Augmenting Autophagy to Treat Acute Kidney Injury during Endotoxemia in Mice

Objective

To determine that 1) an age-dependent loss of inducible autophagy underlies the failure to recover from AKI in older, adult animals during endotoxemia, and 2) pharmacologic induction of autophagy, even after established endotoxemia, is of therapeutic utility in facilitating renal recovery in aged mice.

Design

Murine model of endotoxemia and cecal ligation and puncture (CLP) induced acute kidney injury (AKI).

Setting

Academic research laboratory.

Subjects

C57Bl/6 mice of 8 (young) and 45 (adult) weeks of age.

Intervention

Lipopolysaccharide (1.5 mg/kg), Temsirolimus (5 mg/kg), AICAR (100 mg/kg). Measurements and Main Results: Herein we report that diminished autophagy underlies the failure to recover renal function in older adult mice utilizing a murine model of LPS-induced AKI. The administration of the mTOR inhibitor temsirolimus, even after established endotoxemia, induced autophagy and protected against the development of AKI.

Conclusions

These novel results demonstrate a role for autophagy in the context of LPS-induced AKI and support further investigation into like interventions that have potential to alter the natural history of disease.     

Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy

Background

Acute HIV infection (AHI) is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions.

Methods

Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24.

Results

Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days). Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment.

Discussion

The results emphasize the difficulty in recruiting subjects early in AHI. Viral sequence diversity proved accurate in estimating time of infection. Regardless of aggressive screening, peak viremia and inflammation occurred before enrollment and potential intervention. Given the personal and public health importance, improved AHI detection is urgently needed.     

Oldest Evidence of Toolmaking Hominins in a Grassland-Dominated Ecosystem

Background

Major biological and cultural innovations in late Pliocene hominin evolution are frequently linked to the spread or fluctuating presence of C₄ grass in African ecosystems. Whereas the deep sea record of global climatic change provides indirect evidence for an increase in C₄ vegetation with a shift towards a cooler, drier and more variable global climatic regime beginning approximately 3 million years ago (Ma), evidence for grassland-dominated ecosystems in continental Africa and hominin activities within such ecosystems have been lacking.

Methodology/Principal Findings

We report stable isotopic analyses of pedogenic carbonates and ungulate enamel, as well as faunal data from ∼2.0 Ma archeological occurrences at Kanjera South, Kenya. These document repeated hominin activities within a grassland-dominated ecosystem.

Conclusions/Significance

These data demonstrate what hitherto had been speculated based on indirect evidence: that grassland-dominated ecosystems did in fact exist during the Plio-Pleistocene, and that early Homo was active in open settings. Comparison with other Oldowan occurrences indicates that by 2.0 Ma hominins, almost certainly of the genus Homo, used a broad spectrum of habitats in East Africa, from open grassland to riparian forest. This strongly contrasts with the habitat usage of Australopithecus, and may signal an important shift in hominin landscape usage.     

Treatment of Severe Community-Acquired Pneumonia with Oral Amoxicillin in Under-Five Children in Developing Country: A Systematic Review

Objective

To assess the evidence regarding efficacy of oral amoxicillin compared to standard treatment for WHO-defined severe community acquired pneumonia in under-five children in developing country.

Design

Systematic review and meta-analysis of data from published Randomized trials (RCTs).

Data sources

MEDLINE (1970– July 2012) via PubMed, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 7, July 2012), and EMBASE (1988– June 2012).

Methods

Eligible trials compared oral amoxicillin administered in ambulatory setting versus standard treatment for WHO-defined severe community acquired pneumonia in children under-five. Primary outcomes were proportion of children developing treatment failure at 48 hr, and day 6. GRADE criteria was used to rate the quality of evidence.

Results

Out of 281 full text articles assessed for eligibility, 5 trials including 12364 children were included in the meta-analysis. Oral amoxicillin administered either in hospital or community setting is effective in treatment of severe pneumonia and is not inferior to the standard treatment. None of the clinical predictors of treatment failure by 48 hr (very severe disease, fever and lower chest indrawing, and voluntary with-drawl and loss to follow up) was significant between the two groups. The clinical predictors of treatment failure that were significant by day 6 were very severe disease, inability to drink, change of antibiotic, and fever alone. The effect was almost consistent across the studies.

