Umbilical cord mesenchymal stromal cells transplantation delays the onset of hyperglycemia in the RIP-B7.1 mouse model of experimental autoimmune diabetes through multiple immunosuppressive and anti-inflammatory responses.

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder specifically targeting pancreatic islet beta cells. Despite many efforts focused on identifying new therapies able to counteract this autoimmune attack and/or stimulate beta cells regeneration, TD1M remains without effective clinical treatments providing no clear advantages over the conventional treatment with insulin. We previously postulated that both the inflammatory and immune responses and beta cell survival/regeneration must be simultaneously targeted to blunt the progression of disease. Umbilical cord-derived mesenchymal stromal cells (UC-MSC) exhibit anti-inflammatory, trophic, immunomodulatory and regenerative properties and have shown some beneficial yet controversial effects in clinical trials for T1DM. In order to clarify conflicting results, we herein dissected the cellular and molecular events derived from UC-MSC intraperitoneal administration (i.p.) in the RIP-B7.1 mouse model of experimental autoimmune diabetes. Intraperitoneal (i.p.) transplantation of heterologous mouse UC-MSC delayed the onset of diabetes in RIP-B7.1 mice. Importantly, UC-MSC i. p. transplantation led to a strong peritoneal recruitment of myeloid-derived suppressor cells (MDSC) followed by multiple T-, B- and myeloid cells immunosuppressive responses in peritoneal fluid cells, spleen, pancreatic lymph nodes and the pancreas, which displayed significantly reduced insulitis and pancreatic infiltration of T and B Cells and pro-inflammatory macrophages. Altogether, these results suggest that UC-MSC i. p. transplantation can block or delay the development of hyperglycemia through suppression of inflammation and the immune attack.

The metabolic response to postnatal leptin in rats varies with age and may be litter dependent.

Hyperleptinemia during postnatal life induces long-term effects on metabolism. However, these effects are controversial as both increased and decreased propensity towards obesity has been reported. To further analyze the effects of chronic neonatal hyperleptinemia on the subsequent metabolic profile, male Wistar rats proceeding from 18 different litters (8 pups/litter) received a daily subcutaneous injection of either saline (10 ml/kg, n=36) or leptin (3 µg/g, n=36) from postnatal day (PND) 2 to PND9. Rats were sacrificed at 10, 40, or 150 days of age. At 10 days of age, leptin treated rats had decreased body weight (p<0.001) and body fat (p<0.05). Leptin levels and glycemia were increased (p<0.01), whereas insulin, total lipids, triglycerides and glycerol levels were decreased (p<0.05). At PND40 rats receiving leptin had increased glycemia (p<0.01) and plasma HDL and LDL levels, but decreased total lipids (p<0.05). At PND150 neonatal leptin treatment induced different effects in rats raised in different litters. Rats from litter 1 had increased body weight (p<0.05), body fat (p<0.01), and plasma leptin (p<0.001), cholesterol (p<0.001), triglyceride (p<0.001), total lipid (p<0.001), LDL (p<0.05), and glycerol (p<0.001) levels. In rats from litter 2 these parameters did not differ from controls. Rats from litter 3 had decreased body weight (p<0.05), visceral fat (p<0.01) and plasma leptin (p<0.001), cholesterol (p<0.001), triglyceride (p<0.001), glycerol (p<0.001), and HDL (p<0.001) levels. In conclusion, the metabolic response to postnatal leptin varies with age, with the response in adulthood being variable and most likely influenced by other factors, including the genetic make-up.

Estrogen, astrocytes and the neuroendocrine control of metabolism.

Obesity, and its associated comorbidities such as type 2 diabetes, cardiovascular diseases, and certain cancers, represent major health challenges. Importantly, there is a sexual dimorphism with respect to the prevalence of obesity and its associated metabolic diseases, implicating a role for gonadal hormones. Specifically, estrogens have been demonstrated to regulate metabolism perhaps by acting as a leptin mimetic in the central nervous system (CNS). CNS estrogen receptors (ERs) include ER alpha (ERα) and ER beta (ERß), which are found in nuclear, cytoplasmic and membrane sites throughout the brain. Additionally, estrogens can bind to and activate a G protein-coupled estrogen receptor (GPER), which is a membrane-associated ER. ERs are expressed on neurons as well as glia, which are known to play a major role in providing nutrient supply for neurons and have recently received increasing attention for their potentially important involvement in the CNS regulation of systemic metabolism and energy balance. This brief overview summarizes data focusing on the potential role of astrocytic estrogen action as a key component of estrogenic modulation responsible for mediating the sexual dimorphism in body weight regulation and obesity.

Activation of microglia in specific hypothalamic nuclei and the cerebellum of adult rats exposed to neonatal overnutrition.

