Abstract: Scientific investigators cannot reach consensus in methods and results between sepsis experiments in mice, and it seems unrealistic to expect great leaps in translational human trials based upon these animal data. This is not to say that animal studies are not worth undertaking but rather serve as a call to standardize model protocols in the literature so that results can be more readily compared between different laboratories. In addition, a systematic multiple-model approach in testing potential therapies should also be developed and standardized. Testing can begin in fast, easy-to-use models and proceed through greater levels of complexity as the research progresses [6,10,21]. One only needs to appreciate the failure of anti-TNF antibody trials to see the logic behind this suggestion [26]. Despite the increased time and monetary cost of more complex animal models, they are still generally easier to perform than full-scale human clinical trials, even when multiple animal models are employed. In addition to improvements in standardization and incremental increases in complexity, animal models should strive to replicate the conditions of human trials. For example, testing of novel therapeutic agents in sepsis should also include antibiotics and adequate fluid resuscitation in the model, as they represent the standards of patient care [6,21]. It is difficult to assess the value of new treatment agents if they are not tested in a context relevant to this standard. Others advocate for the use of “humanized” mice that have been transplanted with human cells lines to better replicate the human response to disease [16]. Finally, the stratification of experimental animal responses to septic insult ensures that we are not testing therapies in mice that have gone past the point of salvage or in animals that have not developed a clinically substantial response to the infection [21,46,87]. As more sophisticated methods are constantly being developed, the search will continue for the ideal pre-clinical therapeutic testing platform.

Abstract: Evidence from animal and human studies suggests that moderate acoustic exposure, causing only transient threshold elevation, can nonetheless cause “hidden hearing loss” that interferes with coding of suprathreshold sound. Such noise exposure destroys synaptic connections between cochlear hair cells and auditory nerve fibers; however, there is no clinical test of this synaptopathy in humans. In animals, synaptopathy reduces the amplitude of auditory brainstem response (ABR) wave-I. Unfortunately, ABR wave-I is difficult to measure in humans, limiting its clinical use. Here, using analogous measurements in humans and mice, we show that the effect of masking noise on the latency of the more robust ABR wave-V mirrors changes in ABR wave-I amplitude. Furthermore, in our human cohort, the effect of noise on wave-V latency predicts perceptual temporal sensitivity. Our results suggest that measures of the effects of noise on ABR wave-V latency can be used to diagnose cochlear synaptopathy in humans. SIGNIFICANCE STATEMENT Although there are suspicions that cochlear synaptopathy affects humans with normal hearing thresholds, no one has yet reported a clinical measure that is a reliable marker of such loss. By combining human and animal data, we demonstrate that the latency of auditory brainstem response wave-V in noise reflects auditory nerve loss. This is the first study of human listeners with normal hearing thresholds that links individual differences observed in behavior and auditory brainstem response timing to cochlear synaptopathy. These results can guide development of a clinical test to reveal this previously unknown form of noise-induced hearing loss in humans.

Abstract: Parkinson’s disease (PD) affects millions around the world. The Braak hypothesis proposes that in PD a pathologic agent may penetrate the nervous system via the olfactory bulb, gut, or both and spreads throughout the nervous system. The agent is unknown, but several environmental exposures have been associated with PD. Here, we summarize and examine the evidence for such environmental exposures. We completed a comprehensive review of human epidemiologic studies of pesticides, selected industrial compounds, and metals and their association with PD in PubMed and Google Scholar until April 2016. Most studies show that rotenone and paraquat are linked to increased PD risk and PD-like neuropathology. Organochlorines have also been linked to PD in human and laboratory studies. Organophosphates and pyrethroids have limited but suggestive human and animal data linked to PD. Iron has been found to be elevated in PD brain tissue but the pathophysiological link is unclear. PD due to manganese has not been demonstrated, though a parkinsonian syndrome associated with manganese is well-documented. Overall, the evidence linking paraquat, rotenone, and organochlorines with PD appears strong; however, organophosphates, pyrethroids, and polychlorinated biphenyls require further study. The studies related to metals do not support an association with PD.