Conclusion

Though oral amoxicillin is effective in treatment of severe CAP in under-five children in developing country, the evidence generated is of low-quality. More trials with uniform comparators are needed in order to strengthen the evidence.     

Soil seed bank recovery occurs more rapidly than expected in semi-arid Mediterranean gypsum vegetation

Background and Aims

Seed banks are critical in arid ecosystems and ensure the persistence of species. Despite the importance of seed banks, knowledge about their formation and the extent to which a seed bank can recover after severe perturbation remains scarce. If undisturbed, soil seed banks reflect a long vegetation history; therefore, we would expect that new soil seed banks and those of undisturbed soils require long periods to become similar with respect to both density and composition. In contrast, if soil seed banks are only a short- to mid-term reservoir in which long-term accumulation constitutes only a tiny fraction, they will recover rapidly from the vegetation. To shed light on this question, we evaluated seed bank formation in a semi-arid gypsum community.

Methods

Soils from 300 plots were replaced with sterilized soil in an undisturbed semi-arid Mediterranean community. Seasonal changes in seed bank density and composition were monitored for 3 years by comparing paired sterilized and control soil samples at each plot.

Key Results

Differences in seed bank density between sterilized and control soil disappeared after 18 months. The composition of sterilized seed banks was correlated with that of the control plots from the first sampling date, and both were highly correlated with vegetation. Nearly 24 % of the seed bank density could be attributed to secondary dispersal. Most seeds died before emergence (66·41–71·33 %), whereas the rest either emerged (14·08–15·48 %) or persisted in the soil (14·59–18·11 %).

Conclusions

Seed banks can recover very rapidly even under the limiting and stressful conditions of semi-arid environments. This recovery is based mainly on the seed rain at small scales together with secondary dispersal from intact seed banks in the vicinity. These results emphasize the relevance of processes occurring on short spatial scales in determining community structure.     

Spatio-temporal history of the disjunct family Tecophilaeaceae: a tale involving the colonization of three Mediterranean-type ecosystems

Background and Aims

Tecophilaeaceae (27 species distributed in eight genera) have a disjunct distribution in California, Chile and southern and tropical mainland Africa. Moreover, although the family mainly occurs in arid ecosystems, it has colonized three Mediterranean-type ecosystems. In this study, the spatio-temporal history of the family is examined using DNA sequence data from six plastid regions.

Methods

Modern methods in divergence time estimation (BEAST), diversification (LTT and GeoSSE) and biogeography (LAGRANGE) are applied to infer the evolutionary history of Tecophilaeaceae. To take into account dating and phylogenetic uncertainty, the biogeographical inferences were run over a set of dated Bayesian trees and the analyses were constrained according to palaeogeographical evidence.

Key Results

The analyses showed that the current distribution and diversification of the family were influenced primarily by the break up of Gondwana, separating the family into two main clades, and the establishment of a Mediterranean climate in Chile, coinciding with the radiation of Conanthera. Finally, unlike many other groups, no shifts in diversification rates were observed associated with the dispersals in the Cape region of South Africa.

Conclusions

Although modest in size, Tecophilaeaceae have a complex spatio-temporal history. The family is now most diverse in arid ecosystems in southern Africa, but is expected to have originated in sub-tropical Africa. It has subsequently colonized Mediterranean-type ecosystems in both the Northern and Southern Hemispheres, but well before the onset of the Mediterranean climate in these regions. Only one lineage, genus Conanthera, has apparently diversified to any extent under the impetus of a Mediterranean climate.     

Total skin electron beam (TSEB) therapy in pediatric patients: A review of the literature

Aim

A literature review was undertaken to identify current TSEB therapy in pediatric patients.

Background

Total skin electron beam (TSEB) therapy is a method of irradiation with low energy electron beam dedicated to patients who have superficial skin lesions all over their body. Such skin malignancies are sparse among adults and even more uncommon with pediatric population.

Materials and methods

In this study, all reported case reports were summed up with a special emphasis on techniques used, doses prescribed and special shielding of critical organs. Moreover, potential problems that were encountered during TSEB irradiation of very young patients were depicted.

