Rare Kidney Diseases

Rare kidney diseases comprise a large group of different life-threatening or chronically debilitating disorders that affect very small numbers of people (<1 in 2000 individuals in Europe and <200,000 in USA) with local or systemic manifestations. For several years, the research and development of treatments in this field have been neglected in favor of more common diseases. The main reasons for the lack of interest in rare kidney diseases seem to be the small numbers of patients and limited epidemiological data on the natural history of many of these diseases. Rare diseases can affect people differently. Even patients with the same condition can exhibit very different signs and symptoms, or there may be many subtypes of the same condition. This diversity constitutes a significant challenge to healthcare practitioners and scientists alike, in terms of being able to acquire sufficient experience for the most appropriate and timely definition, diagnosis, and management. Fortunately, in the last ten years, concerted efforts have led to a marked improvement in the understanding of these disorders. In particular, an important step forward has been taken with the employment of innovative technologies (including next-generation sequencing), in order to replace obsolete phenotypic classifications and to discover new useful diagnostic biomarkers. These new tools are, in fact, becoming part of routine clinical practice, increasing diagnostic accuracy and facilitating genetic counseling. Moreover, biomedical research, providing insights into the pathologies of these rare diseases and elucidating their underlying mechanisms, is revealing new therapeutic avenues and driving the industry to develop safer and more effective orphan drugs. Finally, in this field, it is desirable that, in the future, the crosstalk between basic scientists and clinicians could achieve a great clinical benefit by improving the quality of life of these patients as well. This Special Issue welcomes scientific contributions and critical reviews describing new pathogenetic insights, reporting novel and specific disease biomarkers, and underlying new pharmacological targets or therapies for rare diseases of the kidney and urinary tract

Method validation of High Performance Liquid Chromatography for determination of mycolic acid profile of Mycobacterium tuberculosis

This study developed the High Performance Liquid Chromatography (HPLC) for INH resistant M. tuberculosis (MTB) isolate identification based on a chromatogram profile of mycolic acids (MAs). The aim of this study was to validate the HPLC for determining the characteristic profile of MAs chromatogram of the INH resistant MTB. The optimum derivatization process obtained was as follows: the minimum biomass weight was 25 mg. The experimental temperature was performed in (80-90)o C using a water bath for minimum 30 minutes in order to complete the MAs derivatization. Reagent volume used in the range of (200-500 μL) were not influenced the MAs chromatogram profile. The optimum condition of HPLC was as follows: mobile phase was methanol:isopropanol (60:40) for 3 minutes, followed by gradient elution (4:96) in 50 minutes. Thereafter, the mobile phase composition change gradually for 40 minutes to a final composition of (60:40). The sample volume was 20 μL and the mobile phase flow rate was 1 mL/minute. The result of this study showed that the MAs chromatogram profile of INH resistant MTB looked like H37Rv MTB strain. The chromatogramp profile was a cluster with 6 characteristic peaks at the end of the analysis. The other short chain carbon fatty acids were eluted in the first 15 minutes

Nutrition for Musculoskeletal Health

The maintenance of optimal musculoskeletal health is increasingly recognized as a key element for promoting overall health and fostering independent living in advanced age. Growing evidence indicates that nutrition, together with an active lifestyle, plays a central role in supporting musculoskeletal health both aging and in the setting of specific disease conditions. This Special Issue of Nutrients, entitled “Nutrition for Musculoskeletal Health”, includes original research and review contributions highlighting the relevance of nutrition to musculoskeletal health during aging and in the context of specific diseases. The overarching theme of the Special Issue is addressed through a multidisciplinary set of articles embracing clinical, basic science, and translational studies

The design, development and testing of a non-invasive continuous crystalliser system for the study of calcium oxalate crystallisation processes

