Gut Dysbiosis in Experimental Kidney Disease: A Meta-Analysis of Rodent Repository Data.

SIGNIFICANCE STATEMENT: Alterations in gut microbiota contribute to the pathophysiology of a diverse range of diseases, leading to suggestions that chronic uremia may cause intestinal dysbiosis that contributes to the pathophysiology of CKD. Various small, single-cohort rodent studies have supported this hypothesis. In this meta-analysis of publicly available repository data from studies of models of kidney disease in rodents, cohort variation far outweighed any effect of experimental kidney disease on the gut microbiota. No reproducible changes in animals with kidney disease were seen across all cohorts, although a few trends observed in most experiments may be attributable to kidney disease. The findings suggest that rodent studies do not provide evidence for the existence of "uremic dysbiosis" and that single-cohort studies are unsuitable for producing generalizable results in microbiome research. BACKGROUND: Rodent studies have popularized the notion that uremia may induce pathological changes in the gut microbiota that contribute to kidney disease progression. Although single-cohort rodent studies have yielded insights into host-microbiota relationships in various disease processes, their relevance is limited by cohort and other effects. We previously reported finding metabolomic evidence that batch-to-batch variations in the microbiome of experimental animals are significant confounders in an experimental study. METHODS: To attempt to identify common microbial signatures that transcend batch variability and that may be attributed to the effect of kidney disease, we downloaded all data describing the molecular characterization of the gut microbiota in rodents with and without experimental kidney disease from two online repositories comprising 127 rodents across ten experimental cohorts. We reanalyzed these data using the DADA2 and Phyloseq packages in R, a statistical computing and graphics system, and analyzed data both in a combined dataset of all samples and at the level of individual experimental cohorts. RESULTS: Cohort effects accounted for 69% of total sample variance ( P <0.001), substantially outweighing the effect of kidney disease (1.9% of variance, P =0.026). We found no universal trends in microbial population dynamics in animals with kidney disease, but observed some differences (increased alpha diversity, a measure of within-sample bacterial diversity; relative decreases in Lachnospiraceae and Lactobacillus ; and increases in some Clostridia and opportunistic taxa) in many cohorts that might represent effects of kidney disease on the gut microbiota . CONCLUSIONS: These findings suggest that current evidence that kidney disease causes reproducible patterns of dysbiosis is inadequate. We advocate meta-analysis of repository data as a way of identifying broad themes that transcend experimental variation.

Common Oral Lesions.

Familiarity with common oral conditions allows clinicians to observe and treat patients in the primary care setting or refer to a dentist, oral surgeon, otolaryngologist, or other specialist. Recurrent aphthous stomatitis (canker sores) is the most common ulcerative condition of the oral cavity. Recurrent herpes simplex labialis and stomatitis also commonly cause oral ulcers. Corticosteroids, immunocompromise, antibiotics, and dentures can predispose patients to oral candidiasis. Benign migratory glossitis (geographic tongue) occurs in up to 3% of the population but generally lacks symptoms, although some people experience food sensitivity or a burning sensation. Hairy tongue is associated with a low fiber diet, tobacco and alcohol use, and poor oral hygiene in older male patients. Generally, hairy tongue is asymptomatic except for an unattractive appearance or halitosis. Tobacco and alcohol use can cause mucosal changes resulting in leukoplakia and erythroplakia. These can represent precancerous changes and increase the risk of squamous cell carcinoma. Mandibular and maxillary tori are common bony cortical outgrowths that require no treatment in the absence of repeat trauma from chewing or interference with dentures. Oral lichen planus occurs in up to 2% of individuals and can present as lacy reticulations or oral erosions and ulcerations. Traumatic buccal mucosal fibromas and labial mucoceles from biting can be excised.

Association between periodontitis and chronic kidney disease.

Periodontitis and chronic kidney disease are chronic conditions with high community prevalence across the world. Patients with chronic kidney disease have been noted to have a high burden of periodontitis, and several shared risk factors have been associated with the prevalence and severity of both conditions. However, the precise relationship between the two conditions, and the extent to which each may contribute to the development of the other, remains a matter of debate. The goals of the present work were to: (a) provide the most current and relevant literature overview of the association between periodontitis and chronic kidney disease; (b) explore mechanisms underlying this association; and (c) determine if evidence exists for an independent association between these conditions. We also assessed whether improved oral hygiene and periodontal treatment could reduce the risk of developing chronic kidney disease and, if so, what protocols these strategies involve. Finally, we aimed to reveal gaps in our current knowledge to delineate the directions of future research. Although the exact relationship between these two conditions has not yet been defined, we highlight the importance of the interprofessional interaction between dental practitioners and the nephrology team and the importance of oral health assessment in the management of chronic kidney disease.