Results

The literature has described only seven case reports of children undergoing TSEB therapy. Most of them were infants; however, two adolescents were also treated. For all infants, general anesthesia was provided to allow safe and accurate TSEB irradiation. The prescribed dose varied from 16 Gy to 28 Gy depending on the irradiation schedule and patient condition. Usually, boost fields were applied to the scalp and perineum. Typical shields for fingernails, toenails and lenses were usually used.

Conclusion

This paper revealed that TSEB therapy may be considered as a palliative treatment for pediatric patients with leukemia cutis. However, its role is still unclear and should be further investigated.     

A Meta-Analysis of the Impacts of Genetically Modified Crops

Background

Despite the rapid adoption of genetically modified (GM) crops by farmers in many countries, controversies about this technology continue. Uncertainty about GM crop impacts is one reason for widespread public suspicion.

Objective

We carry out a meta-analysis of the agronomic and economic impacts of GM crops to consolidate the evidence.

Data Sources

Original studies for inclusion were identified through keyword searches in ISI Web of Knowledge, Google Scholar, EconLit, and AgEcon Search.

Study Eligibility Criteria

Studies were included when they build on primary data from farm surveys or field trials anywhere in the world, and when they report impacts of GM soybean, maize, or cotton on crop yields, pesticide use, and/or farmer profits. In total, 147 original studies were included.

Synthesis Methods

Analysis of mean impacts and meta-regressions to examine factors that influence outcomes.

Results

On average, GM technology adoption has reduced chemical pesticide use by 37%, increased crop yields by 22%, and increased farmer profits by 68%. Yield gains and pesticide reductions are larger for insect-resistant crops than for herbicide-tolerant crops. Yield and profit gains are higher in developing countries than in developed countries.

Limitations

Several of the original studies did not report sample sizes and measures of variance.

Conclusion

The meta-analysis reveals robust evidence of GM crop benefits for farmers in developed and developing countries. Such evidence may help to gradually increase public trust in this technology.     

Prescription drugs associated with reports of violence towards others

Context

Violence towards others is a seldom-studied adverse drug event and an atypical one because the risk of injury extends to others.

Objective

To identify the primary suspects in adverse drug event reports describing thoughts or acts of violence towards others, and assess the strength of the association.

Methodology

From the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, we extracted all serious adverse event reports for drugs with 200 or more cases received from 2004 through September 2009. We identified any case report indicating homicide, homicidal ideation, physical assault, physical abuse or violence related symptoms.

Main Outcome Measures

Disproportionality in reporting was defined as a) 5 or more violence case reports, b) at least twice the number of reports expected given the volume of overall reports for that drug, c) a χ2 statistic indicating the violence cases were unlikely to have occurred by chance (p<0.01).

Results

We identified 1527 cases of violence disproportionally reported for 31 drugs. Primary suspect drugs included varenicline (an aid to smoking cessation), 11 antidepressants, 6 sedative/hypnotics and 3 drugs for attention deficit hyperactivity disorder. The evidence of an association was weaker and mixed for antipsychotic drugs and absent for all but 1 anticonvulsant/mood stabilizer. Two or fewer violence cases were reported for 435/484 (84.7%) of all evaluable drugs suggesting that an association with this adverse event is unlikely for these drugs.

Conclusions

Acts of violence towards others are a genuine and serious adverse drug event associated with a relatively small group of drugs. Varenicline, which increases the availability of dopamine, and antidepressants with serotonergic effects were the most strongly and consistently implicated drugs. Prospective studies to evaluate systematically this side effect are needed to establish the incidence, confirm differences among drugs and identify additional common features.     

A Blueberry-Enriched Diet Improves Renal Function and Reduces Oxidative Stress in Metabolic Syndrome Animals: Potential Mechanism of TLR4-MAPK Signaling Pathway

Background

Metabolic syndrome (MetS) is characterized by a cluster of health factors that indicate a higher risk for cardio-renal diseases. Recent evidence indicates that antioxidants from berries are alternative to attenuate oxidative stress and inflammation. We tested the hypothesis that inflammation-induced renal damage is triggered by the activation of TLR4, and subsequent modulation of redox-sensitive molecules and mitogen-activated protein kinase (MAPK) pathway.

