics and guiding present-day conservation strategies and land management.

Development of a pharmacist-managed protocol for the transition from intravenous to subcutaneous insulin in critically ill adults.

PURPOSE: To evaluate the efficacy and safety of a pharmacist-managed protocol for transitioning critically ill patients from intravenous (IV) to subcutaneous insulin. METHODS: This single-center, retrospective, observational study included patients admitted to the medical or surgical/trauma intensive care unit who received a continuous infusion of IV insulin from January 2019 to April 2021. Patients were excluded if they were less than 18 years old, pregnant, or incarcerated or received IV insulin for the diagnosis of diabetic ketoacidosis, hyperglycemic hyperosmolar state, calcium channel blocker or ß-blocker overdose, or hypertriglyceridemia. The primary outcome was to evaluate the percentage of blood glucose (BG) concentrations within the target range of 70 to 150 mg/dL within 48 hours of the transition to subcutaneous insulin. Secondary outcomes included the percentage of BG concentrations within the goal range following transition at 0 to 12 hours and 12 to 24 hours, the incidence of hypo- and hyperglycemia, and the percentage of patients requiring dose adjustments after the initial transition. RESULTS: Pharmacists were able to achieve BG concentrations in the target range for 53% of transitions at 12 hours, 40% of transitions at 24 hours, and 47% of transitions at 48 hours. With respect to safety endpoints, the pharmacist-managed group had a low rate of hypoglycemia (1.0%) and no severe hypoglycemia. Hyperglycemia was reported for 28% of BG concentrations while severe hyperglycemia was reported for 27%. Pharmacists transitioned patients to an average of 63% of the 24-hour total daily dose of insulin as basal insulin. CONCLUSION: Pharmacists can effectively and safely transition critically ill patients from IV to subcutaneous insulin utilizing a standardized protocol.

The influence of land use and climate change on forest biomass and composition in Massachusetts, USA.

Land use and climate change have complex and interacting effects on naturally dynamic forest landscapes. To anticipate and adapt to these changes, it is necessary to understand their individual and aggregate impacts on forest growth and composition. We conducted a simulation experiment to evaluate regional forest change in Massachusetts, USA over the next 50 years (2010-2060). Our objective was to estimate, assuming a linear continuation of recent trends, the relative and interactive influence of continued growth and succession, climate change, forest conversion to developed uses, and timber harvest on live aboveground biomass (AGB) and tree species composition. We examined 20 years of land use records in relation to social and biophysical explanatory variables and used regression trees to create "probability-of-conversion" and "probability-of-harvest" zones. We incorporated this information into a spatially interactive forest landscape simulator to examine forest dynamics as they were affected by land use and climate change. We conducted simulations in a full-factorial design and found that continued forest growth and succession had the largest effect on AGB, increasing stores from 181.83 Tg to 309.56 Tg over 50 years. The increase varied from 49% to 112% depending on the ecoregion within the state. Compared to simulations with no climate or land use, forest conversion reduced gains in AGB by 23.18 Tg (or 18%) over 50 years. Timber harvests reduced gains in AGB by 5.23 Tg (4%). Climate change (temperature and precipitation) increased gains in AGB by 17.3 Tg (13.5%). Pinus strobus and Acer rubrum were ranked first and second, respectively, in terms of total AGB throughout all simulations. Climate change reinforced the dominance of those two species. Timber harvest reduced Quercus rubra from 10.8% to 9.4% of total AGB, but otherwise had little effect on composition. Forest conversion was generally indiscriminate in terms of species removal. Under the naive assumption that future land use patterns will resemble the recent past, we conclude that continued forest growth and recovery will be the dominant mechanism driving forest dynamics over the next 50 years, and that while climate change may enhance growth rates, this will be more than offset by land use, primarily forest conversion to developed uses.

Drug-induced acute liver failure and gastrointestinal complications.

