Stem Cell Transplantation in Traumatic Spinal Cord Injury: A Systematic Review and Meta-Analysis of Animal Studies

Spinal cord injury (SCI) is a devastating condition that causes substantial morbidity and mortality and for which no treatments are available. Stem cells offer some promise in the restoration of neurological function. We used systematic review, meta-analysis, and meta-regression to study the impact of stem cell biology and experimental design on motor and sensory outcomes following stem cell treatments in animal models of SCI. One hundred and fifty-six publications using 45 different stem cell preparations met our prespecified inclusion criteria. Only one publication used autologous stem cells. Overall, allogeneic stem cell treatment appears to improve both motor (effect size, 27.2%; 95% Confidence Interval [CI], 25.0%–29.4%; 312 comparisons in 5,628 animals) and sensory (effect size, 26.3%; 95% CI, 7.9%–44.7%; 23 comparisons in 473 animals) outcome. For sensory outcome, most heterogeneity between experiments was accounted for by facets of stem cell biology. Differentiation before implantation and intravenous route of delivery favoured better outcome. Stem cell implantation did not appear to improve sensory outcome in female animals and appeared to be enhanced by isoflurane anaesthesia. Biological plausibility was supported by the presence of a dose–response relationship. For motor outcome, facets of stem cell biology had little detectable effect. Instead most heterogeneity could be explained by the experimental modelling and the outcome measure used. The location of injury, method of injury induction, and presence of immunosuppression all had an impact. Reporting of measures to reduce bias was higher than has been seen in other neuroscience domains but were still suboptimal. Motor outcomes studies that did not report the blinded assessment of outcome gave inflated estimates of efficacy. Extensive recent preclinical literature suggests that stem-cell–based therapies may offer promise, however the impact of compromised internal validity and publication bias mean that efficacy is likely to be somewhat lower than reported here.     

The Relationship between Active Trachoma and Ocular Chlamydia trachomatis Infection before and after Mass Antibiotic Treatment

BackgroundTrachoma is a blinding disease, initiated in early childhood by repeated conjunctival infection with the obligate intracellular bacterium Chlamydia trachomatis. The population prevalence of the clinical signs of active trachoma; ‘‘follicular conjunctivitis” (TF) and/or ‘‘intense papillary inflammation” (TI), guide programmatic decisions regarding the initiation and cessation of mass drug administration (MDA). However, the persistence of TF following resolution of infection at both the individual and population level raises concerns over the suitability of this clinical sign as a marker for C. trachomatis infection.Conclusions/SignificancePrior to MDA, TF is a good indicator of the community prevalence of C. trachomatis infection. Following MDA, the prevalence of TF tends to overestimate the underlying infection prevalence. In order to prevent unnecessary additional rounds of MDA and to accurately ascertain when elimination goals have been reached, a cost-effective test for C. trachomatis that can be administered in low-resource settings remains desirable.     

Structure from motion photogrammetry in ecology: Does the choice of software matter?

Image‐based modeling, and more precisely, Structure from Motion (SfM) and Multi‐View Stereo (MVS), is emerging as a flexible, self‐service, remote sensing tool for generating fine‐grained digital surface models (DSMs) in the Earth sciences and ecology. However, drone‐based SfM + MVS applications have developed at a rapid pace over the past decade and there are now many software options available for data processing. Consequently, understanding of reproducibility issues caused by variations in software choice and their influence on data quality is relatively poorly understood. This understanding is crucial for the development of SfM + MVS if it is to fulfill a role as a new quantitative remote sensing tool to inform management frameworks and species conservation schemes. To address this knowledge gap, a lightweight multirotor drone carrying a Ricoh GR II consumer‐grade camera was used to capture replicate, centimeter‐resolution image datasets of a temperate, intensively managed grassland ecosystem. These data allowed the exploration of method reproducibility and the impact of SfM + MVS software choice on derived vegetation canopy height measurement accuracy. The quality of DSM height measurements derived from four different, yet widely used SfM‐MVS software—Photoscan, Pix4D, 3DFlow Zephyr, and MICMAC, was compared with in situ data captured on the same day as image capture. We used both traditional agronomic techniques for measuring sward height, and a high accuracy and precision differential GPS survey to generate independent measurements of the underlying ground surface elevation. Using the same replicate image dataset (n = 3) as input, we demonstrate that there are 1.7, 2.0, and 2.5 cm differences in RMSE (excluding one outlier) between the outputs from different SfM + MVS software using High, Medium, and Low quality settings, respectively. Furthermore, we show that there can be a significant difference, although of small overall magnitude between replicate image datasets (n = 3) processed using the same SfM + MVS software, following the same workflow, with a variance in RMSE of up to 1.3, 1.5, and 2.7 cm (excluding one outlier) for “High,” “Medium,” and “Low” quality settings, respectively. We conclude that SfM + MVS software choice does matter, although the differences between products processed using “High” and “Medium” quality settings are of small overall magnitude.     

Failure to reduce an isolated Blowfly population by the sterile males method

In 1956 and 1957 pupae of L. sericata were irradiated at 6,000–7,000 rep, and allowed to emerge at three points on Holy Island. The sterilized population was maintained in preponderant numbers by regular replenishments. A test in 1958 showed no reduction in the density of the species. Possible causes of failure of the method are examined, and it is concluded that either the sterilization was inadequate or that the sterilized males were unable to compete with the native males.

