Predictive enrichment for the need of renal replacement in sepsis-associated acute kidney injury: combination of furosemide stress test and urinary biomarkers TIMP-2 and IGFBP-7.

BACKGROUND: In sepsis, initial resuscitation with fluids is followed by efforts to achieve a negative fluid balance. However, patients with sepsis-associated acute kidney injury (SA-AKI) often need diuretic or renal replacement therapy (RRT). The dilemma is to predict whether early RRT might be advantageous or diuretics will suffice. Both the Furosemide Stress Test (FST) and measurements of the urinary biomarkers TIMP-2*IGFBP-7, if applied solely, do not provide sufficient guidance. We tested the hypothesis that a combination of two tests, i.e., an upstream FST combined with downstream measurements of urinary TIMP-2*IGFBP-7 concentrations improves the accuracy in predicting RRT necessity. METHODS: In this prospective, multicenter study 100 patients with sepsis (diagnosed < 48h), AKI stage ≥ 2, and an indication for negative fluid balance were included between 02/2020 and 12/2022. All patients received a standardized FST and urinary biomarkers TIMP-2*IGFBP-7 were serially measured immediately before and up to 12 h after the FST. The primary outcome was the RRT requirement within 7 days after inclusion. RESULTS: 32% (n = 32/99) of SA-AKI patients eventually required RRT within 7 days. With the FST, urine TIMP-2*IGFBP-7 decreased within 2 h from 3.26 ng2/mL2/1000 (IQR: 1.38-5.53) to 2.36 ng2/mL2/1000 (IQR: 1.61-4.87) in RRT and 1.68 ng2/mL2/1000 (IQR: 0.56-2.94) to 0.27 ng2/mL2/1000 (IQR: 0.12-0.89) and non-RRT patients, respectively. While TIMP-2*IGFBP-7 concentrations remained low for up to 12 h in non-RRT patients, we noted a rebound in RRT patients after 6 h. TIMP-2*IGFBP-7 before FST (accuracy 0.66; 95%-CI 0.55-0.78) and the FST itself (accuracy 0.74; 95%-CI: 0.64-0.82) yielded moderate test accuracies in predicting RRT requirement. In contrast, a two-step approach, utilizing FST as an upstream screening tool followed by TIMP-2*IGFBP-7 quantification after 2 h improved predictive accuracy (0.83; 95%-CI 0.74-0.90, p = 0.03) compared to the FST alone, resulting in a positive predictive value of 0.86 (95%-CI 0.64-0.97), and a specificity of 0.96 (95%-CI 0.88-0.99). CONCLUSIONS: The combined application of an upstream FST followed by urinary TIMP-2*IGFBP-7 measurements supports highly specific identification of SA-AKI patients requiring RRT. Upcoming interventional trials should elucidate if this high-risk SA-AKI subgroup, identified by our predictive enrichment approach, benefits from an early RRT initiation.

Quantifying compositional variability in microbial communities with FAVA.

Microbial communities vary across space, time, and individual hosts, presenting new challenges for the development of statistics measuring the variability of community composition. To understand differences across microbiome samples from different host individuals, sampling times, spatial locations, or experimental replicates, we present FAVA, a new normalized measure for characterizing compositional variability across multiple microbiome samples. FAVA quantifies variability across many samples of taxonomic or functional relative abundances in a single index ranging between 0 and 1, equaling 0 when all samples are identical and equaling 1 when each sample is entirely comprised of a single taxon. Its definition relies on the population-genetic statistic F S T , with samples playing the role of "populations" and taxa playing the role of "alleles." Its convenient mathematical properties allow users to compare disparate data sets. For example, FAVA values are commensurable across different numbers of taxonomic categories and different numbers of samples considered. We introduce extensions that incorporate phylogenetic similarity among taxa and spatial or temporal distances between samples. We illustrate how FAVA can be used to describe across-individual taxonomic variability in ruminant microbiomes at different regions along the gastrointestinal tract. In a second example, a longitudinal analysis of gut microbiomes of healthy human adults taking an antibiotic, we use FAVA to quantify the increase in temporal variability of microbiomes following the antibiotic course and to measure the duration of the antibiotic's influence on microbial variability. We have implemented this tool in an R package, FAVA, which can fit easily into existing pipelines for the analysis of microbial relative abundances.

