Fetal cardiac growth is associated with in utero gut colonization.

BACKGROUND AND AIMS: Intra-uterine metabolic environment predicts newborns' cardiac morphology, metabolism and future health. In adults, gut microbiota composition relates to altered cardiac structure and metabolism. We investigated the relationship between gut microbiota colonization and fetal cardiac growth. METHODS AND RESULTS: Bacterial composition in meconium samples of 26 healthy, full-term newborns was assessed by 16S rDNA gene sequencing. Its relationship with birth echocardiographic parameters, and the interaction with cord blood levels of inflammatory markers were investigated. Correlative and cluster analysis, linear discriminant analysis effect size and predictive functional analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were applied. Fetal left ventricle growth was related to gut microbiota composition at birth. Specifically, left ventricle posterior wall thickness (LVPW) greater than 4 mm was associated with lower microbiota beta and alpha diversity, depletion (LDA score > 3) of several bacteria at each taxonomic level, including Lactobacillales, and enrichment (LDA score > 5) in Enterobacteriales and Enterobacteriaceae. The latter was significantly related to cord blood gamma-glutamyltransferase levels (r = 0.58, p = 0.0057). Functionally, a thicker LVPW was related to up-regulation of pathways involved in lipopolysaccharide biosynthesis (+50%, p = 0.045 in correlative analysis) and energy metabolism (+12%, p = 0.028), and down-regulation of pathways involved in xenobiotic biodegradation (-21 to -53%, p = 0.0063-0.039), PPAR signaling (-24%, p = 0.021) and cardiac muscle contraction (-100%, p = 0.049). CONCLUSION: Fetal cardiac growth and gut colonization are associated. Greater neonatal LVPW thickness is related to lower diversity of the gut microbiota community, depletion of bacteria having anti-remodeling effects, and enrichment in bacteria functionally linked to inflammation.

[Articular fractures of the distal femur. Comparative analysis of three surgical treatments]. / Fracturas articulares de fémur distal. Análisis comparativo de tres tratamientos quirúrgicos.

INTRODUCTION: The distal articular femur fracture is a serious injury that for years has been a problem in traumatology. It is often believed that produced varying degrees of permanent disability in the knee and that the fate of the joint was determined by the injury rather than treatment. OBJECTIVES: Present the results of surgical treatment of articular distal femur fractures type C2 with three treatment modalities: dynamic condylar screw (TDC), condylar buttress plate (PSC) and periarticular plate (PPA). MATERIAL AND METHODS: We conducted a comparative study of three therapeutic series designed to compare the effectiveness of dynamic condylar screw, the condylar buttress plate and periarticular plate in treating complete articular fractures of distal femur type C2. Patients of both genders, aged between 16 and 60 years, treated in the IAHULA, with a minimum follow up of 24 months. RESULTS: We included 42 patients divided into three groups. Males predominated with 73.8%, the most affected age group was 21-30 years with 28.57%. The most common type of fracture was the 33C2.3 with 42.86%. The 71.43% of patients experienced complications, highlighting joint stiffness, angular deviation in recurvatum, chronic pain and post traumatic osteoarthritis. CONCLUSION: TDC and the PPA are valid options for the treatment of distal femur fractures AO 33C2, as offered better functional results than PSC.

INTRODUCCIÓN: La fractura articular de fémur distal es una lesión grave que durante años ha representado un problema en la traumatología que con frecuencia ocasiona distintos grados de incapacidad permanente en la rodilla. El destino de la articulación estaba determinado por la lesión más que por su tratamiento. OBJETIVOS: Presentar los resultados del tratamiento quirúrgico de las fracturas articulares de fémur distal tipo C2 con tres modalidades de tratamiento: tornillo dinámico condíleo (TDC), placa de sostén condíleo (PSC) y placa periarticular (PPA). MATERIAL Y MÉTODOS: Estudio comparativo de tres series terapéuticas, diseñado para comparar la efectividad del TDC, la PSC y la PPA en el tratamiento de fracturas articulares completas de fémur distal tipo C2. Se incluyeron 42 pacientes de ambos géneros, con edades entre 16 y 60 años, tratados en el IAHULA, con un seguimiento mínimo de 24 meses. RESULTADOS: Predominó el sexo masculino con 73.8%, el grupo etario más afectado fue de 21-30 años con 28.57%. El tipo de fractura más frecuente fue la 33C2.3 con 42.86%. La PPA mostró mejores resultados que los otros implantes fundamentalmente en la escala funcional de la Knee Society. Setenta y uno punto cuarenta y tres por ciento de los pacientes presentó alguna complicación, resaltando la rigidez articular, la desviación angular en recurvatum, el dolor crónico y la artrosis postraumática. CONCLUSIÓN: El TDC y la PPA son opciones válidas para el tratamiento de las fracturas de fémur distal AO 33C2, puesto que ofrecieron mejores resultados funcionales que la PSC.

