Adult rats sired by obese fathers present learning deficits associated with epigenetic and neurochemical alterations linked to impaired brain glutamatergic signaling.

AIM: Offspring of obese mothers are at high risk of developing metabolic syndrome and cognitive disabilities. Impaired metabolism has also been reported in the offspring of obese fathers. However, whether brain function can also be affected by paternal obesity has barely been examined. This study aimed to characterize the learning deficits resulting from paternal obesity versus those induced by maternal obesity and to identify the underlying mechanisms. METHODS: Founder control and obese female and male Wistar rats were mated to constitute three first-generation (F1) experimental groups: control mother/control father, obese mother/control father, and obese father/control mother. All F1 animals were weaned onto standard chow and underwent a learning test at 4 months of age, after which several markers of glutamate-mediated synaptic plasticity together with the expression of miRNAs targeting glutamate receptors and the concentration of kynurenic and quinolinic acids were quantified in the hippocampus and frontal cortex. RESULTS: Maternal obesity induced a severe learning deficit by impairing memory encoding and memory consolidation. The offspring of obese fathers also showed reduced memory encoding but not impaired long-term memory formation. Memory deficits in offspring of obese fathers and obese mothers were associated with a down-regulation of genes encoding NMDA glutamate receptors subunits and several learning-related genes along with impaired expression of miR-296 and miR-146b and increased concentration of kynurenic acid. CONCLUSION: Paternal and maternal obesity impair offspring's learning abilities by affecting different processes of memory formation. These cognitive deficits are associated with epigenetic and neurochemical alterations leading to impaired glutamate-mediated synaptic plasticity.

Obesity-Induced Memory Deficits in Female Rats Are Oestrous Cycle Dependent and Linked to Impaired Brain Kynurenine Pathway Metabolism.

INTRODUCTION: Obesity is associated with impaired learning, but the mechanisms underlying this cognitive dysfunction are poorly understood. Moreover, whether obesity-induced learning deficits show sexual dimorphism remains controversial. Females are believed to be protected from cognitive decline by oestrogens. These hormones enhance the expression of tryptophan hydroxylase 2, the rate-limiting enzyme in the transformation of tryptophan (Trp) into serotonin which plays a significant role in learning and memory. However, several learning-regulating compounds also arise from Trp metabolism through the kynurenine pathway (KP), including kynurenic acid (KA), xanthurenic acid (XA), and NAD+. The present study aimed to determine the involvement of the KP of Trp metabolism in the regulation of learning in control and obese female rats. METHODS: The learning capabilities of control and obese rats were evaluated using the novel object recognition test. Trp and Trp-derived metabolites were quantified in the hippocampus and frontal cortex by ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: Control rats in proestrus/oestrous performed better than their control mates in metestrus/dioestrus. Likewise, while control and obese rats in dioestrus/metestrus did not show differences in learning, obese rats in proestrus/oestrous displayed decreased memory capacity along with decreased Trp concentration and reduced KA, XA, and NAD+ production in the hippocampus. These neurochemical alterations were associated with impaired expression of mRNAs coding for key enzymes of the KP. CONCLUSION: The results presented here indicate that the deleterious effects of obesity on learning are closely related to the oestrous cycle and associated with an impairment of the KP of Trp metabolism.

Placental Nutrient Transporters and Maternal Fatty Acids in SGA, AGA, and LGA Newborns From Mothers With and Without Obesity.

