Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production.

Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen/nutrient deprivation orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Hypoxia is the best-understood trigger of VEGF expression via the transcription factor HIF1α. Nutrient deprivation is inseparable from hypoxia during ischemia, yet its role in angiogenesis is poorly characterized. Here, we identified sulfur amino acid restriction as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs in vitro, and increased capillary density in mouse skeletal muscle in vivo via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1α. We also identified a requirement for cystathionine-γ-lyase in VEGF-dependent angiogenesis via increased hydrogen sulfide (H2S) production. H2S mediated its proangiogenic effects in part by inhibiting mitochondrial electron transport and oxidative phosphorylation, resulting in increased glucose uptake and glycolytic ATP production.

Down-Regulation of a Profibrotic Transforming Growth Factor-ß1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis.

Idiopathic subglottic stenosis (iSGS) is a progressive fibrotic disease characterized by life-threatening airway narrowing. Although the molecular underpinnings are unknown, previous reports showing that subglottic serial intralesional steroid injections (SILSIs) improve clinical outcomes suggest a steroid-sensitive pathway in iSGS. Herein, a prospective study was conducted to determine the changes in profibrotic markers during SILSI to identify steroid-sensitive profibrotic drivers. Seven newly diagnosed patients with iSGS were recruited for SILSI. Subglottic biopsies before and after SILSI treatments were evaluated for histologic and molecular markers by confocal microscopy and RT-qPCR. At baseline, iSGS subglottises contained abundant vimentin-positive/α-smooth muscle actin-negative fibroblasts, intermingled with a matrix of fibronectin and types I and VI collagen. Transforming growth factor (TGF)-ß1 was up-regulated primarily in glandular epithelium. Cellular communication network factor 2 (CCN2) was mainly up-regulated in stromal fibroblasts surrounding TGF-ß1-positive glandular structures. SILSI improved iSGS by reducing fibroblast infiltration and increasing matrix remodeling. Mechanistically, SILSI counteracted the effects of TGF-ß1 by inducing matrix metalloprotease 9 (MMP9) expression while repressing CCN2 expression, without affecting TGFß1 levels. Treatment of primary iSGS-derived fibroblasts with TGF-ß1 recapitulated aspects of the disease in vivo, demonstrating that the induction in CCN2 and repression of MMP9 are caused by changes in histone acetylation induced by TGF-ß1. Triamcinolone counteracted the coregulation of these genes by impairing SMAD2/3 binding to promoter regions, and not through histone acetylation. In conclusion, this study shows that SILSI counteracts a dysregulated TGF-ß1/CCN2/MMP9 axis involved in iSGS development.

The Salmonella enterica Serovar Typhi ltrR Gene Encodes Two Proteins Whose Transcriptional Expression Is Upregulated by Alkaline pH and Repressed at Their Promoters and Coding Regions by H-NS and Lrp.

LtrR is a LysR-type regulator involved in the positive expression of ompR to promote ompC and ompF expression. This regulatory network is fundamental for the control of bacterial transformation and resistance to the bile salt sodium deoxycholate in Salmonella enterica serovar Typhi. In this work, the transcriptional regulation of ltrR was characterized, revealing that the use of alternative promoters results in two transcripts. The larger one, the ltrR2 mRNA, was repressed at promoter and coding regions by H-NS, whereas Lrp repressed its expression at the coding region. In the case of the second and shorter ltrR1 transcript, it was repressed only at the coding region by H-NS and Lrp. Remarkably, pH 7.5 is a positive signal involved in the transcriptional expression of both ltrR units. Translational fusions and Western blot experiments demonstrated that ltrR2 and ltrR1 mRNAs encode the LtrR2 and LtrR1 proteins. This study adds new data on the complex genetic and regulatory characteristics of one of the most predominant types of transcriptional factors in bacteria, the LysR-type transcriptional regulators.IMPORTANCE The LysR-type transcriptional regulators are present in viruses, archaea, bacteria, and eukaryotic cells. Furthermore, these proteins are the most abundant transcriptional factors in bacteria. Here, we demonstrate that two LysR-type proteins are generated from the ltrR gene. These proteins are genetically induced by pH and repressed at the promoter and coding regions by the global regulators H-NS and Lrp. Thus, novel basic aspects of the complex genetic regulation of the LysR-type transcriptional regulators are described.