Fracturas articulares de fémur distal. Análisis comparativo de tres tratamientos quirúrgicos / Articular fractures of the distal femur. Comparative analysis of three surgical treatments

Resumen: Introducción: La fractura articular de fémur distal es una lesión grave que durante años ha representado un problema en la traumatología que con frecuencia ocasiona distintos grados de incapacidad permanente en la rodilla. El destino de la articulación estaba determinado por la lesión más que por su tratamiento. Objetivos: Presentar los resultados del tratamiento quirúrgico de las fracturas articulares de fémur distal tipo C2 con tres modalidades de tratamiento: tornillo dinámico condíleo (TDC), placa de sostén condíleo (PSC) y placa periarticular (PPA). Material y métodos: Estudio comparativo de tres series terapéuticas, diseñado para comparar la efectividad del TDC, la PSC y la PPA en el tratamiento de fracturas articulares completas de fémur distal tipo C2. Se incluyeron 42 pacientes de ambos géneros, con edades entre 16 y 60 años, tratados en el IAHULA, con un seguimiento mínimo de 24 meses. Resultados: Predominó el sexo masculino con 73.8%, el grupo etario más afectado fue de 21-30 años con 28.57%. El tipo de fractura más frecuente fue la 33C2.3 con 42.86%. La PPA mostró mejores resultados que los otros implantes fundamentalmente en la escala funcional de la Knee Society. Setenta y uno punto cuarenta y tres por ciento de los pacientes presentó alguna complicación, resaltando la rigidez articular, la desviación angular en recurvatum, el dolor crónico y la artrosis postraumática. Conclusión: El TDC y la PPA son opciones válidas para el tratamiento de las fracturas de fémur distal AO 33C2, puesto que ofrecieron mejores resultados funcionales que la PSC

Abstract: Introduction: The distal articular femur fracture is a serious injury that for years has been a problem in traumatology. It is often believed that produced varying degrees of permanent disability in the knee and that the fate of the joint was determined by the injury rather than treatment. Objectives: Present the results of surgical treatment of articular distal femur fractures type C2 with three treatment modalities: dynamic condylar screw (TDC), condylar buttress plate (PSC) and periarticular plate (PPA). Material and methods: We conducted a comparative study of three therapeutic series designed to compare the effectiveness of dynamic condylar screw, the condylar buttress plate and periarticular plate in treating complete articular fractures of distal femur type C2. Patients of both genders, aged between 16 and 60 years, treated in the IAHULA, with a minimum follow up of 24 months. Results: We included 42 patients divided into three groups. Males predominated with 73.8%, the most affected age group was 21-30 years with 28.57%. The most common type of fracture was the 33C2.3 with 42.86%. The 71.43% of patients experienced complications, highlighting joint stiffness, angular deviation in recurvatum, chronic pain and post traumatic osteoarthritis. Conclusion: TDC and the PPA are valid options for the treatment of distal femur fractures AO 33C2, as offered better functional results than PSC.

Imaging of Organ Metabolism in Obesity and Diabetes: Treatment Perspectives.

Obesity and diabetes are growing threats for cardiovascular diseases (CVD) and heart failure. In order to identify early and effective treatment or prevention targets, it is fundamental to dissect the role of each organ and the sequence of events leading from health to obesity, diabetes and cardiovascular diseases. The advancements in imaging modalities to evaluate organ-specific metabolism in humans in vivo is substantially contributing to the stratification of risk, identification of organ-specific culprits and development of targeted treatment strategies. This review summarizes the contribution provided by imaging of the heart, skeletal muscle, adipose tissue, liver, pancreas, gut and brain to the understanding of the pathogenesis and cardio-metabolic complications of obesity and diabetes, and to the monitoring of treatment responses in humans. We conclude by suggesting emerging fields of investigation, including the role of cardiac fat in the pathogenesis of cardiovascular disease, the conversion of white into brown adipose tissue in the treatment of obesity, the control of weight and energy balance by the brain, the integration between omics and imaging technologies to help establish biomarkers, and the characterization of gut metabolism in relation with the gut microbiome, opening a very promising preventive/therapeutic perspective.

Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2: effects on locomotor behavior and seizure susceptibility.

The homeobox-containing transcription factor Otx2 controls the identity, fate and proliferation of mesencephalic dopaminergic (mesDA) neurons. Transgenic mice, in which Otx2 was conditionally overexpressed by a Cre recombinase expressed under the transcriptional control of the Engrailed1 gene (En1(Cre/+); tOtx2(ov/+)), show an increased number of mesDA neurons during development. In adult mice, Otx2 is expressed in a subset of neurons in the ventral tegmental area (VTA) and its overexpression renders mesDA more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (MPTP) neurotoxin. Here we further investigated the neurological consequences of the increased number of mesDA neurons in En1(Cre/+); tOtx2(ov/+) adult mice. Immunohistochemistry for the active, glycosylated form of the dopamine transporter (glyco-Dat) showed that En1(Cre/+); tOtx2(ov/+) adult mice display an increased density of mesocortical DAergic fibers, as compared to control animals. Increased glyco-Dat staining was accompanied by a marked hypolocomotion in En1(Cre/+); tOtx2(ov/+) mice, as detected in the open field test. Since conditional knockout mice lacking Otx2 in mesDA precursors (En1(Cre/+); Otx2(floxv/flox) mice) show a marked resistance to kainic acid (KA)-induced seizures, we investigated the behavioral response to KA in En1(Cre/+); tOtx2(ov/+) and control mice. No difference was observed between mutant and control mice, but En1(Cre/+); tOtx2(ov/+) mice showed a markedly different c-fos mRNA induction profile in the cerebral cortex and hippocampus after KA seizures, as compared to controls. Accordingly, an increased density of parvalbumin (PV)-positive inhibitory interneurons was detected in the deep layers of the frontal cortex of naïve En1(Cre/+); tOtx2(ov/+) mice, as compared to controls. These data indicate that Otx2 overexpression results in increased DAergic innervation and PV cell density in the fronto-parietal cortex, with important consequences on spontaneous locomotor activity and seizure-induced gene expression. Our results strengthen the notion that Otx2 mutant mouse models are a powerful genetic tool to unravel the molecular and behavioral consequences of altered development of the DAergic system.

Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients.

BACKGROUND AND AIMS: Glucagon-like peptide 2 (GLP-2) may improve intestinal absorption in short bowel syndrome (SBS) patients with an end jejunostomy. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analogue, prolongs the intestinotrophic properties of GLP-2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity. METHODS: Teduglutide was given subcutaneously for 21 days once or twice daily to 16 SBS patients in the per protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), one with <50% colon in continuity (dose 0.03 mg/kg/day), and five with > or = 50% colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D-xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last three days of treatment, and after three weeks of follow up. Pre-study fasting native GLP-2 levels were determined for the five patients with > or = 50% colon in continuity. RESULTS: Pooled across groups and compared with baseline, teduglutide increased absolute (+743 (477) g/day; p<0.001) and relative (+22 (16)%; p<0.001) wet weight absorption, urine weight (+555 (485) g/day; p<0.001), and urine sodium excretion (+53 (40) mmol/day; p<0.001). Teduglutide decreased faecal wet weight (-711 (734) g/day; p = 0.001) and faecal energy excretion (-808 (1453) kJ/day (-193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, teduglutide significantly increased villus height (+38 (45)%; p = 0.030), crypt depth (+22 (18)%; p = 0.010), and mitotic index (+115 (108)%; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. The improvements in intestinal absorption and decreases in faecal excretion noted after treatment had reversed after the drug free follow up period. A controlled study with a more robust design is ongoing in order to determine the optimal dosage of teduglutide for SBS patients to achieve the maximal effect and utility of this drug in clinical practice. CONCLUSION: Teduglutide, at three dose levels for 21 days, was safe and well tolerated, intestinotrophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.

NPS 1506, a novel NMDA receptor antagonist and neuroprotectant. Review of preclinical and clinical studies.