Adverse environmental factors in early life result in fetal metabolic programming and increased risk of adult diseases. Birth weight is an indirect marker of the intrauterine environment, modulated by nutrient availability and placental transport capacity. However, studies of placental transporters in idiopathic birth weight alterations and in maternal obesity in relation to neonatal metabolic outcomes are scarce. We aimed to analyze the placental nutrient transporter protein expression in small (SGA, n = 14), adequate (AGA, n = 18), and large (LGA n = 10) gestational age term for newborns from healthy or obese mothers (LGA-OB, n = 9) and their association with maternal fatty acids, metabolic status, placental triglycerides, and neonatal outcomes. The transporter expression was determined by Western blot. The fatty acid profile was evaluated by gas chromatography, and placental triglycerides were quantified by an enzymatic colorimetric method. GLUT1 was higher in LGA and lower in SGA and positively correlated with maternal HbA1c and placental weight (PW). SNAT2 was lower in SGA, while SNAT4 was lower in LGA-OB. FATP1 was lower in SGA and higher in LGA. SNAT4 correlated negatively and FATP1 correlated positively with the PW and birth anthropometry (BA). Placental triglycerides were higher in LGA and LGA-OB and correlated with pregestational BMI, maternal insulin, and BA. Maternal docosahexaenoic acid (DHA) was higher in SGA, specifically in male placentas, correlating negatively with maternal triglycerides, PW, cord glucose, and abdominal perimeter. Palmitic acid (PA) correlated positively with FATP4 and cord insulin, linoleic acid correlated negatively with PA and maternal cholesterol, and arachidonic acid correlated inversely with maternal TG and directly with FATP4. Our study highlights the importance of placental programming in birth weight both in healthy and obese pregnancies.

Roux-en-Y to One Anastomosis Gastric Bypass Conversion: Description of a Novel Technique.

Introduction: Roux-en-Y gastric bypass (RYGB) remains among the most widely performed bariatric procedures. A significant decline in its indication has been observed due to weight regain and reappearance of comorbidities. Moreover, the lack of effective therapeutic alternatives after failure justifies why other techniques are more frequently chosen. We present a novel technique to convert a failed RYGB into a one anastomosis gastric bypass (OAGB). Case Presentation: A 43-year-old male patient with a body mass index (BMI) of 47 kg/m2 and several comorbidities was submitted to RYGB. Initially his surgery was successful, but after 7 years he visited the bariatric and metabolic surgery clinic with reappearance of all comorbidities, and the same BMI as before having bariatric surgery. After proper evaluation and preparation, conversion to OAGB was decided. After anatomy identification, the alimentary limb was transected 20 cm distal to the gastrojejunal anastomosis, and a new anastomosis with the common channel (CC) was created, to form a new long afferent biliopancreatic limb and a new short efferent CC. Results: The surgical procedure and postoperative course were uneventful. One year after the procedure the patient's BMI was 36 kg/m2. He has been able to stop all medications and therapies related to previous comorbidities. To date, the patient has good dietary and supplementation adherence resulting in no nutritional deficiencies, or gastrointestinal symptoms. Conclusion: This new surgical technique is safe and feasible. Short-term results have shown reasonable weight loss (WL), and especially remission of comorbidities with an improved quality of life.

Maternal DHA Supplementation during Pregnancy and Lactation in the Rat Protects the Offspring against High-Calorie Diet-Induced Hepatic Steatosis.

Maternal supplementation during pregnancy with docosahexaenoic acid (DHA) is internationally recommended to avoid postpartum maternal depression in the mother and improve cognitive and neurological outcomes in the offspring. This study was aimed at determining whether this nutritional intervention, in the rat, protects the offspring against the development of obesity and its associated metabolic disorders. Pregnant Wistar rats received an extract of fish oil enriched in DHA or saline (SAL) as placebo by mouth from the beginning of gestation to the end of lactation. At weaning, pups were fed standard chow or a free-choice, high-fat, high-sugar (fc-HFHS) diet. Compared to animals fed standard chow, rats exposed to the fc-HFHS diet exhibited increased body weight, liver weight, body fat and leptin in serum independently of saline or DHA maternal supplementation. Nevertheless, maternal DHA supplementation prevented both the glucose intolerance and the rise in serum insulin resulting from consumption of the fc-HFHS diet. In addition, animals from the DHA-fc-HFHS diet group showed decreased hepatic triglyceride accumulation compared to SAL-fc-HFHS rats. The beneficial effects on glucose homeostasis declined with age in male rats. Yet, the preventive action against hepatic steatosis was still present in 6-month-old animals of both sexes and was associated with decreased hepatic expression of lipogenic genes. The results of the present work show that maternal DHA supplementation during pregnancy programs a healthy phenotype into the offspring that was protective against the deleterious effects of an obesogenic diet.