Treatment of Post-Inflammatory Hyperpigmentation in Skin of Colour: A Systematic Review.

Post inflammatory hyperpigmentation (PIH) affects all skin types with a heightened predilection for darker skin tones. Its course is chronic once developed and treatment is often difficult. This systematic review aims to summarize the treatment outcomes for PIH with a focus on skin of colour (SOC) individuals. A literature search was conducted using MEDLINE (from 1946), Embase (from 1974), PubMed, and Cochrane in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline. Results from 48 studies summarized 1356 SOC individuals. The mean age was 29 years (n = 1036) and 78% were female (n = 786). The ethnic prevalence was 70% Black, 27% Asian, and 3% Latin. Overall, 20% were Fitzpatrick skin type (FST) III, 40% FST IV, 34% FST V, and 6% FST VI. Most cases were precipitated by inflammatory conditions (89%) and localized to the face (83%). The most frequently reported interventions were topical retinoids (22%) and laser therapy (17%). Partial improvement was seen in 85% and 66% of participants, respectively. Laser was the only intervention that offered complete resolution in a subgroup of patients (26%); however, there were reported cases of PIH exacerbation following treatment. Chemical peels (9%) and hydroquinone (7%) were among other treatments with less effective outcomes. PIH and its persistence is a prevalent issue, significantly affecting many affected individuals with darker skin tones. Our results show a lack of robust efficacy across all treatment modalities. There is considerable room for improvement in interventions for at-risk populations.

Quantifying variations associated with dental caries reveals disparity in effect allele frequencies across diverse populations.

BACKGROUND: Dental caries (DC) is a multifaceted oral condition influenced by genetic and environmental factors. Recent advancements in genotyping and sequencing technologies, such as Genome-Wide Association Studies (GWAS) have helped researchers to identify numerous genetic variants associated with DC, but their prevalence and significance across diverse global populations remain poorly understood as most of the studies were conducted in European populations, and very few were conducted in Asians specifically in Indians. AIM: This study aimed to evaluate the genetic affinity of effect alleles associated with DC to understand the genetic relationship between global populations with respect to the Indian context. METHODOLOGY: This present study used an empirical approach in which variants associated with DC susceptibility were selected. These variants were identified and annotated using the GWAS summary. The genetic affinity was evaluated using Fst. RESULTS: The effect of allele frequencies among different populations was examined, revealing variations in allele distribution. African populations exhibited higher frequencies of specific risk alleles, whereas East Asian and European populations displayed distinct profiles. South Asian populations showed a unique genetic cluster. CONCLUSION: Our study emphasises the complex genetic landscape of DC and highlights the need for population-specific research as well as validation of GWAS-identified markers in Indians before defining them as established candidate genes.

Genome-wide comparative analysis reveals selection signatures for reproduction traits in prolific Suffolk sheep.

The identification of genome-wide selection signatures can reveal the potential genetic mechanisms involved in the generation of new breeds through natural or artificial selection. In this study, we screened the genome-wide selection signatures of prolific Suffolk sheep, a new strain of multiparous mutton sheep, to identify candidate genes for reproduction traits and unravel the germplasm characteristics and population genetic evolution of this new strain of Suffolk sheep. Whole-genome resequencing was performed at an effective sequencing depth of 20× for genomic diversity and population structure analysis. Additionally, selection signatures were investigated in prolific Suffolk sheep, Suffolk sheep, and Hu sheep using fixation index (F ST) and heterozygosity H) analysis. A total of 5,236.338 Gb of high-quality genomic data and 28,767,952 SNPs were obtained for prolific Suffolk sheep. Moreover, 99 selection signals spanning candidate genes were identified. Twenty-three genes were significantly associated with KEGG pathway and Gene Ontology terms related to reproduction, growth, immunity, and metabolism. Through selective signal analysis, genes such as ARHGEF4, CATIP, and CCDC115 were found to be significantly correlated with reproductive traits in prolific Suffolk sheep and were highly associated with the mTOR signaling pathway, the melanogenic pathway, and the Hippo signaling pathways, among others. These results contribute to the understanding of the evolution of artificial selection in prolific Suffolk sheep and provide candidate reproduction-related genes that may be beneficial for the establishment of new sheep breeds.