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Zusammenfassung Die Methode sterile Männchen zur Ausrottung einer Art zu benutzen, ist in ihrer Wirkung mathematisch zuverlässig, vorausgesetzt, daß die anerkannten biologischen Erfordernisse vorhanden sind; sie hat sich in der Praxis gegen Callitroga bominivorax (Myiasisfliege) als wirksam erwiesen. In einem in kleinen Maßstabe durchgeführten Versuch gegen die Goldfliege Lucilia sericata wurden Fliegen, die durch eine 6,000–7,000 rep Gamma-Strahlung sterilisiert worden waren, in überwiegenden Zahlen auf einer 5 km² großen Insel in zwei aufeinanderfolgenden Jahren freigelassen. Eine Reduktion der einheimischen L. sericata-Population ließ sich nicht nachweisen. Es wurde experimentell geprüft, daß eine Zuwanderung von Fliegen vom Festland zu vernachlässigen war; wiederholte Versuche bestätigten, daß die Bestrahlungsdosis ausreichte, um sexuelle Sterilität zu erzeugen. Der Ablauf und die technischen Einzelheiten der Versuche wurden analysiert in dem Bestreben, die Ursache des Versagens ausfindig zu machen.Das Verhältnis steriler zu eingeborenen Männchen könnte im ersten Jahr infolge hoher Mortalität der sterilisierten Puppen under die erwartete Relation 5 : 1 gesunken sein. Diese Mortalität stand offenbar mit der Zuchtmethode in Beziehung. Es wurde jedoch gefolgert, daß dies an sich nicht für das Versagen verantwortlich gemacht werden könnte.Er wird vorläufig angenommen, daß hier, als Ergebnis von Sauerstoffmangel, ein geringer aber signifikanter Grad von Resistenz gegen Bestrahlung vorliege, möglicherweise begleitet von einer ähnlich geringgradigen Erholungsfähigkeit von Strahlungswirkungen; andererseits versagte das sterilisierte Sperma in Konkurrenz mit fertilem Sperma bei Doppelbegattungen.

     

Persistent use of false myeloma cell lines

Multiple myeloma (MM) is a neoplasm of a terminally differentiated B-cell. Human myeloma cell lines were shown to be suitable model systems for use in various fields of the biological sciences. Within the last 20 years more than 100 cell lines have been established. So-called 'myeloma cell lines' have been previously reported and are still widely used which are in reality Epstein-Barr virus (EBV)-positive B-lymphoblastoid cell lines. The presence of the EBV-genome in residual normal B-cells provides them with a selective growth advantage after explantation. Cell lines represent an extremely important resource for research in a variety of fields and disciplines. As the cell lines are used as in vitro model systems in lieu of primary material, it is crucial that the cells in the culture flasks faithfully correspond to the purported objects of study. On closer examination, the use of false cell lines may be seen to invalidate a significant percentage of scientific work, or at least cast doubts on the relevance of these in vitro results to the cell type or tumor in vivo. Ultimately, use of cross-contaminated cell lines is a waste of human and material resources. Henceforth, it should be mandatory to prove the proper derivation of each new cell line by comparing DNA fingerprints or karyotypes of the patient's primary cells and the cultured cells. The availability of well characterized and authenticated bona fide MM cell lines is of great importance for the study of the biology, etiology and treatment of the disease.     

Tumor suppressor genes

Although tumor suppressor genes continue to be discovered, the most recent advances have been made in attributing new and exciting functions to existing ones - such as the apparent role of VHL as a regulator of proteolysis. Great insights have also come from piecing genes together into pathways and networks. For instance the discovery that cyclin D1 is regulated by beta-catenin/Tcf-4 allows us to tie the APC pathway to the RB pathway and cell cycle control. Similarly, tumor suppressor genes have been fitted together with oncogenes into the various pathways that regulate apoptosis such that tumor suppressor function is now attributed to some of the basic components of the apoptotic machinery, such as caspases and Apaf-1. The great pace at which mouse models of tumorigenesis continue to advance our knowledge of tumor suppressor gene function has led us to look anew at the role of genes such as TCF-1 and SMAD-3 in human cancer. Finally, the realisation that different growth regulatory pathways give rise to generic signals suggests that future work may lie in integrating the signals from different pathways and in understanding the importance of protein levels to cellular function.     

Analysis of plastid DNA-like sequences within the nuclear genomes of higher plants

A wide-ranging examination of plastid (pt)DNA sequence homologies within higher plant nuclear genomes (promiscuous DNA) was undertaken. Digestion with methylation-sensitive restriction enzymes and Southern analysis was used to distinguish plastid and nuclear DNA in order to assess the extent of variability of promiscuous sequences within and between plant species. Some species, such as Gossypium hirsutum (cotton), Nicotiana tabacum (tobacco), and Chenopodium quinoa, showed homogenity of these sequences, while intraspecific sequence variation was observed among different cultivars of Pisum sativum (pea), Hordeum vulgare (barley), and Triticum aestivum (wheat). Hypervariability of plastid sequence homologies was identified in the nuclear genomes of Spinacea oleracea (spinach) and Beta vulgaris (beet), in which individual plants were shown to possess a unique spectrum of nuclear sequences with ptDNA homology. This hypervariability apparently extended to somatic variation in B. vulgaris. No sequences with ptDNA homology were identified by this method in the nuclear genome of Arabidopsis thaliana.      

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Objective

To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis.

Design

Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action.

Results

We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation.

Conclusions

We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.