Abstract: Acute kidney injury (AKI) is a common complication in hospitalized patients, associated with >50% mortality in those in intensive care who require renal replacement therapy. Data suggest that AKI is a systemic disease that adversely affects the immune system and organ function, and in this way contributes to the high mortality observed in affected patients. Data from patients and animal models indicate that AKI adversely affects the lungs. Respiratory complications are common in patients with AKI and include pulmonary oedema, respiratory failure requiring mechanical ventilation, prolonged duration of mechanical ventilation, and prolonged weaning from mechanical ventilation. The development of respiratory failure in patients with AKI greatly increases the risk of death. Data from animal models support the notion that cardiogenic pulmonary oedema (from volume overload) and non-cardiogenic pulmonary oedema (from endothelial injury due to inflammation and apoptosis) can occur in AKI. In this Review we discuss the clinical, epidemiologic, and animal data that provide insights into the mechanisms by which AKI can lead to lung injury and respiratory complications. Elucidation of the mechanisms of lung injury and respiratory complications after AKI is essential to develop effective therapies and reduce the high mortality associated with AKI and respiratory failure.

Abstract: Building on well-established animal data demonstrating the effects of early maternal support on hippocampal development and adaptive coping, a few longitudinal studies suggest that early caregiver support also impacts human hippocampal development. How caregiving contributes to human hippocampal developmental trajectories, whether there are sensitive periods for these effects, as well as whether related variation in hippocampal development predicts later childhood emotion functioning are of major public health importance. The current study investigated these questions in a longitudinal study of preschoolers assessed annually for behavioral and emotional development, including observed caregiver support. One hundred and twenty-seven children participated in three waves of magnetic resonance brain imaging through school age and early adolescence. Multilevel modeling of the effects of preschool and school-age maternal support on hippocampal volumes across the three waves was conducted. Hippocampal volume increased faster for those with higher levels of preschool maternal support. Subjects with support 1 SD above the mean had a 2.06 times greater increase in total hippocampus volume across the three scans than those with 1 SD below the mean (2.70% vs. 1.31%). No effect of school-age support was found. Individual slopes of hippocampus volume were significantly associated with emotion regulation at scan 3. The findings demonstrate a significant effect of early childhood maternal support on hippocampal volume growth across school age and early adolescence and suggest an early childhood sensitive period for these effects. They also show that this growth trajectory is associated with later emotion functioning.

Abstract: Septic shock is a major cause of death worldwide and a considerable healthcare burden in the twenty-first century. Attention has shifted from damaging effects of the proinflammatory response to the detrimental role of antiinflammation, a phenomenon known as sepsis-induced immunoparalysis. Sepsis-induced immunoparalysis may render patients vulnerable to secondary infections and is associated with impaired outcome. The immunoparalysis hypothesis compels us to reevaluate the current management of septic shock and to assess whether we are inadvertently compromising or altering the host immune response. In this perspective, we discuss the potential detrimental role of norepinephrine, the cornerstone treatment for septic shock, in sepsis-induced immunoparalysis. We provide a short overview of the current understanding of the immunologic pathophysiology of sepsis, followed by a detailed description of the immunomodulatory effects of norepinephrine and alternative vasopressors. We conclude that although the development of novel therapies aimed at reversing immunoparalysis is underway, the use of norepinephrine may aggravate the development, extent, and duration of sepsis-induced immunoparalysis. Current in vitro and animal data indicate that norepinephrine treatment exerts immunosuppressive and bacterial growth-promoting effects and may increase susceptibility toward infections. However, evidence in humans is circumstantial, as immunologic effects of norepinephrine have not been investigated properly in experimental or clinical studies. Alternatives such as vasopressin/selepressin, angiotensin II, and phenylephrine could have a fundamental advantage over norepinephrine with respect to their immunologic properties. However, also for these agents, in vivo immunologic data in humans are largely lacking. As such, human studies on the immunomodulatory properties of norepinephrine and viable alternatives are highly warranted.