π-Extended push-pull azo-pyrrole photoswitches: synthesis, solvatochromism and optical band gaps.

A new family of push-pull biphenyl-azopyrrole compounds 3b-g and 4b-d was efficiently obtained via a Suzuki cross-coupling reaction between 2-(4'-iodophenyl-azo)-N-methyl pyrrole (1a) or 3-(4'-iodophenyl-azo)-1,2,5-trimethyl pyrrole (2a) and 4'-substituted phenyl boronic acids in excellent yields. The influence of the π-biphenyl backbone and pyrrole pattern substitution was correlated with their optical properties. Solvatochromic studies via UV-visible spectrophotometry revealed that the inclusion of a 4'-nitro-biphenyl fragment favors a red-shift of the main absorption band in these azo compounds compared with their non-substituted analogues. Likewise, optical band-gaps were estimated by means of electronic absorption spectra and correlated with TD-DFT studies. The pyrrole pattern substitution and the π-conjugated backbone exhibit a clear influence on their thermal isomerization kinetics at room temperature. In all cases, biphenylazo-pyrrole compounds lead to the formation of J-type aggregates in binary MeOH : H2O solvents. Under these conditions, compounds 3b-c undergo a water-assisted cis-to-trans isomerization at room temperature.

A novel experimental immunomodulatory therapy against Nocardia brasiliensis in a BALB/c murine model.

BACKGROUND: Mycetoma is recognized as a neglected tropical disease and there are still therapeutic challenges, especially in cases recalcitrant to standard therapy or with high risk of dissemination. Subcultures have been used previously to decrease the virulence of human pathogens. Previous reports have demonstrated that after carrying out 200 subcultures of Nocardia brasiliensis, a decrease in virulence was observed. AIM: To evaluate the effect of attenuated N. brasiliensis strains on the development of lesions in an established mycetoma infection. METHODS: Female 8-12-week-old BALB/c mice were injected with N. brasiliensis suspension to establish a mycetoma. Sixty mice were selected and divided into three groups: two of these groups were inoculated in the dorsum with N. brasiliensis subcultured 200 and 400 times, respectively, while the third group served as control. The thickness of each lesion was measured with calipers every week for 12 weeks. RESULTS: After 12 weeks, we observed that inoculation of 1 × 105 colony-forming units of attenuated N. brasiliensis strains was able to modify the natural history of the infection, with a decrease in the size of the lesions, particularly with P400, compared with the control group (P < 0.01). CONCLUSION: In this experimental evaluation of an immunomodulatory therapy with attenuated N. brasiliensis strains in a murine model, there was a greater stability in the size of the lesion over time in BALB/c mice inoculated with the P400 strain. This treatment could open the possibility of using the attenuated strain as immunomodulatory therapy in patients recalcitrant to standard therapy, with high risk of dissemination or who develop drug-related adverse effects.

A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration.

BACKGROUND: Maladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM. RESULTS: The results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of activated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain. CONCLUSIONS: Rapamycin exerts pleotropic effects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM.

Detection of damage on single- or double-stranded DNA in a population exposed to arsenic in drinking water.

Different studies have suggested an association between arsenic (As) exposure and damage to single-stranded DNA by reactive oxygen species derived from the biotransformation of arsenic. The single strand damages are converted to double strand damage upon interaction with ultraviolet radiation. Analysis of genomic integrity is important for assessing the genotoxicity caused by environmental pollutants. In this study, we compared the concentration of As in drinking water, nutritional status, lifestyle variables, and the level of genotoxicity in an exposed population and a control group. Arsenic content of water was determined using a portable Arsenator® kit. DNA fragmentation was determined using the two-tailed comet assay. Our results show that the exposed population had low nutritional consumption compared to the control group (P < 0.05). Furthermore, the water consumed by the exposed group had As concentration of 14.3 ± 8.4 mg/L, whereas the As level in the water consumed by the control group was 7.7 ± 3.5 mg/L. Analysis shows that the frequency of double strand break (DSB) fragmentation was higher in the population exposed to higher levels of As compared to that of the control group. These results suggest a possible association between the concentration of As in drinking water and lifestyle variables, with increasing fragmentation of DSBs in the exposed population.

