Oral supplementation with physiological doses of leptin during lactation in rats improves insulin sensitivity and affects food preferences later in life

We have previously described that neonate rats supplemented with physiological doses of oral leptin during lactation become more protected against overweight in adulthood. The purpose of this study was to characterize further the long-term effects on glucose and leptin homeostasis and on food preferences. Neonate rats were supplemented during lactation with a daily oral dose of leptin or the vehicle. We followed body weight and food intake of animals until the age of 15 months, and measured glucose, insulin, and leptin levels under different feeding conditions: ad libitum feeding, 14-h fasting, and 3-h refeeding after fasting. An oral glucose tolerance test and a leptin resistance test were performed. Food preferences were also measured. Leptin-treated animals were found to have lower body weight in adulthood and to eat fewer calories than their controls. Plasma insulin levels were lower in leptin-treated animals than in their controls under the different feeding conditions, as was the increase in insulin levels after food intake. The homeostatic model assessment for insulin resistance index was significantly lower in leptin-treated animals, and the oral glucose tolerance test also indicated higher insulin sensitivity in leptin-treated animals. In addition, these animals displayed lower plasma leptin levels under the different feeding conditions and were also more responsive to exogenous leptin administration. Leptin-treated animals also showed a lower preference for fat-rich food than their controls. These observations indicate that animals supplemented with physiological doses of oral leptin during lactation were more protected against obesity and metabolic features of the metabolic syndrome.     

Esophageal stenosis in eosinophilic esophagitis

Eosinophilic esophagitis is a rare, recently discovered disease, characterized by esophageal symptoms, such as dysphagia and food impaction, associated with dense eosinophilia on endoscopic biopsy of the esophagus. Other entities such as gastroesophageal reflux disease are absent and there is a lack of response to proton pump inhibitor therapy. This disease mainly affects the pediatric population but is becoming more prevalent in adults. There are several theories on the etiopathogenesis of this entity, which may involve allergies and atopy. In advanced disease, complications such as esophageal stenosis can appear. Treatment is based on dietary elimination, corticosteroids and endoscopic dilatation. We report a case of eosinophilic esophagitis with esophageal stenosis.     

The rs1333049 polymorphism on locus 9p21.3 and extreme longevity in Spanish and Japanese cohorts

GeroScience - The rs1333049 (G/C) polymorphism located on chromosome 9p21.3 is a candidate to influence extreme longevity owing to its association with age-related diseases, notably coronary artery...     