Abstract: Epidemiologic and animal data indicate that night shift work might increase the risk for breast cancer. We evaluated the association of night work with different clinical types of breast cancer in a population based case-control study (MCC-Spain study) taking into account chronotype, an indi- vidual characteristic that may relate to night shift work adaptation. Lifetime occupational history was assessed by face-to-face interviews and shift work information was available for 1708 breast cancer cases and 1778 population controls from 10 Spanish regions, enrolled from 2008 to 2013. We evaluated three shift work domains, including shift work type (permanent vs rotating), lifetime cumulative duration and frequency. We estimated odds ratios (OR) for night work compared to day work using unconditional logistic regression models adjusting for confounders. Having ever worked per- manent or rotating night shift was associated with an increased risk for breast cancer compared to day workers (odds ratio (OR) 1.18; 95 % CI 0.97, 1.43). Chronotype was differentially associated with breast cancer depending on the duration of night shift work. Risk was higher in women with invasive tumors (OR 1.23; 95 % CI 1.00, 1.51) and for estrogen and progestagen positive tumors among premenopausal women (OR 1.44; 95 % CI 1.05, 1.99). Having ever performed night shift was associated with a small increased risk for breast cancer and especially in subgroups of women with particular hormone related characteristics.

Abstract: Medicinal marijuana use is currently legal in 23 US states and the District of Columbia. As more states approve marijuana use for medical indications, physicians will be asked by their patients for more information regarding the risks and benefits of use. This article reviews the history, adverse effects, and proposed mechanisms of action of marijuana and summarizes the available literature regarding symptom relief and therapeutic value in patients with cancer. Observations: Marijuana in oncology may have potential for use as an antiemetic, for refractory cancer pain, and as an antitumor agent. However, much of the data are based on animal data, small trials, or are outdated. Conclusions and relevance: More research is needed in all areas related to the therapeutic use of marijuana in oncology.

Abstract: Optimal iron nutrition in utero is essential for development of the fetus and helps establish birth iron stores adequate to sustain growth in early infancy. In species with hemochorial placentas, such as humans and rodents, iron in the maternal circulation is transferred to the fetus by directly contacting placental syncytiotrophoblasts. Early kinetic studies provided valuable data on the initial uptake of maternal transferrin, an iron-binding protein, by the placenta. However, the remaining steps of iron trafficking across syncytiotrophoblasts and through the fetal endothelium into the fetal blood remain poorly characterized. Over the last 20 years, identification of transmembrane iron transporters and the iron regulatory hormone hepcidin has greatly expanded the knowledge of cellular iron transport and its regulation by systemic iron status. In addition, emerging human and animal data demonstrating comprised fetal iron stores in severe maternal iron deficiency challenge the classic dogma of exclusive fetal control over the transfer process and indicate that maternal and local signals may play a role in regulating this process. This review compiles current data on the kinetic, molecular, and regulatory aspects of placental iron transport and considers new questions and knowledge gaps raised by these advances.

Abstract: The double digest restriction-site associated DNA sequencing technology (ddRAD-seq) is a reduced representation sequencing technology by sampling genome-wide enzyme loci developed on the basis of next-generation sequencing. ddRAD-seq has been widely applied to SNP marker development and genotyping on animals, especially on marine animals as the original ddRAD protocol is mainly built and trained based on animal data. However, wide application of ddRAD-seq technology in plant species has not been achieved so far. Here, we aim to develop an optimized ddRAD library preparation protocol be accessible to most angiosperm plant species without much startup pre-experiment and costs. We first tested several combinations of enzymes by in silico analysis of 23 plant species covering 17 families of angiosperm and 1 family of bryophyta and found AvaII + MspI enzyme pair produced consistently higher number of fragments in a broad range of plant species. Then we removed two purifying and one quantifying steps of the original protocol, replaced expensive consumables and apparatuses by conventional experimental apparatuses. Besides, we shortened P1 adapter from 37 to 25 bp and designed a new barcode-adapter system containing 20 pairs of barcodes of varying length. This is an optimized ddRAD strategy for angiosperm plants that is economical, time-saving and requires little technical expertise or investment in laboratory equipment. We refer to this simplified protocol as MiddRAD and we demonstrated the utility and flexibility of our approach by resolving phylogenetic relationships of two genera of woody bamboos (Dendrocalamus and Phyllostachys). Overall our results provide empirical evidence for using this method on different model and non-model plants to produce consistent data. As MiddRAD adopts an enzyme pair that works for a broad range of angiosperm plants, simplifies library constructing procedure and requires less DNA input, it will greatly facilitate designing a ddRAD project. Our optimization of this method may make ddRAD be widely used in fields of plant population genetics, phylogenetics, phylogeography and molecular breeding.