Relationship between lymphocyte DNA fragmentation and dose of iron oxide (Fe2O3) and silicon oxide (SiO2) nanoparticles.

At present, the use of nanoparticles is a controversial topic, especially when analyzing their effects in human tissues. Nanoparticles (NPs) can cause oxidative stress by increasing membrane lipids peroxidation and reactive oxygen species, and decreasing intracellular glutathione. Oxidative stress plays an important role in cell signaling and inflammatory responses. It can result in genotoxicity, affect cell proliferation, and induce DNA damage. The objective of this study is to evaluate the genotoxic potential of NPs in lymphocyte DNA. Wistar female rats (N = 45) were sorted in three randomized groups as follows: Group 1 (N = 20); Group 2 (N = 20) and a control group (N = 5). A single dose of iron oxide (Fe2O3) and silicon oxide (SiO2) NPs dissolved in saline solution were administered orally to the rats. Cardiac puncture was performed to extract peripheral blood for genotoxic analysis. DNA fragmentation for lymphocytes was performed. Control rats showed a fragmentation percentage of 11.20 ± 2.16%. Rats exposed to SiO2 and Fe2O3 NPs for 24 h showed statistically significant differences in DNA fragmentation percentages as compared with that of the control group. A lineal dose-response correlation between genotoxic damage and exposure to SiO2 and Fe2O3 NPs was found (r2 = 0.99 and 0.98 for SiO2 and Fe2O3, respectively). In conclusion, we found that exposure to Fe2O3 and SiO2 NPs can cause DNA fragmentation in lymphocytes in a dose-dependent manner.

Formaldehyde induces DNA strand breaks on spermatozoa and lymphocytes of Wistar rats.

Formaldehyde (FA) interacts with biological molecules such as DNA and it induces DNA-protein cross-links (DPCs), oxidative stress, reactive oxygen species (ROS), methylation, chromosomal damage, fragmentation, and adducts of DNA, which are considered the most important genotoxic effects caused by exposure to FA. The purpose of this study was to evaluate the percentage of DNA fragmentation on lymphocytes and spermatozoa from Wistar rats exposed to different doses of FA. The results about the percentage of fragmentation of DNA in lymphocytes and spermatozoa, were statistical different from controlled group versus treated groups respectively to (p < 0.05). Pathological changes were observed in the seminiferous tubules, especially in rats exposed to 30 mg/kg of FA. This study provided additional evidence supporting that FA induces DNA strand breaks in both cells and therefore genotoxic damage in Wistar rats.

The Salmonella enterica serovar Typhi ltrR-ompR-ompC-ompF genes are involved in resistance to the bile salt sodium deoxycholate and in bacterial transformation.

A characterization of the LtrR regulator, an S. Typhi protein belonging to the LysR family is presented. Proteomics, outer membrane protein profiles and transcriptional analyses demonstrated that LtrR is required for the synthesis of OmpR, OmpC and OmpF. DNA-protein interaction analysis showed that LtrR binds to the regulatory region of ompR and then OmpR interacts with the ompC and ompF promoters inducing porin synthesis. LtrR-dependent and independent ompR promoters were identified, and both promoters are involved in the synthesis of OmpR for OmpC and OmpF production. To define the functional role of the ltrR-ompR-ompC-ompF genetic network, mutants in each gene were obtained. We found that ltrR, ompR, ompC and ompF were involved in the control of bacterial transformation, while the two regulators and ompC are necessary for the optimal growth of S. Typhi in the presence of one of the major bile salts found in the gut, sodium deoxycholate. The data presented establish the pivotal role of LtrR in the regulatory network of porin synthesis and reveal new genetic strategies of survival and cellular adaptation to the environment used by Salmonella.

Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice.

BACKGROUND: Short-term dietary restriction (DR) without malnutrition preconditions against surgical stress in rodents; however, the nutritional basis and underlying nutrient/energy-sensing pathways remain poorly understood. OBJECTIVES: We investigated the relative contribution of protein restriction (PR) vs. calorie restriction (CR) to protection from renal ischemia reperfusion injury (IRI) and changes in organ-autonomous nutrient/energy-sensing pathways and hormones underlying beneficial effects. METHODS: Mice were preconditioned on experimental diets lacking total calories (0-50% CR) or protein/essential amino acids (EAAs) vs. complete diets consumed ad libitum (AL) for 1 wk before IRI. Renal outcome was assessed by serum markers and histology and integrated over a 2-dimensional protein/energy landscape by geometric framework analysis. Changes in renal nutrient/energy-sensing signal transduction and systemic hormones leptin and adiponectin were also measured. The genetic requirement for amino acid sensing via general control non-derepressible 2 (GCN2) was tested with knockout vs. control mice. The involvement of the hormone leptin was tested by injection of recombinant protein vs. vehicle during the preconditioning period. RESULTS: CR-mediated protection was dose dependent up to 50% with maximal 2-fold effect sizes. PR benefits were abrogated by EAA re-addition and additive with CR, with maximal benefits at any given amount of CR occurring with a protein-free diet. GCN2 was not required for functional benefits of PR. Activation and repression of nutrient/energy-sensing kinases, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1), respectively, on PR reflected a state of negative energy balance, paralleled by 13% weight loss and an 87% decrease in leptin, independent of calorie intake. Recombinant leptin administration partially abrogated benefits of dietary preconditioning against renal IRI. CONCLUSIONS: In male mice, PR and CR both contributed to the benefits of short-term DR against renal IRI independent of GCN2 but partially dependent on reduced circulating leptin and coincident with AMPK activation and mTORC1 repression.

Sperm chromatin dispersion by formaldehyde in Wistar rats.

Formaldehyde (FA) is an environmental xenobiotic, which is genotoxic and carcinogenic to humans and animals; it induces DNA damage, mutations, and clastogenicity during critical cytogenetic events. FA-mediated oxidative stress is an important mechanism that has been associated with the induction of cytotoxic and genotoxic damage. Therefore, the objective of this study was to evaluate the dispersion of sperm chromatin and reproductive parameters induced by exposure to different concentrations of FA in Wistar rats. Compared to the percentage of sperm with fragmented DNA in the control group (18.10 ± 8.62%), the percentage of sperm with fragmented DNA increased following exposure to 5, 10, and 30 mg FA/kg body weight (29.60 ± 8.44, 85.20 ± 20.94 and 96.0 ± 7.87, respectively; P = 0.0001). Histopathological alterations were evident, especially in the seminiferous tubules. In conclusion, this study provides experimental evidence concerning the genotoxicity of FA, with particular reference to the decreased sperm concentration and motility and increased dispersion of DNA chromatin in rats.

[Revision surgery of anterior cruciate ligament plasty]. / Cirugía de revisión de plastía de ligamento cruzado anterior.

INTRODUCTION: anterior cruciate ligament injuries (ACL) continue increasing in frecuency in the general population and sportmen who practice soccer and american football where we can locate 53% of the total of cases, the annual incidence is 70 per 100,000 persons. The incidence of this injuries has being increasing in women probably of the increase of the participation in such sports. OBJECTIVE: to document the causes of anterior cruciate ligament (ACL) plasty failure, as well as the diagnosis, surgical technique, and postoperative care of a revision ACL plasty surgery. MATERIAL AND METHODS: a search for relevant information, original research articles, clinical trials, and reviews in indexed journals was performed. RESULTS: anterior cruciate ligament injuries continue to increase among the general population and athletes who play soccer and American soccer mainly, in this population group we found 53% of the total cases. The gold standard for treatment is arthroscopic reconstruction of the ligament. ACL reconstruction surgery has good results, with an estimated 75-90% success rate. Long-term failures of anterior cruciate ligament repair represent 5-25%. Among the factors associated with this failure are technical errors, traumatic antecedents, biological factors, among others. CONCLUSIONS: in ACL revision surgery good results can be achieved with respect to graft stability, return to play and functional stability of the knee, but the results are generally inferior to those of primary ACL reconstruction.