A Comprehensive Review of Non-Surgical Treatments for Hypertrophic and Keloid Scars in Skin of Color.

Hypertrophic and keloid scars are fibroproliferative growths resulting from aberrant wound healing. Individuals with Fitzpatrick skin types (FSTs) IV-VI are particularly predisposed to hypertrophic and keloid scarring, yet specific guidelines for these populations are still lacking within the literature. Therefore, this comprehensive review provides a list of various treatments and considerations for hypertrophic and keloid scarring in patients with skin of color. We constructed a comprehensive PubMed search term and performed quadruple-blinded screening on all resulting studies to achieve this objective. Our findings demonstrate 1) the lack of efficacious treatments for raised scars within this population and 2) the need to empirically investigate individualized and multimodal therapeutic options for those with skin of color.

Furosemide stress test to predict acute kidney injury progression in critically ill children.

BACKGROUND: Furosemide stress test (FST) is a novel functional biomarker for predicting severe acute kidney injury (AKI); however, pediatric studies are limited. METHODS: Children 3 months to 18 years of age admitted to the intensive care unit (ICU) of a tertiary care hospital from Nov 2019 to July 2021 were screened and those who developed AKI stage 1 or 2 within 7 days of admission underwent FST (intravenous furosemide 1 mg/kg). Urine output was measured hourly for the next 6 h; a value > 2 ml/kg within the first 2 h was deemed furosemide responsive. Other biomarkers like plasma neutrophil gelatinase-associated lipocalin (NGAL) and proenkephalin (PENK) were also evaluated. RESULTS: Of the 480 admitted patients, 51 developed AKI stage 1 or 2 within 7 days of admission and underwent FST. Nine of these patients were furosemide non-responsive. Thirteen (25.5%) patients (eight of nine from FST non-responsive group) developed stage 3 AKI within 7 days of FST, nine (17.6%) of whom (seven from non-responsive group) required kidney support therapy (KST). FST emerged as a good biomarker for predicting stage 3 AKI and need for KST with area-under-the-curve (AUC) being 0.93 ± 0.05 (95% CI 0.84-1.0) and 0.96 ± 0.03 (95% CI 0.9-1.0), respectively. FST outperformed NGAL and PENK in predicting AKI stage 3 and KST; however, the combination did not improve the diagnostic accuracy. CONCLUSIONS: Furosemide stress test is a simple, inexpensive, and robust biomarker for predicting stage 3 AKI and KST need in critically ill children. Further research is required to identify the best FST cut-off in children.

Assessment of Genomic Diversity and Selective Pressures in Crossbred Dairy Cattle of Pakistan.

Improving the low productivity levels of native cattle breeds in smallholder farming systems is a pressing concern in Pakistan. Crossbreeding high milk-yielding holstein friesian (HF) breed with the adaptability and heat tolerance of Sahiwal cattle has resulted in offspring that are well-suited to local conditions and exhibit improved milk yield. The exploration of how desirable traits in crossbred dairy cattle are selected has not yet been investigated. This study aims to provide the first overview of the selective pressures on the genome of crossbred dairy cattle in Pakistan. A total of eighty-one crossbred, thirty-two HF and twenty-four Sahiwal cattle were genotyped, and additional SNP genotype data for HF and Sahiwal were collected from a public database to equate the sample size in each group. Within-breed selection signatures in crossbreds were investigated using the integrated haplotype score. Crossbreds were also compared to each of their parental breeds to discover between-population signatures of selection using two approaches: cross-population extended haplotype homozygosity and fixation index. We identified several overlapping genes associated with production, immunity, and adaptation traits, including U6, TMEM41B, B4GALT7, 5S_rRNA, RBM27, POU4F3, NSD1, PRELID1, RGS14, SLC34A1, TMED9, B4GALT7, OR2AK3, OR2T16, OR2T60, OR2L3, and CTNNA1. Our results suggest that regions responsible for milk traits have generally experienced stronger selective pressure than others.