Simplified management of epistaxis.

ABSTRACT: Primary care, urgent care, and emergency department providers periodically treat epistaxis, either as recurrent nosebleed or an acute persistent episode. Silver nitrate application to the decongested and anesthetized nasal mucosa addresses the former in most cases. The plethora of commercial nasal packing devices testifies to the discomfort, technical difficulty, and frustration associated with traditional gauze-packing methods. Inflatable anterior nasal balloon packs reliably control most nosebleeds. Addition of a Foley catheter nasopharyngeal balloon pack manages most posterior epistaxis. Cautery and the two packing techniques mentioned above should treat most cases not requiring otolaryngology consultation or interventional radiology. Appropriate anesthetic and analgesics lessen the unpleasantness for both the patient and the provider. Topical moisturizing facilitates mucosal healing. Oxymetazoline 0.05% nasal spray provides the patient means to address rebleeding after discharge from treatment.

Triangulation of methods using insect cell lines to investigate insecticidal mode-of-action.

BACKGROUND: This study investigated three in vitro models to assist in elucidating possible mode-of-action, which could be adopted to evaluate insecticidal activity of complex, unknown, or multi-constituent formulations. We used a combination of absorbance spectrometry, confocal scanning laser microscopy and microelectrode ion flux estimation (MIFE) to provide insight into potential target sites for insecticides. This study used two insect cell lines and evaluated three pyrethroid insecticides. RESULTS: We observed that the two cell lines produced distinctly different responses. Drosophila melanogaster D.mel-S2 cell line was a useful model to monitor ion flux changes, resulting from insecticides with neural toxicity; however, it was less useful to determine some metabolic pathway indicators of toxic stress. Conversely, the Spodoptera frugiperda Sf9 cell line produced acute reactive oxygen species (ROS) in response to insecticide treatments, but was not highly responsive in electrophysiological experiments. We also showed that the natural, multi-constituent botanical extract of pyrethrum elicited different Na+ , Cl- and Ca2+ ion fluxes than its synthetic, single constituent analogues, α-cypermethrin and esfenvalerate. These two methods used in combination with absorbance spectrometry measuring cell growth inhibition plus cell mortality assays shed some light on cytotoxic responses in differing model cell lines. CONCLUSION: This research highlights the importance of using multiple cell types and interdisciplinary methods to provide a better insight into mode of insecticidal action. This is especially pertinent to novel biopesticide discovery, as the underlying mechanisms for toxicity in initial screening processes are likely to be unknown.

Current Indications for Tonsillectomy and Adenoidectomy.

This paper reviews current indications for otolaryngology consultation for tonsillectomy and adenoidectomy (T&A). Despite often being performed concurrently, these procedures should be considered separate surgeries done for different indications. The American Academy of Otolaryngology - Head and Neck Surgery published tonsillectomy guidelines for children in 2019. These recommendations are often extrapolated to adults in clinical practice despite less robust literature support for this age group. T&A should be recommended for pediatric obstructive sleep apnea. Specific frequencies of tonsillitis have been identified that indicate benefit from tonsillectomy in normal children; certain modifying health factors warrant consideration of surgery with fewer infections. The guidelines include consideration of tonsillectomy for poorly validated indications such as halitosis, febrile seizure, dental malocclusion, dysphagia, dysphonia, and psoriasis.

Clouds and Convective Self-Aggregation in a Multimodel Ensemble of Radiative-Convective Equilibrium Simulations.

The Radiative-Convective Equilibrium Model Intercomparison Project (RCEMIP) is an intercomparison of multiple types of numerical models configured in radiative-convective equilibrium (RCE). RCE is an idealization of the tropical atmosphere that has long been used to study basic questions in climate science. Here, we employ RCE to investigate the role that clouds and convective activity play in determining cloud feedbacks, climate sensitivity, the state of convective aggregation, and the equilibrium climate. RCEMIP is unique among intercomparisons in its inclusion of a wide range of model types, including atmospheric general circulation models (GCMs), single column models (SCMs), cloud-resolving models (CRMs), large eddy simulations (LES), and global cloud-resolving models (GCRMs). The first results are presented from the RCEMIP ensemble of more than 30 models. While there are large differences across the RCEMIP ensemble in the representation of mean profiles of temperature, humidity, and cloudiness, in a majority of models anvil clouds rise, warm, and decrease in area coverage in response to an increase in sea surface temperature (SST). Nearly all models exhibit self-aggregation in large domains and agree that self-aggregation acts to dry and warm the troposphere, reduce high cloudiness, and increase cooling to space. The degree of self-aggregation exhibits no clear tendency with warming. There is a wide range of climate sensitivities, but models with parameterized convection tend to have lower climate sensitivities than models with explicit convection. In models with parameterized convection, aggregated simulations have lower climate sensitivities than unaggregated simulations.