The objective of this article is to describe adverse drug events related to the liver and gastrointestinal tract in critically ill patients. PubMed and other resources were used to identify information related to drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis in critically ill patients. This information was reviewed, and data regarding pathophysiology, common drug causes, and guidelines for prevention and management were collected and summarized. In cases in which data in critically ill patients were unavailable, data were extrapolated from other patient populations. Drug-induced acute liver failure can be caused by many drugs routinely used in the intensive care unit and may be associated with significant morbidity and mortality. Drug-related hypomotility and constipation and drug-related diarrhea are reported with many drugs, and these are common adverse drug events in critically ill patients that can substantially complicate the care of these patients. Drug-induced gastrointestinal bleeding and drug-induced pancreatitis occur less frequently, can range in disease severity, and can be associated with morbidity and mortality. Many drugs used in critically ill patients are associated with adverse drug events related to the liver and gastrointestinal tract. Critical care clinicians should be aware of common drug causes of drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis, and should be familiar with the prevention and management of these diverse conditions.

A prospective analysis describing the innovative use of liposomal bupivacaine in burn patients.

Burn patients frequently require autograft harvesting to facilitate wound healing, often resulting in significant pain. Liposomal bupivacaine is indicated for administration into a surgical site to produce postsurgical analgesia. The objective of this study was to evaluate efficacy, safety, and duration of postoperative analgesia with liposomal bupivacaine for donor site pain in burn patients. This was an observational, case-control study including adult patients with <20% total body surface area (TBSA) burned who received liposomal bupivacaine for postoperative pain management after autograft harvesting from lower extremity donor site(s). Patients from the case group were matched to historical control patients treated with traditional pain management. The primary outcome was the cumulative pain scores on postoperative day one measured by the area under the curve (AUC0-24). Secondary outcomes included AUC0-72, total milligram morphine equivalents (MME), length of stay, and adverse events. Data were collected in 36 patients who received liposomal bupivacaine, with 21 patients eligible for matching to historical controls. Patients included in the intervention and control groups were well-matched at baseline. Patients in the intervention group had a significantly lower median (IQR) AUC0-24 [578 (408,740) vs. 680 (544,803); p = 0.05] and shorter length of stay [4 days (1,9.5) vs. 6 days (318); p = 0.01]. No differences in adverse events related to the administration of liposomal bupivacaine or opioid-related adverse events were observed. Results indicate liposomal bupivacaine is safe and effective in burn patients. The results of this study add to the limited body of literature examining efficacy in this population.

A Multicenter Evaluation of Outcomes Following the Use of Nebulized Heparin for Inhalation Injury (HIHI2 Study).

Inhalation injury causes significant morbidity and mortality secondary to compromise of the respiratory system as well as systemic effects limiting perfusion and oxygenation. Nebulized heparin reduces fibrin cast formation and duration of mechanical ventilation in patients with inhalation injury. To date, no study has compared both dosing strategies of 5000 and 10,000 units to a matched control group. This multicenter, retrospective, case-control study included adult patients with bronchoscopy-confirmed inhalation injury. Each control patient, matched according to age and percent of total body surface area, was matched to a patient who received 5000 units and a patient who received 10,000 units of nebulized heparin. The primary endpoint of the study was duration of mechanical ventilation. Secondary endpoints included 28-day mortality, ventilator-free days in the first 28 days, difference in lung injury scores, length of hospitalization, incidence of ventilator-associated pneumonia, and rate of major bleeding. Thirty-five matched patient trios met inclusion criteria. Groups were well-matched for age (P = .975) and total body surface area (P = .855). Patients who received nebulized heparin, either 5000 or 10,000 units, had 8 to 11 less days on the ventilator compared to controls (P = .001). Mortality ranged from 3 to 14% overall and was not statistically significant between groups. No major bleeding events related to nebulized heparin were reported. Mechanical ventilation days were significantly decreased in patients who received 5000 or 10,000 units of nebulized heparin. Nebulized heparin, either 5000 units or 10,000 units, is a safe and effective treatment for inhalation injury.

Lack of interaction between the peptidomimetic substrates captopril and cephradine.