Eco-Transformation of construction: Harnessing machine learning and SHAP for crumb rubber concrete sustainability.

Researchers have focused their efforts on investigating the integration of crumb rubber as a substitute for conventional aggregates and cement in concrete. Nevertheless, the manufacture of crumb rubber concrete (CRC) has been linked to the release of noxious pollutants, hence presenting potential environmental hazards. Rather than developing novel CRC formulations, the primary objective of this work is to construct an extensive database by leveraging prior research efforts. The study places particular emphasis on two crucial concrete properties: compressive strength (fc') and tensile strength (fts). The database includes a total of 456 data points for fc' and 358 data points for fts, focusing on nine essential characteristics that have a substantial impact on both attributes. The research employs several machine learning algorithms, including both individual and ensemble methods, to undertake a comprehensive analysis of the created databases for fc' and fts. In order to ascertain the correctness of the models, a comparative analysis of machine learning techniques, namely decision tree (DT) and random forest (RF), is conducted using statistical evaluation. Cross-validation approaches are used in order to address the possible issues of overfitting. Furthermore, the Shapley additive explanations (SHAP) approach is used to investigate the influence of input parameters and their interrelationships. The findings demonstrate that the RF methodology has superior performance compared to other ensemble techniques, as shown by its lower error rates and higher coefficient of determination (R2) of 0.87 and 0.85 for fc' and fts respectively. When comparing ensemble approaches, it can be seen that AdaBoost outperforms bagging by 6 % for both outcome models and individual decision tree learners by 17% and 21% for fc' and fts respectively in terms of performance. The average accuracy of AdaBoost algorithm for both the models is 84%. Significantly, the age and the inclusion of crumb rubber in CRC are identified as the primary criteria that have a substantial influence on the mechanical properties of this particular kind of concrete.

The role of mGluR5 on the therapeutic effects of ketamine in Wistar rats.

RATIONALE: Ketamine produces dissociative, psychomimetic, anxiolytic, antidepressant, and anesthetic effects in a dose dependent manner. It has a complex mechanism of action that involve alterations in other glutamate receptors. The metabotropic glutamate receptor 5 (mGluR5) has been investigated in relation to the psychotic and anesthetic properties of ketamine, while its role in mediating the therapeutic effects of ketamine remains unknown. OBJECTIVES: We investigated the role of mGluR5 on the antidepressant, anxiolytic and fear memory-related effects of ketamine in adult male Wistar rats. METHODS: Two sets of experiments were conducted. We first utilized the positive allosteric modulator CDPPB to investigate how acute mGluR5 activation regulates the therapeutic effects of ketamine (10 mg/kg). We then tested the synergistic antidepressant effect of mGluR5 antagonism and ketamine by combining MTEP with a sub-effective dose of ketamine (1 mg/kg). Behavioral despair, locomotor activity, anxiety-like behavior, and fear memory were respectively assessed in the forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and auditory fear conditioning. RESULTS: Enhancing mGluR5 activity via CDPPB occluded the antidepressant effect of ketamine without changing locomotor activity. Furthermore, concomitant administration of MTEP and ketamine exhibited a robust synergistic antidepressant effect. The MTEP + ketamine treatment, however, blocked the anxiolytic effect observed by sole administration of MTEP or the low dose ketamine. CONCLUSIONS: These findings suggest that suppressed mGluR5 activity is required for the antidepressant effects of ketamine. Consequently, the antagonism of mGluR5 enhances the antidepressant effectiveness of low dose ketamine, but eliminates its anxiolytic effects.

Genetic diversity of SNPs associated with candidate genes for heat stress in Coreño Creole cattle in Mexico.