Using VR to Investigate the Relationship between Visual Acuity and Severity of Simulated Oscillopsia.

PURPOSE: Oscillopsia is a debilitating symptom resulting from involuntary eye movement most commonly associated with acquired nystagmus. Investigating and documenting the effects of oscillopsia severity on visual acuity (VA) is challenging. This paper aims to further understanding of the effects of oscillopsia using a virtual reality simulation. METHODS: Fifteen right-beat horizontal nystagmus waveforms, with different amplitude (1°, 3°, 5°, 8° and 11°) and frequency (1.25 Hz, 2.5 Hz and 5 Hz) combinations, were produced and imported into virtual reality to simulate different severities of oscillopsia. Fifty participants without ocular pathology were recruited to read logMAR charts in virtual reality under stationary conditions (no oscillopsia) and subsequently while experiencing simulated oscillopsia. The change in VA (logMAR) was calculated for each oscillopsia simulation (logMAR VA with oscillopsia - logMAR VA with no oscillopsia), removing the influence of different baseline VAs between participants. A one-tailed paired t-test was used to assess statistical significance in the worsening in VA caused by the oscillopsia simulations. RESULTS: VA worsened with each incremental increase in simulated oscillopsia intensity (frequency x amplitude), either by increasing frequency or amplitude, with the exception of statistically insignificant changes at lower intensity simulations. Theoretical understanding predicted a linear relationship between increasing oscillopsia intensity and worsening VA. This was supported by observations at lower intensity simulations but not at higher intensities, with incremental changes in VA gradually levelling off. A potential reason for the difference at higher intensities is the influence of frame rate when using digital simulations in virtual reality. CONCLUSIONS: The frequency and amplitude were found to equally affect VA, as predicted. These results not only consolidate the assumption that VA degrades with oscillopsia but also provide quantitative information that relates these changes to amplitude and frequency of oscillopsia.

Surface-Atmosphere Coupling Scale, the Fate of Water, and Ecophysiological Function in a Brazilian Forest.

Tropical South America plays a central role in global climate. Bowen ratio teleconnects to circulation and precipitation processes far afield, and the global CO2 growth rate is strongly influenced by carbon cycle processes in South America. However, quantification of basin-wide seasonality of flux partitioning between latent and sensible heat, the response to anomalies around climatic norms, and understanding of the processes and mechanisms that control the carbon cycle remains elusive. Here, we investigate simulated surface-atmosphere interaction at a single site in Brazil, using models with different representations of precipitation and cloud processes, as well as differences in scale of coupling between the surface and atmosphere. We find that the model with parameterized clouds/precipitation has a tendency toward unrealistic perpetual light precipitation, while models with explicit treatment of clouds produce more intense and less frequent rain. Models that couple the surface to the atmosphere on the scale of kilometers, as opposed to tens or hundreds of kilometers, produce even more realistic distributions of rainfall. Rainfall intensity has direct consequences for the "fate of water," or the pathway that a hydrometeor follows once it interacts with the surface. We find that the model with explicit treatment of cloud processes, coupled to the surface at small scales, is the most realistic when compared to observations. These results have implications for simulations of global climate, as the use of models with explicit (as opposed to parameterized) cloud representations becomes more widespread.

Batch effect exerts a bigger influence on the rat urinary metabolome and gut microbiota than uraemia: a cautionary tale.