Intestinal peptide transporters, including hPEPT1, facilitate the absorption of cephalosporins and angiotensin-converting enzyme inhibitors, and have been investigated as a means to improve oral drug absorption. Renal peptide transporters including hPEPT2, may also facilitate renal reabsorption of such compounds. In vitro and animal studies suggest that co-administration of peptidomimetic compounds may alter oral pharmacokinetics, although this has not been well studied in humans. The purpose of this study was to determine whether co-administration of the hPEPT substrates captopril and cephradine alters the oral pharmacokinetics of either agent. Nine healthy male volunteers received a single oral 25-mg dose of captopril, a single oral 500-mg dose of cephradine, or concurrent ingestion of captopril and cephradine in a cross-over manner. Venous blood samples were taken and captopril and cephradine pharmacokinetics were determined using noncompartmental analyses. No significant differences were observed in captopril or cephradine pharmacokinetics when administered together as compared to each agent alone (a marginal decrease in C(max) was observed for both captopril and cephradine during co-administration [5-15%]; however, differences were not statistically significant). The results of our study suggest that hPEPT1 and hPEPT2 are unlikely to contribute to clinically important drug interactions in humans.

Intestinal dipeptide absorption is preserved during thermal injury and cytokine treatment.

BACKGROUND: Intestinal barrier function is impaired during thermal injury; however, the effects of thermal injury on the absorption of dietary peptides are not well characterized. The purpose of this study was to determine the impact of thermal injury on dipeptide absorption in rats and to describe the influence of inflammatory cytokines on the expression of the oligopeptide transporter PEPT1 and dipeptide permeability in cultured intestinal cells (Caco-2 cells). METHODS: Sprague Dawley rats were assigned to 30% body surface area burn (n = 7) or sham (n = 8) groups. Twenty-four hours following burn/sham, the proximal jejunum was cannulated. The jejunal segment was perfused with buffer containing the dipeptide glycylsarcosine (Gly-Sar), and intestinal permeability (P(eff)) was calculated. For in vitro experiments, Caco-2 cells were grown on permeable supports and treated with tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 (10 ng/mL) alone and in combination for 48 hours. The effective apical-to-basolateral permeabilities (P(eff)) of Gly-Sar were measured, and PEPT1 expression was determined using reverse transcription-polymerase chain reaction. RESULTS: Gly-Sar P(eff) was similar in burn and sham rats (6.67 +/- 2.27 x 10(-5) vs 7.58 +/- 2.20 x 10(-5) cm/s, respectively, P = .45). In Caco-2 cells, cytokine treatment did not alter PEPT1 expression (P = .954) or the P(eff) of Gly-Sar (P = .806). CONCLUSIONS: Intestinal absorption of the dipeptide Gly-Sar is preserved 24 hours following thermal injury in rats. Likewise, PEPT1 expression and peptide absorption are preserved following treatment with TNF-alpha, IL-6, and IL-10 in Caco-2 monolayers. These findings imply that intestinal dipeptide absorption may be preserved during burn injury. This may lead to new strategies to optimize enteral protein delivery in burn patients.

The influence of successional processes and disturbance on the structure of Tsuga canadensis forests.

Old-growth forests are valuable sources of ecological, conservation, and management information, yet these ecosystems have received little study in New England, due in large part to their regional scarcity. To increase our understanding of the structures and processes common in these rare forests, we studied the abundance of downed coarse woody debris (CWD) and snags and live-tree size-class distributions in 16 old-growth hemlock forests in western Massachusetts. Old-growth stands were compared with eight adjacent second-growth hemlock forests to gain a better understanding of the structural differences between these two classes of forests resulting from contrasting histories. In addition, we used stand-level dendroecological reconstructions to investigate the linkages between disturbance history and old-growth forest structure using an information-theoretic model selection framework. Old-growth stands exhibit a much higher degree of structural complexity than second-growth forests. In particular, old-growth stands had larger overstory trees and greater volumes of downed coarse woody debris (135.2 vs. 33.2 m3/ha) and snags (21.2 vs. 10.7 m3/ha). Second-growth stands were characterized by either skewed unimodal or reverse-J shaped diameter distributions, while old-growth forests contained bell-shaped, skewed unimodal, rotated sigmoid, and reverse J-shaped distributions. The variation in structural attributes among old-growth stands, particularly the abundance of downed CWD, was closely related to disturbance history. In particular, old-growth stands experiencing moderate levels of canopy disturbance during the last century (1930s and 1980s) had greater accumulations of CWD, highlighting the importance of gap-scale disturbances in shaping the long-term development and structural characteristics of old-growth forests. These findings are important for the development of natural disturbance-based silvicultural systems that may be used to restore important forest characteristics lacking in New England second-growth stands by integrating structural legacies of disturbance (e.g., downed CWD) and resultant tree-size distribution patterns. This silvicultural approach would emulate the often episodic nature of CWD recruitment within old-growth forests.