Mexican Coreño Creole cattle are an important genetic resource adapted to local environmental conditions, so the study of their genetic diversity is essential to know their status and implement conservation programs and their use for crossbreeding. This study evaluated the genetic diversity of heat stress tolerance characteristics of Coreño Creole cattle, and a gene ontology enrichment was performed to know the biological processes in which candidate genes are involved. A total of 48 samples from three localities of Nayarit were genotyped using 777 K Illumina BovineHD BeadChip and 34 single nucleotide polymorphisms associated with candidate genes were selected. Genetic diversity was analyzed using allelic frequencies, expected heterozygosity (He), and Wright's fixation index (FST) using PLINK v1.9 software. Candidate genes were uploaded to the open-source GOnet for pathway analysis and linkage to biological processes. Coreño Creole cattle showed low genetic diversity (He = 0.35), the average FST obtained was 0.044, and only eight markers had allele frequencies higher than 0.80 in the three locations. We found that the genes GOT1 and NCAD are related in the biological processes of stress response, cell differentiation, and homeostatic process. The results revealed that Coreño Creole cattle have low genetic diversity; this could be due to the isolation of these populations.

Population Subdivision and Migration Assessment of Mangalica Pig Breeds Based on Pedigree Analysis.

In conserving the genetic diversity of domestic animal breeds, strategies that emphasise between-breed diversity may not be optimal, as they neglect within-breed variation. The aim of the present study was to assess the extent of population subdivision in three Mangalica pig breeds and the contribution of migration to their substructure. Wright's FST coefficient was calculated based on genealogical data with breeding animals born between 1981 and 2023, with three colour variants (Blonde, Swallow-Belly and Red). These Wright's FST coefficients were analysed using multidimensional scaling to reveal the population substructure. The average FST coefficient was 0.04 for the Blonde breed and 0.047 for the Swallow-Belly and Red Mangalica breeds, while these parameters were lower in the active herds at 0.03 and 0.04, respectively. The migration of individuals between herds was 61.63% for the Blonde breed and 75.53% and 63.64% for the Swallow-Belly and Red Magalica breeds, respectively. No population substructure was observed in any of the Mangalica breeds, which can be explained by the extensive migration between herds.

Correlation of fitzpatrick skin type and iris color with tumor size in 823 patients with uveal melanoma.

PURPOSE: To determine the correlation of Fitzpatrick Skin Type (FST) and iris color with tumor size (tumor thickness and basal diameter) in patients with uveal melanoma. DESIGN: Retrospective Cohort METHODS: Retrospective cohort from a single ocular oncology center of 823 patients with uveal melanoma and documented FST, iris color, and tumor size. Patients were classified by FST (type I, II, and III-V) and iris color (blue, green, and brown) on the basis of external facial photography. There were no FST type VI patients. Tumor thickness was classified into small [< 3 millimeter (mm)], medium (3.1-8.0 mm), or large (> 8.0 mm), and basal diameter into small (< 10 mm), medium (10.1-15 mm) or large (> 15 mm). The correlation of FST and iris color with tumor thickness and basal diameter was evaluated using the Kruskal-Wallis H test. RESULTS: The FST classification was type I (n = 92, 11%), type II (n = 643, 78%), or III-V (n = 88, 11%), and iris color was blue (n = 472, 57%), green (n = 102, 12%), or brown (n = 249, 30%). A comparison of FST revealed differences in mean tumor thickness (P = 0.04) and basal diameter (P = 0.006). Iris color showed no difference for mean tumor thickness (P = 0.41) or basal diameter (P = 0.48). There was a statistically significant difference with brown iris color relative to FST III-V for mean tumor thickness (P = 0.003) and basal diameter (P = 0.001) but no difference with blue or green iris color (P > 0.05). CONCLUSIONS: Iris color alone showed no difference in tumor size, but those with brown iris color and FST type III-V demonstrated larger tumor thickness and basal diameter.

Evaluation of genetic differentiation and search for candidate genes for reproductive traits in pigs.