Includes bibliographies.The MSMPR was designed according to chemical engineering principles and tests showed that it conforms to the assumptions necessary for conventional MSMPR analysis. Various crystalliser offtakes and six system designs were developed and tested to allow measurements using the thermostatted flow cell. The flow cell allows for continuous measurement of the sample dispersion using a noninvasive monitoring instrument - a Malvern Particle Size Analyser. In this technique, measurement of the steady state crystal size distribution is based on a diffraction pattern produced by the particles in a parallel beam of monochromatic light. Comparative measurements were obtained by sampling directly from the crystalliser and analysing the product in a Coulter Counter. In this technique, the steady state crystal size distribution is measured by the change in resistance as particles, in an electrically conductive liquid, pass through the Coulter aperture. Due to the large volumes required by the crystalliser, it was necessary to pool urines. Aliquots of volume 1. 5 dm3 from the 24 hour urines of each of 8 male controls were pooled. The first series of experiments were performed to investigate the effect on calcium oxalate crystallisation of varying the concentration of sodium oxalate solutions used to initiate crystallisation, and also to investigate the effect of varying the temperature. A further series of experiments was performed to determine the effect of adding inhibitors individually (citrate, magnesium, chondroitin sulphate A) and in combination (citrate and magnesium). The inhibitor experiments were performed using two different approaches. In the first, the pooled urine was pre-treated with the inhibitor prior to being introduced into the crystalliser. In the second set of experiments, the inhibitor was introduced into the crystalliser via a separate, independent feed. It is suggested that these approaches represent crude models respectively of (a) the endogenous presence of inhibitors and (b) the oral administration of such inhibitors. Each individual experiment was performed using three different urine pools. The steady state crystal size distributions obtained from both the Coulter and the Malvern instruments were used to determine nucleation and growth rates in each urine. Scanning electron microscopy was used to obtain qualitative and semi-quantitative data related to crystal morphology, number, size and degree of aggregation. Both nucleation and growth rates increased as the concentrations of the initiating sodium oxalate solutions increased. Nucleation and growth rates also increased with increasing temperatures. In the latter series of experiments, different calcium oxalate crystal phases precipitated at the various temperatures. Citrate inhibited nucleation and growth of calcium oxalate, irrespective of how it was admitted to the crystalliser. Magnesium was found to inhibit growth only and, like citrate, this role was independent of how it was introduced into the crystalliser. Although both inhibited growth, the effect of the citrate was greater. When both components were added in combination, inhibition was observed to be additive. In all cases, inhibitory effects increased with increasing concentration. Chondroitin sulphate A was found to inhibit nucleation; inhibition of growth was minimal at the concentrations tested. Aggregation of calcium oxalate crystals was found to be inhibited by chondroitin sulphate A. The results of the calcium oxalate crystallisation kinetic studies, obtained by using Malvern particle sizing and Coulter Counter techniques independently of each other, showed general agreement. These results, in turn, were in agreement with the published results of others, thereby lending confidence to the findings and highlighting the potential application of the non-invasive continuous crystalliser in urolithiasis research

Towards Metabolic Biomarkers for the Diagnosis and Prognosis of CKD

Chronic kidney disease, the gradual loss of renal function, is an increasingly recognized burden for patients and health care systems; globally, it has a high and rapidly growing prevalence, a significant mortality, and causes disproportionately high costs, particularly for hemodialysis and kidney transplantations. Yet, the available diagnostic tools are either impractical in clinical routine or have serious shortcomings preventing a well-informed disease management, although optimized treatment strategies with impressive benefits for patients have been established. Advances in bioanalytics have facilitated the identification of many genomic, proteomic, and metabolic biomarker candidates, some of which have been validated in independent cohorts. Summarizing the markers discovered so far, this chapter focuses on compounds or pathways, for which quantitative data, substantiating evidence from translational research, and a mechanistic understanding is available. Also, multiparametric marker panels have been suggested with promising diagnostic and prognostic performance in initial analyses, although the data basis from prospective trials is very limited. Large-scale studies, however, are underway and will validate certain sets of parameters and discard others. Finally, the path from clinical research to routine application is discussed, focusing on potential obstacles such as the use of mass spectrometry, and the feasibility of obtaining regulatory approval for metabolomics assays

Identification of inhibitors from a functional food-based plant Perillae Folium against hyperuricemia via metabolomics profiling, network pharmacology and all-atom molecular dynamics simulations