INTRODUCCIÓN: las lesiones del ligamento cruzado anterior (LCA) continúan en aumento entre la población general y deportistas que practican fútbol soccer y americano en donde se encuentra 53% del total de los casos; la incidencia anual es de 70 por cada 100,000 personas. La incidencia de estas lesiones ha ido en aumento en mujeres, probablemente por el incremento de la participación deportiva. OBJETIVO: documentar las causas de fracaso de plastía de ligamento cruzado anterior (LCA), así como el diagnóstico, técnica quirúrgica, cuidado postquirúrgico de una cirugía de revisión de plastía LCA. MATERIAL Y MÉTODOS: se ha realizado una búsqueda de información relevante, artículos de investigación originales, ensayos clínicos y revisiones en revistas indexadas. RESULTADOS: las lesiones del ligamento cruzado anterior continúan en aumento entre la población general y deportistas que practican futbol soccer y americano principalmente; en este grupo de la población encontramos 53% del total de los casos. El estándar de oro para su tratamiento es la reconstrucción del ligamento por vía artroscópica. La cirugía de reconstrucción de LCA presentan buenos resultados, se estima 75-90% de éxito. Los fracasos a largo plazo de la reparación de ligamento cruzado anterior representan de 5-25%. Dentro de los factores asociados a este fracaso encontramos errores técnicos, antecedentes traumáticos, factores biológicos, entre otros. CONCLUSIONES: en la cirugía de revisión de LCA se pueden lograr buenos resultados con respecto a la estabilidad del injerto, regreso al juego y estabilidad funcional de la rodilla, pero los resultados son generalmente inferiores a los de la reconstrucción primaria del LCA.

Ixodicidal effect of extracts from Cordia boissieri, Artemisia ludoviciana and Litchi chinensis on Rhipicephalus (Boophilus) microplus (Acari: Ixodidae).

The ixodicidal activity of the methanolic extracts of Artemisia ludoviciana (Astereceae), Cordia boissieri (Boraginaceae) and Litchi chinensis (Sapindaceae) against two field populations of Rhipicephalus (Boophilus) microplus from the state of Nuevo Leon (NL) and Veracruz (VER) was evaluated. The extract of L. chinensis in the concentration of 150 mg/ml showed efficacies of 100% and 99% against engorged females and mortalities of 98% and 99% against larvae. C. boissieri in the same concentration showed efficacies of 71% and 37% against engorged adults and mortalities of 33.04% and 10.33% against larvae and A. ludoviciana had efficacies of 94% and 83% in adults and mortalities of 89.39% and 89.21% against larvae in both populations respectively. The enzymatic activity of Acetylcholinesterase (AChE), Carboxylesterase (CaE), Glutathione-S-Transferase (GST) and Alkaline Phosphatase (ALP) was measured in both populations of ticks. As a result, a significant difference between both populations was shown, being the VER population the one that exhibited a higher enzymatic activity (p ≤ 0.05). It can be concluded that the methanolic extract of the seed of L. chinensis shows potential ixodicidal activity and can be used as an alternative source of tick control, however, prior characterization, toxicity and formulation studies are necessary.

Nocardia brasiliensis cell wall lipids modulate macrophage and dendritic responses that favor development of experimental actinomycetoma in BALB/c mice.