OBJECTIVE: The use of molecular genetic methods in pig breeding can significantly increase the efficiency of breeding and breeding work. We applied the Fst (fixsacion index) method, the main focus of the work was on the search for common options related to the number of born piglets and the weight of born piglets, since today the urgent task is to prevent a decrease in the weight of piglets at birth while maintaining high fertility of sows. METHODS: One approach is to scan the genome, followed by an assessment of Fst and identification of selectively selected regions. We chose Large White sows (n = 237) with the same conditions of keeping and feeding. The data were collected from the sows across three farrowing. For genotyping, we used GeneSeek GGP Porcine HD Genomic Profiler v1, which included 68,516 single nucleotide polymorphisms evenly distributed with an average spacing of 25 kb (Illumina Inc, San Diego, CA, USA). RESULTS: Based on the results of the Fst analysis, 724 variants representing selection signals for the signs BALWT, BALWT1, NBA, and TNB (weight of piglets born alive, average weight of the 1st piglets born alive, total number born alive, total number born). At the same time, 18 common variants have been identified that are potential markers for both the number of piglets at birth and the weight of piglets at birth, which is extremely important for breeding work to improve reproductive characteristics in sows. CONCLUSION: Оur work resulted in identification of variants associated with the reproductive characteristics of pigs. Moreover, we identified, variants which are potential markers for both the number of piglets at birth and the weight of piglets at birth, which is extremely important for breeding work to improve reproductive performance in sows.

[The French National College of Oncology Teachers (CNEC): Missions, organization, and projects]. / Le Collège national des enseignants de cancérologie (CNEC) : missions, organisation et projets.

The National College of Cancerology Teachers (CNEC) was created in September 1986. Its missions are to develop the teaching of oncology, to promote educational actions in the discipline, to participate in the development of teaching content and the definition of curricula and the control of knowledge for the training of medical students and specialists, to develop and validate educational documents relating to the above teaching, to ensure the representation of oncology teaching to of the National University Council (CNU) and administrative authorities, to ensure and coordinate relations with other university disciplines, scientific societies, national, European, and international professional groups, and to contribute to the development of research in the discipline. The current office was elected in September 2022 for three years.

Synthesis and antibacterial activity of FST and its effects on inflammatory response and intestinal barrier function in mice infected with Escherichia coli O78.

Pathogenic Escherichia coli (E. coli) can cause intestinal diseases in humans and livestock, damage the intestinal barrier, increase systemic inflammation, and seriously threaten human health and the development of animal husbandry. In this study, we designed and synthesized a novel conjugate florfenicol sulfathiazole (FST) based on drug combination principles, and investigated its antibacterial activity in vitro and its protective effect on inflammatory response and intestinal barrier function in E. coli O78-infected mice in vivo. The results showed that FST had superior antibacterial properties and minimal cytotoxicity compared with its prodrugs as florfenicol and sulfathiazole. FST protected mice from lethal E. coli infection, reduced clinical signs of inflammation, reduced weight loss, alleviated intestinal structural damage. FST decreased the expression of inflammatory cytokines IL-1ß, IL-6, TNF-α, and increased the expression of claudin-1, Occludin, and ZO-1 in the jejunum, improved the intestinal barrier function, and promoted the absorption of nutrients. FST also inhibited the expression of TLR4, MyD88, p-p65, and p-p38 in the jejunum. The study may lay the foundation for the development of FST as new drugs for intestinal inflammation and injury in enteric pathogen infection.

Assessment of genetic diversity in Cattleya intermedia Lindl. (Orchidaceae)

Orchids are valuable pot plants and Cattleya intermedia is a promising species underused in breeding programs. Recently, breeding work with this species produced superior plants that are believed to be not the true species owing to the morphological differences from wild plants. The aim of this study was to estimate the level of genetic diversity and interrelationships between wild and bred Cattleya intermedia collected at three different Brazilian states and from commercial breeders with RAPD markers. A total of 65 polymorphic bands were used to generate a genetic distance matrix. No specific groupings were revealed by the cluster analysis as bred materials were not different from wild plants. The genetic differentiation (F ST = 0.01626) was very low indicating a high gene flow in C. intermedia due to artificial crosses and a high differentiation between populations. The genetic variability available within this species is high enough to allow genetic progress in flower shape and size.