Association of placental nutrient sensing pathways with birth weight.

Birth weight (BW) is an important indicator for newborn health. Both high and low BW is associated with increased risks for adult metabolic diseases. AMPK (AMP-activated protein kinase), mTOR (mechanistic target of rapamycin), and insulin/IGF1 (insulin-like growth factor 1) pathways may function as placental sensors of maternal hormonal and nutritional status. However, the physiological role of these pathways in placenta has not been completely elucidated. To evaluate expression and activation of AMPK, mTOR, and insulin/IGF1 pathways and its association with placental weight (PW), BW, and maternal hormonal and metabolic status, we performed a cross-sectional study in placentas from non-obese mothers with SGA (n = 17), AGA (n = 19) and LGA (n = 10) newborns. We analyzed placental expression of total and phosphorylated key proteins from the AMPK, mTOR and insulin/IGF1 pathways. Maternal and cord blood hormones were determined by ELISA. AMPK and LKB1 activation correlated negatively with PW and BW, cord leptin, and pregestational BMI. Placental SIRT1 inversely correlated with BW, cord leptin, neonatal HOMA-IR, and maternal IGF1. PGC1α correlated negatively with PW and BW. Phosphorylated mTOR positively correlated with maternal glucose, PW and BW. IGF1R was lower in SGA. No changes in p-IGF1R, INSRb, total AKT or p-AKT were found, and pPDK1 was lower in SGA and LGA. These results suggest that placental AMPK, insulin/IGF1, and mTOR pathways may influence fetal growth, perhaps regulating placental physiology, even in metabolically healthy pregnancies. Our study highlights these nutrient sensing pathways as potential molecular mechanisms modulating placental adaptations and, thus, long-term metabolic health.

Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis.

Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0-24) were 109.49, 97.86, 145.33, and 207.04 µg · h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 µg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.).

An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens: study protocol for a randomized controlled trial.

BACKGROUND: Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined. METHODS/DESIGN: We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient's Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen. DISCUSSION: Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01918397 . Registered on 5 August 2013.

[Clinic-pathologic pattern and survival range in resectable gastric carcinoma]. / Cuadro Clínico Patológico y sobrevida en Carcinoma Gástrico Operable.

The present retrospective study evaluated 180 patients with resectable (Group I ) and 128 patients with unresectable (Group II) gastric carcinoma at Belen Hospital, Trujillo, Peru, from 1966 to 1998, with the aim to identify the clinical and pathological features, actuarial survival rate and surgical morbidity and mortality rates of both groups. The mean age of the total series was of 58.3 + 14.8 years (range, 18 to 85 years). The most frequent symptoms in both groups were abdominal pain (89.4% and 94.5% respectively) and the most common sign was pallor (62.8% and 54.5% respectively). The unresectable cases presented a higher frequency of palpable mass (p<0.001), upper two thirds neoplasms (p=0.0032), T4 lesions (p<0.001), distant metastasis (p<0.001), stage IV (p<0.001), hepatic metastasis (p<0.001) and peritoneal metastasis (p<0.001), compared with resectable gastric cancer patients. The total surgical mortality rate was of 19.5% (Group I: 12.1%, Group II: 28.9%). The most frequent complications were pneumonia (Group I: 8.9%, Group II: 7.8%) and surgical wound infection (Group I: 10.6%, Group II: 3.9%). In Group II, the exploratory laparotomy was carried out in 82 cases, whilst 46 cases underwent gastroenterostomy (n=34), gastrostomy (n=6), gastrectomy by exclusion (n=5) and ileotransversoanastomosis (n=1). The 5-year survival rate in resectable patients was of 18.5% and in unresectable cases the survival rate at 12 and 36 months was of 9% and 0% respectively. The early diagnosis of this neoplasm, mainly in high risk patients, would offer better possibilities of an opportune treatment.