Abstract: The dynamical fluctuations in the rhythms of biological systems provide valuable information about the underlying functioning of these systems. During the past few decades analysis of cardiac function based on the heart rate variability (HRV; variation in R wave to R wave intervals) has attracted great attention, resulting in more than 17000-publications (PubMed list). However, it is still controversial about the underling mechanisms of HRV. In this study, we performed both linear (time domain and frequency domain) and nonlinear analysis of HRV data acquired from humans and animals to identify the relationship between HRV and heart rate (HR). The HRV data consists of the following groups: (a) human normal sinus rhythm (n = 72); (b) human congestive heart failure (n = 44); (c) rabbit sinoatrial node cells (SANC; n = 67); (d) conscious rat (n = 11). In both human and animal data at variant pathological conditions, both linear and nonlinear analysis techniques showed an inverse correlation between HRV and HR, supporting the concept that HRV is dependent on HR, and therefore, HRV cannot be used in an ordinary manner to analyse autonomic nerve activity of a heart.

Abstract: The internal or circadian timing system is deeply integrated in female reproductive physiology. Considerable details of rheostatic timing function in the neuroendocrine control of pituitary hormone secretion, adenohypophyseal hormone gene expression and secretion, gonadal steroid hormone biosynthesis and secretion, ovulation, implantation, and parturition have been reported. The molecular clock, an autonomous feedback loop oscillator of interacting transcriptional regulators, dictates the timing and amplitude of gene expression in each tissue of the female hypothalamic-pituitary-gonadal (HPG) axis. Although multiple targets of the molecular clock have been identified, many associated with critical physiological functions in the HPG axis, the full extent of clock-driven gene expression and physiology in this critical system remains unknown. Environmental circadian disruption (ECD), the disturbance of temporal relationships within and between internal clocks (brain and periphery), and external timing cues (eg, light, nutrients, social cues) due to rotating/night shift work or transmeridian travel have been linked to reproductive dysfunction and subfertility. Moreover, ECD resulting from exposure to endocrine disrupting chemicals, environmental toxins, and/or irregular hormone levels during sexual development can also reduce fertility. Thus, perturbations that disturb clock function at the molecular, cellular or systemic level correlate with significant declines in female reproductive function. Here we briefly review the evidence for molecular clock function in each tissue of the female HPG axis (GnRH neuron, pituitary, uterus, oviduct, and ovary), describe the human epidemiological and animal data supporting the negative effects of ECD on fertility, and explore the potential for novel chronotherapeutics in women's health and fertility.

Abstract: Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.