BACKGROUND: Rodent models are invaluable for studying biological processes in the context of whole organisms. The reproducibility of such research is based on an assumption of metabolic similarity between experimental animals, controlled for by breeding and housing strategies that minimise genetic and environmental variation. Here, we set out to demonstrate the effect of experimental uraemia on the rat urinary metabolome and gut microbiome but found instead that the effect of vendor shipment batch was larger in both areas than that of uraemia. RESULTS: Twenty four Wistar rats obtained from the same commercial supplier in two separate shipment batches underwent either subtotal nephrectomy or sham procedures. All animals undergoing subtotal nephrectomy developed an expected uraemic phenotype. The urinary metabolome was studied using 1H-NMR spectroscopy and found to vary significantly between animals from different batches, with substantial differences in concentrations of a broad range of substances including lactate, acetate, glucose, amino acids, amines and benzoate derivatives. In animals from one batch, there was a complete absence of the microbiome-associated urinary metabolite hippurate, which was present in significant concentrations in animals from the other batch. These differences were so prominent that we would have drawn quite different conclusions about the effect of uraemia on urinary phenotype depending on which batch of animals we had used. Corresponding differences were seen in the gut microbiota between animals in different batches when assessed by the sequencing of 16S rRNA gene amplicons, with higher alpha diversity and different distributions of Proteobacteria subtaxa and short-chain fatty acid producing bacteria in the second batch compared to the first. Whilst we also demonstrated differences in both the urinary metabolome and gut microbiota associated with uraemia, these effects were smaller in size than those associated with shipment batch. CONCLUSIONS: These results challenge the assumption that experimental animals obtained from the same supplier are metabolically comparable, and provide metabolomic evidence that batch-to-batch variations in the microbiome of experimental animals are significant confounders in an experimental study. We discuss strategies for reducing such variability and the need for transparency in research publications about the supply of experimental animals.

Evolution of chloroplast retrograde signaling facilitates green plant adaptation to land.

Chloroplast retrograde signaling networks are vital for chloroplast biogenesis, operation, and signaling, including excess light and drought stress signaling. To date, retrograde signaling has been considered in the context of land plant adaptation, but not regarding the origin and evolution of signaling cascades linking chloroplast function to stomatal regulation. We show that key elements of the chloroplast retrograde signaling process, the nucleotide phosphatase (SAL1) and 3'-phosphoadenosine-5'-phosphate (PAP) metabolism, evolved in streptophyte algae-the algal ancestors of land plants. We discover an early evolution of SAL1-PAP chloroplast retrograde signaling in stomatal regulation based on conserved gene and protein structure, function, and enzyme activity and transit peptides of SAL1s in species including flowering plants, the fern Ceratopteris richardii, and the moss Physcomitrella patens Moreover, we demonstrate that PAP regulates stomatal closure via secondary messengers and ion transport in guard cells of these diverse lineages. The origin of stomata facilitated gas exchange in the earliest land plants. Our findings suggest that the conquest of land by plants was enabled by rapid response to drought stress through the deployment of an ancestral SAL1-PAP signaling pathway, intersecting with the core abscisic acid signaling in stomatal guard cells.

An alternative introduction to reading and evaluating the primary literature for beginning graduate students.

Students are challenged in transitioning from acquiring knowledge and understanding through reading textbooks to their learning to select, read, evaluate, and synthesize the primary literature. A customary approach to teaching this transition to beginning graduate students is for a faculty member to assign "readings" from the recent literature that promise to become key publications; such assignments generally underscore recent, novel scientific content. We advocate here an alternative approach for coaching students very early in their training: first, to read, analyze, and discuss a paper that highlights critically important features of effective and valid experimental design; and, second, to study a paper that can be shown historically to have fundamentally changed the way in which physiological function is understood. We consider as an example of the first goal a study that purports to demonstrate a principle of thermoregulation, but that interaction between students and instructor reveals the study's lack of an essential control. The second goal requires sufficient time for the publication to concretely validate its contribution(s). The purpose is to identify those essential properties of the selected paper that contributed to its having become a truly exemplary study. We present a 1957 paper by Dr. A. C. Burton ( Am Heart J 54: 801-810, 1957) as an illustration and analyze the study with respect to those attributes that contributed to its lasting importance. These alternative approaches to introduce inexperienced students to the original literature can produce critical insight into the process and can help students inculcate essential practices, guiding them to more productive careers.

Stress, cognitive appraisal, coping, and event free survival in patients with heart failure.

OBJECTIVES: To describe self-reported stress level, cognitive appraisal and coping among patients with heart failure (HF), and to examine the association of cognitive appraisal and coping strategies with event-free survival. METHODS: This was a prospective, longitudinal, descriptive study of patients with chronic HF. Assessment of stress, cognitive appraisal, and coping was performed using Perceived Stress Scale, Cognitive Appraisal Health Scale, and Brief COPE scale, respectively. The event-free survival was defined as cardiac rehospitalization and all-cause death. RESULTS: A total of 88 HF patients (mean age 58 ± 13 years and 53.4% male) participated. Linear and cox regression showed that harm/loss cognitive appraisal was associated with avoidant emotional coping (ß = -0.28; 95% CI: -0.21 - 0.02; p = 0.02) and event free survival (HR = 0.53; 95% CI: 0.28 - 1.02; p = 0.05). CONCLUSIONS: The cognitive appraisal of the stressors related to HF may lead to negative coping strategies that are associated with worse event-free survival.