Caso Clínico: Diastomatomielia, una Forma Rara de Disrafia Espinal Oculta / Case Report: Diastomatomyelia, a Rare Form of Hidden Spinal Disraphy

INTRODUCCIÓN: La diastematomielia es una malformación raquimedular, un desdoblamiento sagital de la médula espinal, frecuentemente por debajo de la quinta vértebra dorsal; siendo una presentación rara de disrafismo espinal (menos del 3 %), más frecuente en el sexo femenino (3:1), se presenta entre los 10 y 76 años de edad. Puede ser asintomática y un descubrimiento incidental. Su diagnóstico es básicamente radiológico. CASO CLÍNICO: Paciente de sexo masculino de 20 años de edad, con cuadro de lumbalgia crónica, habiendo sido tratado por diferentes especialistas y tratamientos. Se solicitó estudios de imagen con la finalidad de esclarecer el diagnóstico; en la exploración física reportó zona de hipertricosis localizada a nivel lumbosacro y escoliosis dorsolumbar leve. EVOLUCIÓN: Los estudios radiológicos, tomográficos y de resonancia magnética evidenciaron la fusión de los cuerpos vertebrales L2 - L3 (espolón óseo), asociando anomalías de fusión de los elementos posteriores con división del canal raquídeo, y en médula espinal dos hemimédulas. Al momento el paciente se encuentra en controles periódicos por el servicio de traumatología con tratamiento clínico. CONCLUSIONES: No es sencillo el diagnóstico, frecuentemente se realiza en etapas tardías, cuando las alteraciones neurológicas son explícitas. Es preciso permanecer alerta ante alteraciones cutáneas de la línea media; dado que puede ser indicadora de diastematomielia o de cualquier disrafismo oculto.

BACKGROUND: Diastematomyelia is a spinal cord malformation consisting of a sagittal split spinal cord, often below the fifth thoracic vertebra and being a rare presentation of occult spinal dysraphism (less than 3 %), and it is more common in females (3:1), in the age of 10 and 76 years old. It can be asymptomatic and be discovered incidentally. It is basically radiological diagnosis. CASE REPORT: A 20 - years old, male patient presents chronic and unwilling back pain treatment, which has been treated by different specialists and treatments. If was requested image exams in order to clarify the diagnosis. Physical examination zone localized hypertrichosis and lumbosacral thoracolumbar scoliosis reported. EVOLUTION: The computed tomography and magnetic resonance showed the fusion of the L2 - L3 (bone spurs) associated with abnormalities fusion of the posterior elements with division of the spinal canal into two compartments, vertebral bodies and spinal cord in two hemicords. At present, the patient is under periodic controls by the traumatology service with clinical treatment. CONCLUSIONS: It is not easy diagnosis diastematomyelia often is performed in later stages, when neurological disorders are already flowered. Because of this, must remain alert to any skin disorder midline, it can be indicative of diastematomyelia or any of the hidden dysraphisms.

Prevalence of persistent blood eosinophilia: relation to outcomes in patients with COPD.

The impact of blood eosinophilia in chronic obstructive pulmonary disease (COPD) remains controversial.To evaluate the prevalence and stability of a high level of blood eosinophils (≥300 cells·µL-1) and its relationship to outcomes, we determined blood eosinophils at baseline and over 2 years in 424 COPD patients (forced expiratory volume in 1 s (FEV1) 60% predicted) and 67 smokers without COPD from the CHAIN cohort, and in 308 COPD patients (FEV1 60% predicted) in the BODE cohort. We related eosinophil levels to exacerbations and survival using Cox hazard analysis.In COPD patients, 15.8% in the CHAIN cohort and 12.3% in the BODE cohort had persistently elevated blood eosinophils at all three visits. A significant proportion (43.8%) of patients had counts that oscillated above and below the cut-off points, while the rest had persistent eosinophil levels <300 cells·µL-1 A similar eosinophil blood pattern was observed in controls. Exacerbation rates did not differ in patients with and without eosinophilia. All-cause mortality was lower in patients with high eosinophils compared with those with values <300 cells·µL-1 (15.8% versus 33.7%; p=0.026).In patients with COPD, blood eosinophils ≥300 cells·µL-1 persisting over 2 years was not a risk factor for COPD exacerbations. High eosinophil count was associated with better survival.