Abstract: Bilateral vestibular failure (BVF) is a severe chronic disorder of the labyrinth or the eighth cranial nerve characterized by unsteadiness of gait and disabling oscillopsia during head movements. According to animal data, vestibular input to the hippocampus is proposed to contribute to spatial memory and spatial navigation. Except for one seminal study showing the association of impaired spatial navigation and hippocampal atrophy, patient data in BVF are lacking. Therefore, we performed a voxel-wise comparison of the hippocampal gray matter volume (GMV) in a clinically representative sample of 27 patients with incomplete BVF and 29 age- and gender-matched healthy controls to test the hypothesis of hippocampal atrophy in BVF. Although the two groups did not generally differ in their hippocampal GMV, a reduction of GMV in the bilateral hippocampal CA3 region was significantly correlated with increased vestibulopathy-related clinical impairment. We propose that GMV reduction in the hippocampus of BVF patients is related to the severity of vestibular-induced disability which is in line with combined hippocampal atrophy and disorders of spatial navigation in complete vestibular deafferentation due to bilateral nerve section. Clinically, however, the most frequent etiologies of BVF cause incomplete lesions. Accordingly, hippocampus atrophy and deficits in spatial navigation occur possibly less frequently than previously suspected. Hum Brain Mapp 37:1998-2006, 2016. © 2016 Wiley Periodicals, Inc.

Abstract: Human exposure to particulate matter (PM) has been associated with adverse health effects. While inhalation exposure to airborne PM is a prominent research subject, exposure to PM of geological origin (i.e., generated from soil/soil-like material) has received less attention. This review discusses the contaminants in PM of geological origin and their relevance for human exposure and then evaluates lung bioaccessibility assessment methods and their use. PM of geological origin can contain toxic elements as well as organic contaminants. Observed/predicted PM lung clearance times are long, which may lead to prolonged contact with lung environment. Thus, certain exposure scenarios warrant the use of in vitro bioaccessibility testing to predict lung bioavailability. Limited research is available on lung bioaccessibility test development and test application to PM of geological origin. For in vitro tests, test parameter variation between different studies and concerns about physiological relevance indicate a crucial need for test method standardization and comparison with relevant animal data. Research is recommended on (1) developing robust in vitro lung bioaccessibility methods, (2) assessing bioaccessibility of various contaminants (especially polycyclic aromatic hydrocarbons (PAHs)) in PM of diverse origin (surface soils, mine tailings, etc.), and (3) risk characterization to determine relative importance of exposure to PM of geological origin.

Abstract: The gastrointestinal tract regulates glucose and energy metabolism, and there is increasing recognition that bile acids function as key signalling molecules in these processes. For example, bile acid changes that occur after bariatric surgery have been implicated in the effects on satiety, lipid and cholesterol regulation, glucose and energy metabolism, and the gut microbiome. In recent years, Takeda-G-protein-receptor-5 (TGR5), a bile acid receptor found in widely dispersed tissues, has been the target of significant drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including type 2 diabetes, obesity, atherosclerosis, fatty liver disease and cancer. Although the benefits of targeting the TGR5 receptor are potentially great, drug development work to date has identified risks that include histopathological changes, tumorigenesis, gender differences, and questions about the translation of animal data to humans. The present article reviews the noteworthy challenges that must be addressed along the path of development of a safe and effective TGR5 agonist therapy.

Abstract: Context: Ibogaine is a psychoactive indole alkaloid found in the African rainforest shrub Tabernanthe Iboga. It is unlicensed but used in the treatment of drug and alcohol addiction. However, reports of ibogaine’s toxicity are cause for concern. Objectives: To review ibogaine’s pharmacokinetics and pharmacodynamics, mechanisms of action and reported toxicity. Methods: A search of the literature available on PubMed was done, using the keywords “ibogaine” and “noribogaine”. The search criteria were “mechanism of action”, “pharmacokinetics”, “pharmacodynamics”, “neurotransmitters”, “toxicology”, “toxicity”, “cardiac”, “neurotoxic”, “human data”, “animal data”, “addiction”, “anti-addictive”, “withdrawal”, “death” and “fatalities”. The searches identified 382 unique references, of which 156 involved human data. Further research revealed 14 detailed toxicological case reports. Pharmacokinetics and pharmacodynamics: Ibogaine is metabolized mainly by CYP2D6 to the primary metabolite noribogaine (10-hydrox...