Role of xenobiotic efflux transporters in resistance to vincristine.

This study characterized interactions between efflux transporters (P-glycoprotein (MDR1) and multidrug resistance associated proteins (MRPs1-3)) and vincristine (VCR), using cell lines with differential transporter expression, and studied effects of P-glycoprotein inhibition on VCR transport and toxicity. Caco2 (express MDR1, MRPs 1-3), LS174T (express MDR1, MRPs 1, 3), and A549 (express MRPs 1-3) cells were used. To study VCR transport (effective permeability, P(eff)), VCR (1-500 nM) was added to the donor chambers of permeable supports containing Caco2 monolayers, and receiving chamber concentrations were measured. Cytotoxicity experiments were conducted with escalating concentrations of VCR in all cell lines. To determine the contribution of MDR1, experiments were also conducted with LY335979, a specific MDR1 inhibitor. VCR P(eff) was 2 x 10(-6)cm/s in Caco2 cells. LY335979 increased P(eff) in a dose dependent manner (up to 7-fold with 1 microM LY335979) in Caco2 cells. Caco2 and LS174T cell viability decreased significantly when co-incubated with both VCR and LY335979 (1 microM) (P<0.05), however this was not observed in A549 cells. In summary, MDR1 plays an important role in VCR efflux; MDR1 inhibition increased VCR P(eff) in Caco2 cells, and increased VCR cytotoxicity in Caco2 and LS174T cells (both express MDR1), but not A549 cells (minimal MDR1 expression). Inhibition of MDR1 may be a viable strategy to overcome VCR resistance in tumors expressing MDR1, however the presence of other efflux transporters should also be considered, as this will influence the success of such strategies.

Cephalexin inhibits N-formylated peptide transport and intestinal hyperpermeability in Caco2 cells.

PURPOSE: Intestinal barrier integrity is diminished in critical illness and inflammatory bowel disease. Bacterial-derived N-formylated peptides, absorbed by the intestinal oligopeptide transporter, hPEPT1, are involved in the pathogenesis of disease-induced intestinal barrier dysfunction, via stimulation of polymorphonuclear leukocyte (PMN) migration. The purpose of this study was to determine if the hPEPT1 substrate, cephalexin, inhibits the absorption of the N-formylated peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine ("fMLP"), thereby preventing hyperpermeability in Caco2 cells. METHODS: Caco2 monolayers were grown on permeable supports. fMLP (0.1 microM) was added to apical chambers with and without cephalexin (5 and 10 mM), and fMLP effective permeability was calculated. To determine the ability of cephalexin to attenuate intestinal dysfunction, Caco2 cells were co-cultured with human PMN's in the presence of fMLP, cephalexin, and inflammatory cytokines. Monolayer integrity was assessed by measuring mannitol permeability. RESULTS: Cephalexin 10 mM significantly reduced fMLP permeability (p=0.007). Monolayer integrity (as indicated mannitol permeability) was decreased in cultures treated with inflammatory cytokines and fMLP, an effect that was attenuated by cephalexin (p<0.01). CONCLUSION: Cephalexin inhibits fMLP transport across cultured intestinal monolayers, and partially attenuates PMN-induced intestinal hyperpermeability. The use of pharmacologic hPEPT1 substrates may represent a novel means of preserving intestinal barrier integrity.

Outcomes Following the Use of Nebulized Heparin for Inhalation Injury (HIHI Study).