The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase

Complex hereditary spastic paraplegia (HSP) is a genetic disorder that causes lower limb spasticity and weakness and intellectual disability. Deleterious mutations in the poorly characterized serine hydrolase DDHD2 are a causative basis for recessive complex HSP. DDHD2 exhibits phospholipase activity in vitro, but its endogenous substrates and biochemical functions remain unknown. Here, we report the development of DDHD2^−/− mice and a selective, in vivo-active DDHD2 inhibitor and their use in combination with mass spectrometry-based lipidomics to discover that DDHD2 regulates brain triglycerides (triacylglycerols, or TAGs). DDHD2^−/− mice show age-dependent TAG elevations in the central nervous system, but not in several peripheral tissues. Large lipid droplets accumulated in DDHD2^−/− brains and were localized primarily to the intracellular compartments of neurons. These metabolic changes were accompanied by impairments in motor and cognitive function. Recombinant DDHD2 displays TAG hydrolase activity, and TAGs accumulated in the brains of wild-type mice treated subchronically with a selective DDHD2 inhibitor. These findings, taken together, indicate that the central nervous system possesses a specialized pathway for metabolizing TAGs, disruption of which leads to massive lipid accumulation in neurons and complex HSP syndrome.Determining the genetic basis for rare hereditary human diseases has benefited from advances in DNA sequencing technologies (1). As a greater number of disease-causing mutations are mapped, however, it is also becoming apparent that many of the affected genes code for poorly characterized proteins. Assigning biochemical and cellular functions to these proteins is critical to achieve a deeper mechanistic understanding of human genetic disorders and for identifying potential treatment strategies.Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurologic syndrome marked by spasticity and lower extremity weakness (2). Many genetic types of HSP have been identified and are numbered according to their order of discovery [spastic paraplegia (SPG) 1-72] (2, 3). Of these genetic variants, more than 40 have been mapped to causative mutations in protein-coding genes. HSP genes code for a wide range of proteins that do not conform to a single sequence- or function-related class. A subset of HSP genes, including PNPLA6 (or neuropathy-target esterase) (SPG39) (4), DDHD1 (SPG28) (5), and DDHD2 (SPG54) (3, 6–8), code for serine hydrolases. These enzymes have been designated as (lyso)phospholipases based on in vitro substrate assays (9–11), but their endogenous substrates and physiological functions remain poorly understood. The mutational landscape that affects these lipid hydrolases to cause recessive HSP is complex but collectively represents a mix of null and putatively null and/or functional mutations. Moreover, the type of HSP appears to differ in each case, with DDHD1 mutations causing uncomplicated HSP, whereas PNPLA6 and DDHD2 mutations lead to complex forms of the disease that exhibit additional phenotypes including, in the case of DDHD2, intellectual disability. Human subjects with DDHD2 mutations also displayed evidence of brain lipid accumulation as detected by cerebral magnetic resonance spectroscopy (6). Both rodent and human DDHD2 enzymes are highly expressed in the brain compared with most peripheral tissues (6, 9); however, the specific lipids regulated by DDHD2 in the central nervous system (CNS) have not yet been identified.Determining the metabolic function of DDHD2 in the brain is an important step toward understanding how mutations in this enzyme promote complex HSP and for identifying possible therapeutic strategies for the disease. Toward this end, we report herein the generation and characterization of DDHD2^−/− mice and a selective DDHD2 inhibitor. DDHD2^−/− mice exhibit defects in movement and cognitive function. Mass spectrometry (MS)-based lipidomics (12, 13) revealed a striking and selective elevation in triglycerides (triacylglycerols, or TAGs) throughout the CNS, but not in peripheral tissues, of DDHD2^−/− mice. This metabolic change correlated with pervasive lipid droplet (LD) accumulation in neuronal cell bodies of DDHD2^−/− mice. Biochemical assays confirmed that DDHD2 possesses TAG hydrolase activity. Finally, wild-type mice treated subchronically with a DDHD2 inhibitor also exhibited significant elevations in CNS TAGs. These data, taken together, indicate that DDHD2 is a principal TAG hydrolase of the mammalian brain and point to deregulation of this pathway as a major contributory factor to complex HSP.     

Evaluation of liver MRI examinations with two dosages of gadobenate dimeglumine: a blinded intra-individual study

Abdominal Radiology - There is discrepancy in the literature regarding the optimal dose of gadobenate for liver MRI. We evaluated the quality of liver MRIs performed in the same individual using...     

Sepsis of a prosthetic joint and biological therapies

SIR, We read with interest the article of Ledingham and Deighton[1] updating the guidelines for prescribing TNF- blockers inadults with rheumatoid arthritis. The guidelines establish thatthe sepsis of a prosthetic joint that remains in situ is animportant exclusion criterion for     

Cronobiología de la muerte en insuficiencia cardiaca

Introduction and objectives

In the general population, heart events occur more often during early morning, on Mondays, and during winter. However, the chronobiology of death in heart failure has not been analyzed. The aim of this study was to determine the circadian, day of the week, and seasonal variability of all-cause mortality in chronic heart failure.

Methods

This was an analysis of all consecutive heart failure patients followed in a heart failure unit from January 2003 to December 2008. The circadian moment of death was analyzed at 6-h intervals and was determined by reviewing medical records and by information provided by the relatives.

Results

Of 1196 patients (mean [standard deviation] age, 69 [13] years; 62% male), 418 (34.9%) died during a mean (standard deviation) follow-up of 29 (21) months. Survivors were younger, had higher body mass index, left ventricular ejection fraction, glomerular filtration rate, hemoglobin and sodium levels, and lower Framingham risk scores, amino-terminal pro-B type natriuretic peptide, troponin T, and urate values. They were more frequently treated with angiotensin receptor blockers, beta-blockers, mineralocorticoids receptor antagonists, digoxin, nitrates, hydralazine, statins, loop diuretics, and thiazides. The analysis of the circadian and weekly variability did not reveal significant differences between the four 6-h intervals or the days of the week. Mortality occurred more frequently during the winter (30.6%) compared with the other seasons (P = .024).

Conclusions

All cause mortality does not follow a circadian pattern, but a seasonal rhythm in patients with heart failure. This finding is in contrast to the circadian rhythmicity of cardiovascular events reported in the general population.Full English text available from:www.revespcardiol.org/en