Plomo, genotoxicidad y salud humana / Plomo, genotoxicidad and human health

Se determinaron las concentraciones de Pb en sangre y las frecuencias de aberraciones cromosómicas en una población expuesta laboralmente al Pb y en una población testigo con estructura étnica y ubicación geográfica similar a la población expuesta. Teniendo en cuenta que los niveles sanguíneos de Pb en Ecuador son más altos que en otros países debido al empleo de combustibles y pinturas plomadas, se consideraron como niveles altos de Pb en sangre las concentraciones superiores a 39ug/dl. El promedio de Pb en sangre en la población testigo fue 20,1 +8,6 ug/dl, mientras que en la población expuesta se encontraron niveles promedio de Pb sanguíneo de 71.8 + 25.4 ug/dl (p 0,0001). El análisis comparativo de las anomalías cromosómicas entre la población testigo y la expuesta mostró, en esta última, un incremento significativo de brechas de isocromátida, fragmentos acéntricos, cromosomas desespiralizados, y pulverizaciones cromosómicas. Estos resultados indican que la contaminación por Pb produce aberraciones cromosómicas, probablemente mediante un mecanismo indirecto por bloqueo en la síntesis de ADN. La población expuesta también exhibió un incremento muy significativo de asociaciones cromosómicas satelitales (3 o más cromosomas asociados por adhesividad de satélites). El significado de este hallazgo no es claro, pero sugiere que la población expuesta podría tener un aumento en el riesgo de nacimientos con trisomías. El agregado de bleomicina a los cultivos de sangre permitió determinar que el Pb no potencia la acción clastogénica de este compuesto (p 0.05).

Estudio comparado de niños amamantados en el primer trimestre con incremento normal y deficitario de peso / Compared study between first trimester breastfeed infants with normal weight gain deficient weight gain

Introducción.El incremento deficitario de peso(IDP)en los lactantes exclusivamente amamantados tiene factores asociados("respuestaas de riesgo")investigados en un estudio previo.El objetivo de este trabajo fue determinar,en una nueva muestra,cúales respuestas de riesgo presentaron una mayor frecuencia absoluta y ,por comparación entre lactantes con incremento normal de peso(INP)e IDP,cúales presentaron una diferencia de frecuencia significativa.Material y Métodos.La muestra se compuso de 40 lactantes de ambos sexos,exclusivamentes amamantados,de entre 10 a 90 días de vida,pertenecientes a familias de clase media.Veinte tenían INP(incremento diario de peso<18g)Por medio de una historia previamente confeccionada se estudiaron en todos los niños de la muestra veinte variables.El análisis estadístico se hizo con la prueba exacta de Fisher,con nivel de significación de 0,05.Conclusiones.1.En los niños con IDP se hallaron factores asociados que deberán ser investigados en todo lactante del primer trimestre con IDP.2.Estos resultados deberán ser confirmados con estudios con tamaño muestral más grande e incluyendo niños provenientes de distintos sectores sociales

Estudio comparado de niños amamantados en el primer trimestre con incremento normal y deficitario de peso / Compared study between first trimester breastfeed infants with normal weight gain deficient weight gain

Introducción.El incremento deficitario de peso(IDP)en los lactantes exclusivamente amamantados tiene factores asociados("respuestaas de riesgo")investigados en un estudio previo.El objetivo de este trabajo fue determinar,en una nueva muestra,cúales respuestas de riesgo presentaron una mayor frecuencia absoluta y ,por comparación entre lactantes con incremento normal de peso(INP)e IDP,cúales presentaron una diferencia de frecuencia significativa.Material y Métodos.La muestra se compuso de 40 lactantes de ambos sexos,exclusivamentes amamantados,de entre 10 a 90 días de vida,pertenecientes a familias de clase media.Veinte tenían INP(incremento diario de peso<18g)Por medio de una historia previamente confeccionada se estudiaron en todos los niños de la muestra veinte variables.El análisis estadístico se hizo con la prueba exacta de Fisher,con nivel de significación de 0,05.Conclusiones.1.En los niños con IDP se hallaron factores asociados que deberán ser investigados en todo lactante del primer trimestre con IDP.2.Estos resultados deberán ser confirmados con estudios con tamaño muestral más grande e incluyendo niños provenientes de distintos sectores sociales