Abstract: In human skin, keratinopoiesis is based on a functional hierarchy among keratinocytes, with rare slow-cycling stem cells responsible for the long-term maintenance of the tissue through their self-renewal potential, and more differentiated daughter progenitor cells actively cycling to permit epidermal renewal and turn-over every month. Skin is a radio-responsive tissue, developing all types of radiation damage and pathologies, including early tissue reactions such as dysplasia and denudation in epidermis, and later fibrosis in the dermis and acanthosis in epidermis, with the TGF-beta 1 pathway as a known master switch. Also there is a risk of basal cell carcinoma, which arises from epidermal keratinocytes, notably after oncogenic events in PTCH1 or TP53 genes. This review will cover the mechanisms of adverse human skin reactions and carcinogenesis after various types of exposures to ionizing radiation, with comparison with animal data when necessary, and will discuss the possible role of stem cells and their progeny in the development of these disorders. The main endpoints presented are basal cell intrinsic radiosensitivity, genomic stability, individual factors of risk, dose specific responses, major molecular pathways involved and the cellular origin of skin reactions and cancer. Although major advances have been obtained in recent years, the precise implications of epidermal stem cells and their progeny in these processes are not yet fully characterized.

Abstract: We present three in silico volume of distribution at steady state (VDss) models generated on a training set comprising 1096 compounds, which goes well beyond the conventional drug space delineated by the Rule of 5 or similar approaches. We have performed a careful selection of descriptors and kept a homogeneous Molecular Interaction Field-based descriptor set and linear (Partial Least Squares, PLS) and nonlinear (Random Forest, RF) models. We have tested the models, which we deem orthogonal in nature due to different descriptors and statistical approaches, with good results. In particular we tested the RF model, via a leave-class-out approach and by using a set of 34 additional compounds not used for training. We report comparable results against in vivo scaling approaches with geometric mean-fold error at or below 2 (for a set of 60 compounds with animal data available) and discuss the predictive performance based on the ionization states of the compounds. Lastly, we report the findings using a two-tier ...

Abstract: Nowadays molecular imaging plays a vital role in achieving a successful targeted and personalized treatment. Hence, the approach of combining two or more medical imaging modalities was developed. The objective of this review is to systematically compare recent dual contrast agents in Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) and in some cases Single photon emission computed tomography (SPECT)/MRI in terms of some their characteristics, such as tumor uptake, and reticuloendothelial system uptake (especially liver) and their relaxivity rates for early detection of primary cancer tumor. To the best of our knowledge, this is the first systematic and integrated overview of this field. Two reviewers individually directed the systematic review search using PubMed, MEDLINE and Google Scholar. Two other reviewers directed quality assessment, using the criteria checklist from the CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) tool, and differences were resolved by consensus. After reviewing all 49 studies, we concluded that a size range of 20-200 nm can be used for molecular imaging, although it is better to try to achieve as small a size as it is possible. Also, small nanoparticles with a hydrophilic coating and positive charge are suitable as a T2 contrast agent. According to our selected data, the most successful dual probes in terms of high targeting were with an average size of 40 nm, PEGylated using peptides as a biomarker and radiolabeled with copper 64 and gallium 68. Copyright © 2017 John Wiley & Sons, Ltd.

Abstract: Prostate immune system plays a critical role in the regulation of prostate cancer development regarding androgen-deprivation therapy (ADT) and/or immunotherapy (vaccination). In this study, we developed a mathematical model to explore the interactions between prostate tumor and immune microenvironment. This model was used to predict treatment outcomes for prostate cancer with ADT, vaccination, Treg depletion and/or IL-2 neutralization. Animal data were used to guide construction, parameter selection, and validation of our model. Our analysis shows that Treg depletion and/or IL-2 neutralization can effectively improve the treatment efficacy of combined therapy with ADT and vaccination. Treg depletion has a higher synergetic effect than that from IL-2 neutralization. This study highlights a potential therapeutic strategy in effectively managing prostate tumor growth and provides a framework of systems biology approach in studying tumor-related immune mechanism and consequent selection of therapeutic regimens.