NPS 1506 is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2-hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1-1.0 mg/kg, with peak plasma concentrations ranging from 8-80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK-801-like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization. In a Phase I study, intravenous (i.v.) doses of NPS 1506 from 5-100 mg were well tolerated and provided plasma concentrations in excess of those required for neuroprotection in rodents. Adverse events at the 100-mg dose included mild dizziness and lightheadedness, and mild to moderate ataxia. Neither PCP-like psychotomimetic effects nor cardiovascular effects were noted. The long plasma half-life of NPS 1506 (approximately 60 hr) suggests that a single i.v. dose will provide prolonged neuroprotection in humans.

Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism.

BACKGROUND: Surgery is the usual therapy for patients with primary hyperparathyroidism. We investigated the ability of a calcimimetic drug that inhibits parathyroid hormone secretion in vitro to decrease serum parathyroid hormone and calcium concentrations in patients with this disorder. METHODS: We performed a randomized, placebo-controlled study of single oral doses of 4 to 160 mg of the calcium-receptor agonist drug R-568 in 20 postmenopausal women with mild primary hyperparathyroidism. At base line, the mean (+/-SE) serum calcium concentration was 10.7+/-0.2 mg per deciliter (2.67+/-0.05 mmol per liter). Serum parathyroid hormone and calcium were measured repeatedly after each dose, and safety was assessed. RESULTS: Administration of R-568 resulted in a dose-dependent inhibition of parathyroid hormone secretion. The mean serum parathyroid hormone concentration, which was 77+/-11 pg per milliliter (18.8+/-2.7 pmol per liter; normal range, 16 to 65 pg per milliliter [3.9 to 15.9 pmol per liter) at base line, fell by 26+/-8 percent after 20 mg of R-568 (P=0.03), by 42+/-7 percent after 80 mg (P = 0.01), and by 51+/-5 percent after 160 mg (P=0.005). Serum ionized calcium concentrations fell only after the 160-mg dose, with the decrease closely following the decrease in the serum parathyroid hormone concentration. CONCLUSIONS: The calcimimetic drug R-568 reduces serum parathyroid hormone and ionized calcium concentrations in postmenopausal women with primary hyperparathyroidism.

Potential antisecretory antidiarrheals. 2. Alpha 2-adrenergic 2-[(aryloxy)alkyl]imidazolines.

Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber with a rabbit ileum preparation. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The 2,6-dimethyl derivative of lofexidine, 4a, was as active as lofexidine in vivo, but derivatives with 2,6-substituents larger than ethyl were inactive. (Aryloxy)alkyl derivatives which have an imidazoline and a methyl or larger group as part of the alkyl exhibited the best antisecretory activity. Compounds with substituents in the para position of the phenyl ring were generally inactive. 3-Amino-2,6-dimethyl derivative 21 was twice as active as 4a. A 2-methyl substituent is required in the 3-amino series to retain good activity. 2-Methyl derivative 12a had activity comparable to that of 4a, while 6-methyl derivative 12f was inactive. Substituents on the 3-amino group did not affect the activity, but substituting a hydroxyl for the amino group produced an inactive compound. Replacing the phenyl moiety with a 4-indole resulted in retention of activity, but other heterocycles were inactive. Compound 12a was resolved and d isomer 32 was five times more potent than l isomer 33. The more active compounds in the rat cholera toxin assay (RCTA), when evaluated in the dog, exhibited antisecretory activity but also exhibited central nervous system (CNS) effects, sedation and ataxia, at 10 mg/kg, and in spontaneously hypertensive rats at 50 mg/kg. A measure of polarity, log P, was calculated for the (aryloxy)alkyl groups. Regression analysis showed no correlation of antisecretory ED50 to the calculated log P. The active compounds did not show a separation of the central CNS effects from the peripheral antisecretory activity by increasing the polarity.

Potential antisecretory antidiarrheals. 1. Alpha 2-adrenergic aromatic aminoguanidine hydrazones.

Guanabenz, a centrally acting antihypertensive agent, has been shown to have intestinal antisecretory properties. A series of aromatic aminoguanidine hydrazones was made in an effort to separate the antisecretory and cardiovascular activities. Benzaldehyde, naphthaldehyde, and tetralone derivatives were synthesized. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber using a rabbit ileum preparation. A number of compounds, including members of each structural class, were active upon subcutaneous administration in the rat. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The compound displaying the best separation of activities was the aminoguanidine hydrazone of 2,6-dimethyl-4-hydroxybenzaldehyde (20).