Nocardia brasiliensis is a Gram-positive facultative intracellular bacterium frequently isolated from human actinomycetoma. However, the pathogenesis of this infection remains unknown. Here, we used a model of bacterial delipidation with benzine to investigate the role of N. brasiliensis cell wall-associated lipids in experimental actinomycetoma. Delipidation of N. brasiliensis with benzine resulted in complete abolition of actinomycetoma without affecting bacterial viability. Chemical analyses revealed that trehalose dimycolate and an unidentified hydrophobic compound were the principal compounds extracted from N. brasiliensis with benzine. By electron microscopy, the extracted lipids were found to be located in the outermost membrane layer of the N. brasiliensis cell wall. They also appeared to confer acid-fastness. In vitro, the extractable lipids from the N. brasiliensis cell wall induced the production of the proinflammatory cytokines interleukin-1ß (IL-1ß), IL-6, and CCL-2 in macrophages. The N. brasiliensis cell wall extractable lipids inhibited important macrophage microbicidal effects, such as tumor necrosis factor alpha (TNF-α) and nitric oxide (NO) production, phagocytosis, bacterial killing, and major histocompatibility complex class II (MHC-II) expression in response to gamma interferon (IFN-γ). In dendritic cells (DCs), N. brasiliensis cell wall-associated extractable lipids suppressed MHC-II, CD80, and CD40 expression while inducing tumor growth factor ß (TGF-ß) production. Immunization with delipidated N. brasiliensis induced partial protection preventing actinomycetoma. These findings suggest that N. brasiliensis cell wall-associated lipids are important for actinomycetoma development by inducing inflammation and modulating the responses of macrophages and DCs to N. brasiliensis.

Candida pericarditis presenting with cardiac tamponade and multiple organ failure after combined damage control thoracotomy and laparotomy with splenectomy in a trauma patient: Case report and review of literature.

Candida pericarditis is a rare condition which has previously been described after cardiothoracic surgery and immunosuppressive states (Geisler et al., 1981; Eng et al., 1981; Kraus et al., 1988; Kaufman et al., 1988; Tang et al., 2009; Glower et al., 1990; Carrel et al., 1991; Rabinovici et al., 1997; Canver et al., 1998; Farjah et al., 2005; Gronemeyer et al., 1982 [1-11]). We describe the case of a 19-year-old male blunt trauma patient, who survived a damage control thoracotomy and laparotomy with splenectomy, who later developed a loculated Candida pericardial effusion, complicated with cardiac tamponade and multiple organ failure, and required antifungals and surgical reintervention with thoracotomy for drainage. A literature search of the reported cases demonstrates that Candida pericarditis is indeed a rare but fatal condition if not identified and treated appropriately. This article discusses the difficulties we encountered while recognizing the disorder in our patient and proposes a guideline to adequately treat the condition in an effective and timely manner. Candida pericarditis poses a special challenge for the physician since its correct diagnosis and management requires a multidisciplinary approach.

[Diagnostic correlation between magnetic resonance imaging and arthroscopic findings in anterior cruciate ligament injuries]. / Correlación diagnóstica entre resonancia magnética y hallazgos artroscópicos en lesiones de ligamento cruzado anterior.

PURPOSE OF THE STUDY: determine the sensitivity and specificity of magnetic resonance imaging in anterior cruciate ligament injuries and associated injuries through arthroscopic findings. MATERIAL AND METHODS: this is a retrospective, longitudinal, cross-sectional study in 96 patients with ACL injuries were included and who underwent arthroscopic surgery; arthroscopic findings were compared with diagnostic magnetic resonance images as well as associated lesions. RESULTS: for ACL lesions the following data were found in relation to the agreement by MRI and arthroscopic findings; 93.68% sensitivity, 100% specificity. Negative predictor value of 14.28% and a positive predictor value of 100%. CONCLUSION: MRI is an accurate and non-invasive imaging modality for the evaluation of knee injuries, the diagnostic association is considerably high.

PROPÓSITO DEL ESTUDIO: determinar la sensibilidad y especificidad de la resonancia magnética en lesiones de ligamento cruzado anterior, así como las lesiones asociadas mediante los hallazgos artroscópicos. MATERIAL Y MÉTODOS: se trata de un estudio retrospectivo, longitudinal, transversal en el cual se incluyeron 96 pacientes con lesiones de ligamento cruzado anterior (LCA) que fueron sometidos a cirugía artroscópica; los hallazgos artroscópicos se compararon con las imágenes diagnósticas de resonancia magnética así como lesiones asociadas. RESULTADOS: en lesiones de LCA se encontraron los siguientes datos en relación a la concordancia por resonancia magnética nuclear (RMN) y hallazgos artroscópicos; sensibilidad de 93.68%, especificidad de 100%. Valor predictor negativo de 14.28% y un valor predictor positivo de 100%. CONCLUSIÓN: la RMN es una modalidad de imagen precisa y no invasiva para la evaluación de lesiones de la rodilla, la asociación diagnóstica con el examen clínico es considerablemente alta.

Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation.

Radiation therapy damages and depletes total bone marrow (BM) cellularity, compromising safety and limiting effective dosing. Aging also strains total BM and BM hematopoietic stem and progenitor cell (HSPC) renewal and function, resulting in multi-system defects. Interventions that preserve BM and BM HSPC homeostasis thus have potential clinical significance. Here, we report that 50% calorie restriction (CR) for 7-days or fasting for 3-days prior to irradiation improved mouse BM regrowth in the days and weeks post irradiation. Specifically, one week of 50% CR ameliorated loss of total BM cellularity post irradiation compared to ad libitum-fed controls. CR-mediated BM protection was abrogated by dietary sulfur amino acid (i.e., cysteine, methionine) supplementation or pharmacological inhibition of sulfur amino acid metabolizing and hydrogen sulfide (H2S) producing enzymes. Up to 2-fold increased proliferative capacity of ex vivo-irradiated BM isolated from food restricted mice relative to control mice indicates cell autonomy of the protective effect. Pretreatment with H2S in vitro was sufficient to preserve proliferative capacity by over 50% compared to non-treated cells in ex vivo-irradiated BM and BM HSPCs. The exogenous addition of H2S inhibited Ten eleven translocation 2 (TET2) activity in vitro, thus providing a potential mechanism of action. Short-term CR or fasting therefore offers BM radioprotection and promotes regrowth in part via altered sulfur amino acid metabolism and H2S generation, with translational implications for radiation treatment and aging.

Multiomics assessment of dietary protein titration reveals altered hepatic glucose utilization.

Dietary protein restriction (PR) has rapid effects on metabolism including improved glucose and lipid homeostasis, via multiple mechanisms. Here, we investigate responses of fecal microbiome, hepatic transcriptome, and hepatic metabolome to six diets with protein from 18% to 0% of energy in mice. PR alters fecal microbial composition, but metabolic effects are not transferable via fecal transplantation. Hepatic transcriptome and metabolome are significantly altered in diets with lower than 10% energy from protein. Changes upon PR correlate with calorie restriction but with a larger magnitude and specific changes in amino acid (AA) metabolism. PR increases steady-state aspartate, serine, and glutamate and decreases glucose and gluconeogenic intermediates. 13C6 glucose and glycerol tracing reveal increased fractional enrichment in aspartate, serine, and glutamate. Changes remain intact in hepatic ATF4 knockout mice. Together, this demonstrates an ATF4-independent shift in gluconeogenic substrate utilization toward specific AAs, with compensation from glycerol to promote a protein-sparing response.

cAMP receptor protein (CRP) positively regulates the yihU-yshA operon in Salmonella enterica serovar Typhi.

Salmonella enterica serovar Typhi (S. Typhi) is the aetiological agent of typhoid fever in humans. This bacterium is also able to persist in its host, causing a chronic disease by colonizing the spleen, liver and gallbladder, in the last of which the pathogen forms biofilms in order to survive the bile. Several genetic components, including the yihU-yshA genes, have been suggested to be involved in the survival of Salmonella in the gallbladder. In this work we describe how the yihU-yshA gene cluster forms a transcriptional unit regulated positively by the cAMP receptor global regulator CRP (cAMP receptor protein). The results obtained show that two CRP-binding sites on the regulatory region of the yihU-yshA operon are required to promote transcriptional activation. In this work we also demonstrate that the yihU-yshA transcriptional unit is carbon catabolite-repressed in Salmonella, indicating that it forms part of the CRP regulon in enteric bacteria.