Timing of progesterone and allopregnanolone effects in a serial forced swim test / Duración del efecto de progesterona y alopregnanolona en la prueba de nado forzado seriada

The forced swim test (FST) is commonly employed to test the potency of drugs to reduce immobility as an indicator of anti-despair. Certainly, antidepressant drugs reduce the total time of immobility and enlarge the latency to the first immobility period. FST is preceded by the open field test (OFT) to discard any influence of changes in general motor activity that could interfere with immobility in the FST. Albeit progesterone and its a-reduced metabolite allopregnanolone produce antidepressant-like effects in the FST, the timing of actions is unknown. We hypothesized that the latency and duration of effects produced by progesterone and allopregnanolone may be characterized by repeated FST sessions; we therefore devised a serial-FST experimental design to evaluate the timing effects of these steroids on immobility, locomotion in the open field test, and grooming in the later as an indicator of response to stress. We included fifty-one ovariectomized adult Wistar rats weighing 200-250 g at the beginning of the experiments. They were ovariectomized by abdominal approach under anesthesia. Rats were housed six per cage, at room temperature (25 ± 1°C) under a 12 h/12 h light/dark cycle (lights ON at 7:00 a.m.) with ad libitum access to purified water and food. All of the experimental procedures followed National Institutes of Health Guidelines. The local Ethics Committee (Biomedical Research Institute, Universidad Nacional Autónoma de México) approved the experimental protocol. A first group received vehicle (2-hidroxypropyl-γ-cyclodextrin dissolved in injectable sterilized water to obtain a 35% solution, control group n=17), the second group progesterone (1.0 mg/kg, n=17), and the third group allopregnanolone (1.0 mg/kg, n=17). All single injections were applied by intraperitoneal route at a volume of 0.8 ml/kg. The effects of treatments were evaluated in the serial-FST at 0.25, 0.5, 1, 2, 4, 6, and 24 h after injection, in a rectangular pool (height, 60 cm; length, 30 cm; width, 50 cm), with 24 cm deep water (25 ± 1°C). We evaluated the total time of immobility, during 5 min, considered as the principal indicator of an anti-despair effect. Before each session of serial-FST, locomotion was evaluated in the OFT during 5 minutes. The apparatus consisted on an acrylic box (height, 20 cm; length, 44 cm; width, 33 cm), with twelve squares delineated on the floor (11x11 cm). In the same OFT sessions, grooming was evaluated as an indicator of response to stress. Statistical analysis consisted in two-way analysis of variance (ANOVA) and Student-Newman-Keuls as post hoc test. Total time in immobility was the highest and remained at similar levels only in the control group throughout the seven sessions of the serial-FST. In the allopregnanolone group a reduction in immobility was observed beginning 0.5 h after injection and lasted approximately 1.5 h. Similarly, progesterone reduced immobility beginning 1.0 h after injection, and the reduction lasted for approximately 5.0 h. In all groups, locomotion in the OFT was reduced after the first serial-FST session and remained at similar low levels during the serial-FST. In the control group, grooming was reduced after the first serial-FST session and lasted 24 h, but grooming did not change in the progesterone-or allopregnanolone-treated rats. From a serial-FST design, we conclude that progesterone and allopregnanolone exert short time-dependent reductions in immobility and anti-stress-like effects no longer than 24 hrs, and seemingly a reduction in the response to stress, which may have some clinical applications.