Methods

Five-week old lean and obese Zucker rats (LZR and OZR) were fed a blueberry-enriched diet or an isocaloric control diet for 15 weeks. A glucose tolerance test and acute renal clearance experiments were performed. Gene and protein expression levels for TLR4, cytokines and phosphorylation of ERK and p38MAPK were measured. Kidney redox status and urinary albumin levels were quantified. Renal pathology was evaluated histologically.

Results

Control OZR exhibited lower glucose tolerance; exacerbated renal function parameters; increased oxidative stress. Gene and protein expression levels of TLR4 were higher and this was accompanied by increased renal pathology with extensive albuminuria and deterioration in antioxidant levels in OZR. In addition, OZR had increased phosphorylation of ERK and p38MAPK. Blueberry-fed OZR exhibited significant improvements in all these parameters compared to OZR.

Conclusion

TLR4-MAPK signaling pathway is a key to the renal structural injury and dysfunction in MetS and blueberry (BB) protect against this damage by inhibiting TLR4.

Significance

This is the first study to put forth a potential mechanism of TLR4-induced kidney damage in a model of MetS and to elucidate a downstream mechanism by which blueberry exert their reno-protective effects.     

Morphological and physiological responses of rice seedlings to complete submergence (flash flooding)

Background and Aims

Reducing damage to rice seedlings caused by flash flooding will improve the productivity of rainfed lowland rice in West Africa. Accordingly, the morphological and physiological responses of different forms of rice to complete submergence were examined in field and pot experiments to identify primary causes of damage.

Methods

To characterize the physiological responses, seedlings from a wide genetic base including Oryza sativa, O. glaberrima and interspecific hybrids were compared using principle component analysis.

Key Results

Important factors linked to flash-flood tolerance included minimal shoot elongation underwater, increase in dry matter weight during submergence and post-submergence resistance to lodging. In particular, fast shoot elongation during submergence negatively affected plant growth after de-submergence. Also shoot-elongating cultivars showed a strong negative correlation between dry matter weight of the leaves that developed before submergence and leaves developing during submergence.

Conclusions

Enhancement of shoot elongation during submergence in water that is too deep to permit re-emergence by small seedlings represents a futile escape strategy that takes place at the expense of existing dry matter in circumstances where underwater photosynthetic carbon fixation is negligible. Consequently, it compromises survival or recovery growth once flood water levels recede and plants are re-exposed to the aerial environment. Tolerance is greater in cultivars where acceleration of elongation caused by submergence is minimal.Key words: Africa, flash floods, Oryza glaberrima, rainfed lowland, rice, shoot elongation, stress tolerance, submergence     

Non-Surgical Interventions for Adolescents with Idiopathic Scoliosis: An Overview of Systematic Reviews

Background

Non-surgical interventions for adolescents with idiopathic scoliosis remain highly controversial. Despite the publication of numerous reviews no explicit methodological evaluation of papers labeled as, or having a layout of, a systematic review, addressing this subject matter, is available.

Objectives

Analysis and comparison of the content, methodology, and evidence-base from systematic reviews regarding non-surgical interventions for adolescents with idiopathic scoliosis.

Design

Systematic overview of systematic reviews.

Methods

Articles meeting the minimal criteria for a systematic review, regarding any non-surgical intervention for adolescent idiopathic scoliosis, with any outcomes measured, were included. Multiple general and systematic review specific databases, guideline registries, reference lists and websites of institutions were searched. The AMSTAR tool was used to critically appraise the methodology, and the Oxford Centre for Evidence Based Medicine and the Joanna Briggs Institute’s hierarchies were applied to analyze the levels of evidence from included reviews.

Results

From 469 citations, twenty one papers were included for analysis. Five reviews assessed the effectiveness of scoliosis-specific exercise treatments, four assessed manual therapies, five evaluated bracing, four assessed different combinations of interventions, and one evaluated usual physical activity. Two reviews addressed the adverse effects of bracing. Two papers were high quality Cochrane reviews, Three were of moderate, and the remaining sixteen were of low or very low methodological quality. The level of evidence of these reviews ranged from 1 or 1+ to 4, and in some reviews, due to their low methodological quality and/or poor reporting, this could not be established.