Much attention has been drawn to the possible involvement of hypothalamic inflammation in the pathogenesis of metabolic disorders, especially in response to a high-fat diet. Microglia, the macrophages of the central nervous system, can be activated by proinflammatory signals resulting in the local production of specific interleukins and cytokines, which in turn could exacerbate the pathogenic process. Because obesity itself is considered to be a state of chronic inflammation, we evaluated whether being overweight results in microglial activation in the hypothalamus of rats on a normal diet. Accordingly, we used a model of neonatal overnutrition that entailed adjustment of litter size at birth (small litters: four pups/dam versus normal litters: 12 pups/dam) and resulted in a 15% increase in bodyweight and increased circulating leptin levels at postnatal day 60. Rats that were overnourished during neonatal life had an increased number of activated microglia in specific hypothalamic areas such as the ventromedial hypothalamus, which is an important site for metabolic control. However, this effect was not confined to the hypothalamus because significant microglial activation was also observed in the cerebellar white matter. There was no change in circulating tumour necrosis factor (TNF) α levels or TNFα mRNA levels in either the hypothalamus or cerebellum. Interleukin (IL)6 protein levels were higher in both the hypothalamus and cerebellum, with no change in IL6 mRNA levels. Because circulating IL6 levels were elevated, this rise in central IL6 could be a result of increased uptake. Thus, activation of microglia occurs in adult rats exposed to neonatal overnutrition and a moderate increase in weight gain on a normal diet, possibly representing a secondary response to systemic inflammation. Moreover, this activation could result in local changes in specific hypothalamic nuclei that in turn further deregulate metabolic homeostasis.

Búsqueda activa de casos entre familiares de primer grado de niños celíacos / Case finding study among first degree relatives of coeliac children

Objetivo. Conocer la prevalencia de la enfermedad celíaca entre familiares de primer grado de niños afectos de celiaquía. Estudiar el comportamiento del HLA DQ2 entre los niños y sus familiares. Material y Métodos. Estudio descriptivo transversal de serología de celíaca y de HLA DQ2 entre los familiares de primer grado de niños diagnosticados de enfermedad celíaca en nuestro Área Sanitaria entre 1992 y 2003.Resultados. Se diagnosticaron 54 casos nuevos de enfermedad celíaca en el periodo de estudio (17 varones y 37 mujeres), con una mediana de edad en la biopsia yeyunal de 24 meses. De ellos, el 89 por ciento presentaban clínica digestiva, el 46 por ciento hipocrecimiento/fallo de medro y el 2 por ciento eran asintomáticos. Todos presentaron serología y biopsia yeyunal típica de enfermedad celíaca. El 85 por ciento eran HLA DQ2 positivos. Se pudieron estudiar 44 familias de las 54 iniciales. Se realizó la serología de celíaca en 115 familiares, detectándose cuatro nuevos casos (dos hermanos, una hermana y una madre) (3,5 por ciento de los familiares estudiados). El HLA DQ2 se estudió en 110 familiares, siendo positivo en el 64 por ciento de los mismos (74 por ciento de los padres, 59 por ciento de las madres y 60 por ciento de los hermanos). Los cuatro nuevos casos eran HLA DQ2 positivos. Conclusión. El 3,5 por ciento de los familiares de primer grado de nuestros niños celíacos presentaban marcadores serológicos de celíaca. El HLA DQ2 fue positivo en el 85 por ciento de los niños celíacos y en el 64 por ciento de los familiares estudiados. Los cuatro nuevos casos detectados eran HLA DQ2 positivos (AU)

Diarrea en una mujer de 49 años de edad con síndrome de solapamiento / Diarrhoea in a 49-year old female with overlap syndrome

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[Familial study of patients with hereditary hemorrhagic telangiectasia]. / Estudio familiar de pacientes con telangiectasia hemorrágica hereditaria.

Rendu-Osler-Weber's disease or Hereditary Hemorrhagic Telangiectasia (HTT) is an autosomal dominant hereditary clinical entity characterized by the presence of telangiectasias on skin, mucous membranes and internal organs. The incidence of hepatic, pulmonary or cerebral complications justifies an early diagnostic. A familiar study of patients previously diagnosed of HTT in our hospital was made, establishing a protocol for the identification of asymptomatic or pauci-symptomatic cases. Fourteen patients were studied: 6 with a previous diagnostic, and 8 familiar contacts. Penetrance was of 85%. Epistaxis (80%) and telangiectasias on skin were the most frequent clinical findings. The visceral lesions found were gastrointestinal (28%), hepatic (15%), urological (15%) and pulmonary (7%). All patients were included in an hepatitis B virus vaccination program. It was also made a morphological study with Werhoeff's staining of the elastic layer, that allowed to distinguish both arterial and venous alterations.

[Muscular pseudohypertrophy and intraspinal neurinoma]. / Seudohipertrofia muscular y neurinoma intrarraquídeo.

We present a patient with protracted hypertrophy of the left calf, light triceps suralis weakness, and mild inconstant left foot pain. The clinical picture evolved slowly throughout more than eight years, and lately slight weakness in anterior right leg musculature appeared. The magnetic resonance examination revealed the existence of an intrarachideal extraspinal tumor adjacent to the conus medullaris that histologically was a neurinoma. Although the neurogenic pseudohypertrophy has diverse etiology, the present association is unpublished.