IntroductionHyperuricemia (HUA) is a metabolic disorder caused by purine metabolism dysfunction in which the increasing purine levels can be partially attributed to seafood consumption. Perillae Folium (PF), a widely used plant in functional food, has been historically used to mitigate seafood-induced diseases. However, its efficacy against HUA and the underlying mechanism remain unclear. MethodsA network pharmacology analysis was performed to identify candidate targets and potential mechanisms involved in PF treating HUA. The candidate targets were determined based on TCMSP, SwissTargetPrediction, Open Targets Platform, GeneCards, Comparative Toxicogenomics Database, and DrugBank. The potential mechanisms were predicted via Gene Ontology (GO) and Kyoto Gene and Genome Encyclopedia (KEGG) analyses. Molecular docking in AutoDock Vina and PyRx were performed to predict the binding affinity and pose between herbal compounds and HUA-related targets. A chemical structure analysis of PF compounds was performed using OSIRIS DataWarrior and ClassyFire. We then conducted virtual pharmacokinetic and toxicity screening to filter potential inhibitors. We further performed verifications of these inhibitors’ roles in HUA through molecular dynamics (MD) simulations, text-mining, and untargeted metabolomics analysis. ResultsWe obtained 8200 predicted binding results between 328 herbal compounds and 25 potential targets, and xanthine dehydrogenase (XDH) exhibited the highest average binding affinity. We screened out five promising ligands (scutellarein, benzyl alpha-D-mannopyranoside, elemol, diisobutyl phthalate, and (3R)-hydroxy-beta-ionone) and performed MD simulations up to 50 ns for XDH complexed to them. The scutellarein-XDH complex exhibited the most satisfactory stability. Furthermore, the text-mining study provided laboratory evidence of scutellarein’s function. The metabolomics approach identified 543 compounds and confirmed the presence of scutellarein. Extending MD simulations to 200 ns further indicated the sustained impact of scutellarein on XDH structure. ConclusionOur study provides a computational and biomedical basis for PF treating HUA and fully elucidates scutellarein's great potential as an XDH inhibitor at the molecular level, holding promise for future drug design and development

Bibliometric analysis of the global scientific production on machine learning applied to different cancer types

This work has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement no. 860627 (CLARIFY Project), from the Spanish Ministry of Science and Innovation under project PID2019-105142RB-C22, and by FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades under the project P20_00286. Funding for open access charge: Universidad de Granada/CBUA.Cancer disease is one of the main causes of death in the world, with million annual cases in the last decades. The need to find a cure has stimulated the search for efficient treatments and diagnostic procedures. One of the most promising tools that has emerged against cancer in recent years is machine learning (ML), which has raised a huge number of scientific papers published in a relatively short period of time. The present study analyzes global scientific production on ML applied to the most relevant cancer types through various bibliometric indicators. We find that over 30,000 studies have been published so far and observe that cancers with the highest number of published studies using ML (breast, lung, and colon cancer) are those with the highest incidence, being the USA and China the main scientific producers on the subject. Interestingly, the role of China and Japan in stomach cancer is correlated with the number of cases of this cancer type in Asia (78% of the worldwide cases). Knowing the countries and institutions that most study each area can be of great help for improving international collaborations between research groups and countries. Our analysis shows that medical and computer science journals lead the number of publications on the subject and could be useful for researchers in the field. Finally, keyword co-occurrence analysis suggests that ML-cancer research trends are focused not only on the use of ML as an effective diagnostic method, but also for the improvement of radiotherapy- and chemotherapy-based treatments.Horizon 2020 European Union under the Marie Sklodowska Curie 860627Spanish Government PID2019-105142RB-C22FEDER/Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y Universidades P20_00286Universidad de Granada/CBU

Occupational kidney disease among young populations in northwest Nicaragua

Chronic kidney disease of undetermined aetiology (CKDu) is mainly responsible for the deaths of young males in agricultural lowland regions of Central America. The aim of this thesis was to advance the understanding of the causes of CKDu by conducting several different epidemiological research studies. The systematic review identified a number of cross-sectional studies and occupational cohort studies with limited follow-up periods, but the findings were inconclusive regarding the causes of CKDu. The cohort study described in this PhD thesis is the first community-based cohort study in the region to evaluate the natural history of disease in apparently healthy people aged 18-30 years. It collected information about a wide range of exposure conditions with a questionnaire, biological samples, and water samples. There was an unparalleled, asymptomatic and very rapid decline in renal function among 10% of males and 3.5% of females who had normal renal function at baseline. Meanwhile, the group displaying established renal dysfunction (mean estimated glomerular filtration rate, eGFR: 58 mL/min/1.73 m2) at baseline showed a slower subsequent decline in kidney function (3.6 mL/min/1.73 m2/year). A rapid decrease in eGFR was associated with outdoor work, agricultural work, and a lack of shade during work breaks. The nested case-control study measured eGFR, and urinary neutrophil gelatinase-associated lipocalin (uNGAL) at baseline. After adjusting for eGFR, uNGAL did not improve prediction a rapid decline in kidney function among individuals who initially presented a normal eGFR. This is the first study to show that in northwest Nicaragua, 10% of the male and 3.5% of the female population aged 18-30 years showed a very strong decline in kidney function. Larger community-based and occupational longitudinal studies with more detailed analyses of exposure data are needed to identify the cause(s) of CKDu