Conclusions

Higher quality reviews indicate that generally there is insufficient evidence to make a judgment on whether non-surgical interventions in adolescent idiopathic scoliosis are effective. Papers labeled as systematic reviews need to be considered in terms of their methodological rigor; otherwise they may be mistakenly regarded as high quality sources of evidence.

Protocol registry number

CRD42013003538, PROSPERO     

Rapid amygdala gamma oscillations in response to eye gaze

Background

The eye gaze of other individuals conveys important social information and can trigger multiple psychological activities; some of which, such as emotional reactions and attention orienting, occur very rapidly. Although some neuroscientific evidence has suggested that the amygdala may be involved in such rapid gaze processing, no evidence has been reported concerning the speed at which the amygdala responds to eye gaze.

Methodology/Principal Findings

To investigate this issue, we recorded electrical activity within the amygdala of six subjects using intracranial electrodes. Subjects observed images of eyes and mosaics pointing in averted and straight directions. The amygdala showed higher gamma-band oscillations for eye gaze than for mosaics, which peaked at 200 ms regardless of the direction of the gaze.

Conclusion

These results indicate that the human amygdala rapidly processes eye gaze.     

Association between Proton Pump Inhibitor Therapy and Clostridium difficile Infection: A Contemporary Systematic Review and Meta-Analysis

Introduction

Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI).

Methods

Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings.

Results

We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I² = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26–1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year.

Conclusions

In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship.     

Regeneration of the exocrine pancreas is delayed in telomere-dysfunctional mice

Introduction

Telomere shortening is a cell-intrinsic mechanism that limits cell proliferation by induction of DNA damage responses resulting either in apoptosis or cellular senescence. Shortening of telomeres has been shown to occur during human aging and in chronic diseases that accelerate cell turnover, such as chronic hepatitis. Telomere shortening can limit organ homeostasis and regeneration in response to injury. Whether the same holds true for pancreas regeneration in response to injury is not known.

Methods

In the present study, pancreatic regeneration after acute cerulein-induced pancreatitis was studied in late generation telomerase knockout mice with short telomeres compared to telomerase wild-type mice with long telomeres.

Results

Late generation telomerase knockout mice exhibited impaired exocrine pancreatic regeneration after acute pancreatitis as seen by persistence of metaplastic acinar cells and markedly reduced proliferation. The expression levels of p53 and p21 were not significantly increased in regenerating pancreas of late generation telomerase knockout mice compared to wild-type mice.

Conclusion

Our results indicate that pancreatic regeneration is limited in the context of telomere dysfunction without evidence for p53 checkpoint activation.     

Trampling, defoliation and physiological integration affect growth, morphological and mechanical properties of a root-suckering clonal tree

Background and Aims

Grazing is a complex process involving the simultaneous occurrence of both trampling and defoliation. Clonal plants are a common feature of heavily grazed ecosystems where large herbivores inflict the simultaneous pressures of trampling and defoliation on the vegetation. We test the hypothesis that physiological integration (resource sharing between interconnected ramets) may help plants to deal with the interactive effects of trampling and defoliation.

Methods

In a field study, small and large ramets of the root-suckering clonal tree Populus simonii were subjected to two levels of trampling and defoliation, while connected or disconnected to other ramets. Plant responses were quantified via survival, growth, morphological and stem mechanical traits.

Key Results

Disconnection and trampling increased mortality, especially in small ramets. Trampling increased stem length, basal diameter, fibrous root mass, stem stiffness and resistance to deflection in connected ramets, but decreased them in disconnected ones. Trampling decreased vertical height more in disconnected than in connected ramets, and reduced stem mass in disconnected ramets but not in connected ramets. Defoliation reduced basal diameter, leaf mass, stem mass and leaf area ratio, but did not interact with trampling or disconnection.

Conclusions

Although clonal integration did not influence defoliation response, it did alleviate the effects of trampling. We suggest that by facilitating resource transport between ramets, clonal integration compensates for trampling-induced damage to fine roots.