Inhalation injury (IHI) causes significant morbidity and mortality in burn victims due to both local and systemic effects. Nebulized heparin promotes improvement in lung function and decreased mortality in IHI by reducing the inflammatory response and fibrin cast formation. The study objective was to determine if nebulized heparin 10,000 units improves lung function and decreases mechanical ventilation duration, mortality, and hospitalization length in IHI with minimal systemic adverse events. This retrospective, case-control study evaluated efficacy and safety of nebulized heparin administered to mechanically ventilated adults admitted within 48 hr of confirmed IHI. Nebulized heparin 10,000 units was administered Q4H for 7 days, or until extubation if sooner, alternating with albuterol and a mucolytic. Patients were matched on a case-by-case basis based on percent TBSA burn and age to patients from a historical group with IHI before heparin protocol implementation. The primary outcome was duration of mechanical ventilation. Secondary outcomes included lung injury score, ventilator-free days during the first 28 days, 28-day mortality, hospitalization length, ventilator-associated pneumonia incidence, bronchoscopy incidence, and bleeding events. Data were collected in 72 patients, 36 of which received nebulized heparin and 36 historical controls. Two patients from the heparin group and three patients from the control group died/were discharged while on the ventilator. Data were analyzed separately with 1) all subjects included and 2) with subjects who died/were discharged on the ventilator excluded. In the latter comparison, patients receiving nebulized heparin demonstrated a statistically significant decrease in median (interquartile range) duration of initial mechanical ventilation compared with controls [7.0 (4.0, 13.5) vs. 14.5 (5.3, 22.3) days; P = .044]. Patients in the heparin group had a significantly increased number of median (interquartile range) ventilator-free days in the first 28 days [21.0 (14.5-24.0) vs 13.5 (4.3-22.8) days; P = .031]. There were no differences in hospitalization length, lung injury score during the first 7 days post injury, 28-day mortality, ventilator-associated pneumonia rate, or bleeding events. Nebulized heparin 10,000 units in conjunction with a beta-agonist and mucolytic produced a significant decrease in duration of mechanical ventilation and increase in ventilator-free days in adult patients with IHI. Nebulized heparin was safe and did not result in an increase in bleeding events. To our knowledge, this is the first case-control study with matched cohorts based on age and %TBSA which are significant factors contributing to morbidity and mortality in IHI.

Vincristine transcriptional regulation of efflux drug transporters in carcinoma cell lines.

The increased expression of drug transporters following cancer chemotherapy contributes to resistance. This may reflect transcriptional up-regulation and/or clonal selection. We quantified the expression of mRNA for ABCB1 (mdr1), ABCC1 (mrp1), ABCC2 (mrp2) and ABCC3 (mrp3) to evaluate the potential contribution of induction. ABCB1, ABCC1-3 mRNAs were quantified by real time RT-PCR and normalized to GAPDH. We used intestinal cells that express high pregnane X receptor (LS174T), low pregnane X receptor (Caco-2) and lung cells (A549) that express glucocorticoid receptor and low pregnane X receptor. Rifampin (10 microM) caused significant induction of ABCB1 (595+/-263%, p<0.05) in LS174T cells but induction was absent in Caco-2 or A549 cells. ABCC1 was not induced in any cell at 24, 48 and 72 h following rifampin treatment. In contrast, vincristine (10 nM and 100 nM), a ligand for ABCB1 and ABCC1-3 and a potential PXR/CAR ligand, induced ABCC2 and ABCC3 expression in LS174T cells at 48 h (372+/-87% and 303+/-42%, respectively, p<0.05). A similar induction of ABCC2 and ABCC3 genes was also seen with 10 nM VCR in A549 cells following 48 h treatment. In summary, there may be a significant contribution of transcriptional activation to multi-drug resistance. However, this is cell selective and is not necessarily dependent on PXR mediated effects.

A climatic driver for abrupt mid-Holocene vegetation dynamics and the hemlock decline in New England.

The mid-Holocene decline of eastern hemlock is widely viewed as the sole prehistorical example of an insect- or pathogen-mediated collapse of a North American tree species and has been extensively studied for insights into pest-host dynamics and the consequences to terrestrial and aquatic ecosystems of dominant-species removal. We report paleoecological evidence implicating climate as a major driver of this episode. Data drawn from sites across a gradient in hemlock abundance from dominant to absent demonstrate: a synchronous, dramatic decline in a contrasting taxon (oak); changes in lake sediments and aquatic taxa indicating low water levels; and one or more intervals of intense drought at regional to continental scales. These results, which accord well with emerging climate reconstructions, challenge the interpretation of a biotically driven hemlock decline and highlight the potential for climate change to generate major, abrupt dynamics in forest ecosystems.