Introducción La progesterona y su metabolito activo alopregnanolona se han estudiado ampliamente en modelos experimentales de ansiedad y depresión, y por su propiedad de ser sintetizadas en el cerebro se les considera como neuroesteroides. Entre las pruebas que permiten determinar la potencia antidepresiva de ciertos fármacos se encuentra la prueba de nado forzado, la cual se diseñó originalmente para detectar la potencia de sustancias con propiedades antidepresivas. Estas sustancias reducen el tiempo de inmovilidad y alargan la latencia al primer periodo de inmovilidad, lo cual es considerado como un efecto antidepresivo. Usualmente, la prueba de nado forzado se aplica dos veces, una sesión de preprueba que dura 15 minutos, en la cual la rata o ratón desarrolla el estado de desesperanza. La preprueba es seguida de la sesión de prueba que se realiza 24 horas después durante 5 minutos. En ella se evalúa el efecto de las sustancias con propiedades antidepresivas. Además, la prueba de nado forzado es precedida por la prueba de campo abierto con la finalidad de identificar cambios en la actividad motora general (hipoactividad o hiperactividad) que pudiera interferir con la interpretación de las variables evaluadas en la prueba de nado forzado. Algunos esteroides, como la progesterona y alopregnanolona, reducen la inmovilidad y alargan la latencia a la primera inmovilidad en la prueba de nado forzado, lo que indica su efecto tipo-antidepresivo. Sin embargo, la latencia y la duración de los efectos farmacológicos son desconocidas. La hipótesis de este trabajo fue que, si utilizábamos la prueba de nado forzado de forma repetida, podríamos identificar el tiempo de duración de los efectos de estos esteroides. Por lo tanto, diseñamos un experimento con la prueba de nado forzado seriada para evaluar el tiempo de permanencia de los efectos de progesterona y alopregnanolona en esta prueba conductual. Materiales y métodos Sujetos: En este estudio se incluyeron 51 ratas adultas ovariectomizadas de la cepa Wistar, con peso entre 200 y 250 g al inicio de los experimentos. Las ratas fueron anestesiadas y ovariectomizadas por aproximación ventral y fueron alojadas en cajas de acrílico trasparente (n=6), con una temperatura ambiente de 25 ± 1°C y con un ciclo de luz-oscuridad de 12 ×12 h (la luz se encendió a las 7:00 am). Las ratas tuvieron libre acceso al agua purificada y al alimento (Purina). Todos los procedimientos realizados en este estudio fueron de acuerdo con las normas éticas en el uso de animales de experimentación, basándonos en la Guía del National Institute of Health, y el protocolo fue aprobado por el Comité de Ética del Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México. Grupos y tratamientos: Las ratas del grupo control recibieron el vehículo (solución al 35% de 2-hidroxipropil-g-ciclodextrina), el segundo grupo recibió progesterona (1.0 mg/kg) y el tercero recibió alopregnanolona (1.0 mg/kg) por vía intraperitoneal, en un volumen de 0.8 ml/kg. Pruebas conductuales: El efecto de los tratamientos fue evaluado en la prueba de nado forzado a las 0.25, 0.5, 1, 2, 4, 6 y 24 horas después de la administración. Utilizamos un estanque rectangular (base 50 × 34 cm, altura 60 cm), con agua a 25°C y una altura de 24 cm. Sólo se evaluó el tiempo total de inmovilidad, considerando que es el principal indicador de un efecto antidesesperanza. Antes de cada sesión de nado forzado se evaluó la actividad motora (cuadros deambulados) y el acicalamiento en campo abierto. Esta prueba consistió en colocar a la rata en una caja de acrílico (base 33 × 44 cm, altura 20 cm) con el piso dividido en 12 cuadros de 11 × 11 cm. Los resultados obtenidos de ambas pruebas fueron evaluados por medio de una ANOVA de dos vías y como prueba post hoc se aplicó Student-Newman-Keuls. Resultados La prueba de nado forzado aplicada de forma repetida resultó ser útil para evaluar los efectos temporales producidos por dos esteroides con potencia antidepresiva. Las ratas del grupo control mostraron los valores más altos de inmovilidad en la prueba de nado forzado, los cuales se mantuvieron así durante las sesiones de prueba. En los grupos tratados con progesterona o alopregnanolona hubo una reducción de la inmovilidad, gradual y temporal. Los animales tratados con alopregnanolona redujeron la inmovilidad a partir de las 0.5 horas después de la administración, efecto que se mantuvo por un periodo de 1.5 h. Los animales tratados con progesterona redujeron la inmovilidad a partir de 1.0 hora después de la administración, efecto que se mantuvo por un periodo de 5.0h. En campo abierto, independientemente del tratamiento, hubo una reducción del número de cuadros cruzados después de la primera sesión de nado forzado, efecto que permaneció hasta las 24h. En el acicalamiento, se observó que sólo los animales del grupo control redujeron significativamente el tiempo empleado en esta conducta, mientras que los animales inyectados con progesterona o alopregnanolona no modificaron esta variable. Es decir, mantuvieron niveles semejantes durante todas las sesiones de prueba y estuvieron por arriba de los valores encontrados en los animales control. Conclusión La progesterona y la alopregnanolona ejercen un efecto antidesesperanza de breve latencia, no mayor a 24 horas. Este hallazgo podría tener implicaciones clínicas en pacientes con depresión refractaria al tratamiento convencional.