Obesity induces hypothalamic endoplasmic reticulum stress and impairs proopiomelanocortin (POMC) post-translational processing.

It was shown previously that abnormal prohormone processing or inactive proconverting enzymes that are responsible for this processing cause profound obesity. Our laboratory demonstrated earlier that in the diet-induced obesity (DIO) state, the appetite-suppressing neuropeptide α-melanocyte-stimulating hormone (α-MSH) is reduced, yet the mRNA of its precursor protein proopiomelanocortin (POMC) remained unaltered. It was also shown that the DIO condition promotes the development of endoplasmic reticulum (ER) stress and leptin resistance. In the current study, using an in vivo model combined with in vitro experiments, we demonstrate that obesity-induced ER stress obstructs the post-translational processing of POMC by decreasing proconverting enzyme 2, which catalyzes the conversion of adrenocorticotropin to α-MSH, thereby decreasing α-MSH peptide production. This novel mechanism of ER stress affecting POMC processing in DIO highlights the importance of ER stress in regulating central energy balance in obesity.

Hypothalamic control of lipid metabolism: focus on leptin, ghrelin and melanocortins.

The hypothalamus plays a crucial role in the regulation of food intake and energy expenditure. One of the main regulatory factors within the hypothalamus is AMP-activated protein kinase (AMPK), which is involved in a large number of biological actions including the modulation of energy balance. Leptin and ghrelin-induced changes in hypothalamic AMPK lead to important alterations in hypothalamic fatty acid metabolism. Furthermore, it is well known that the hypothalamus controls peripheral lipid metabolism through the sympathetic nervous system, and those actions are independent of food intake. In this short review, we highlight the main molecular pathways triggered by leptin and ghrelin altering both central and peripheral lipid metabolism and, therefore, controlling feeding behavior and energy expenditure.

The central Sirtuin 1/p53 pathway is essential for the orexigenic action of ghrelin.

OBJECTIVE: Ghrelin is a stomach-derived peptide that increases food intake through the activation of hypothalamic AMP-activated protein kinase (AMPK). However, the molecular mechanisms initiated by the activation of the ghrelin receptor, which in turn lead to AMPK activation, remain unclear. Sirtuin 1 (SIRT1) is a deacetylase activated in response to calorie restriction that acts through the tumor suppressor gene p53. We tested the hypothesis that the central SIRT1/p53 pathway might be mediating the orexigenic action of ghrelin. RESEARCH DESIGN AND METHODS: SIRT1 inhibitors, such as Ex527 and sirtinol, and AMPK activators, such as AICAR, were administered alongside ghrelin in the brain of rats and mice (wild-type versus p53 knockout [KO]). Their hypothalamic effects on lipid metabolism and changes in transcription factors and neuropeptides were assessed by Western blot and in situ hybridization. RESULTS: The central pretreatment with Ex527, a potent SIRT1 inhibitor, blunted the ghrelin-induced food intake in rats. Mice lacking p53, a target of SIRT1 action, failed to respond to ghrelin in feeding behavior. Ghrelin failed to phosphorylate hypothalamic AMPK when rats were pretreated with Ex527, as it did in p53 KO mice. It is noteworthy that the hypothalamic SIRT1/p53 pathway seems to be specific for mediating the orexigenic action of ghrelin, because central administration of AICAR, a potent AMPK activator, increased food intake in p53 KO mice. Finally, blockade of the central SIRT1 pathway did not modify ghrelin-induced growth hormone secretion. CONCLUSIONS: Ghrelin specifically triggers a central SIRT1/p53 pathway that is essential for its orexigenic action, but not for the release of growth hormone.

Central GLP-1 actions on energy metabolism.

Glucagon-like peptide 1 (GLP-1) is secreted mainly by the intestine in a nutrient-dependent manner and stimulates glucose-induced insulin secretion, inhibits gastric emptying, food intake, and glucagon secretion. All these beneficial effects make GLP-1 as a promising, and currently in the market, drug candidate for the treatment of type 2 diabetes. More recently, it has been also demonstrated that within the central nervous system, GLP-1 also exerts important metabolic actions inhibiting food intake, increasing insulin secretion, and modulating behavioral responses. In this review, we will focus on the metabolic actions and mechanisms of the central GLP-1 system: modulation of energy intake, glucose metabolism, and fatty acid metabolism.

Maintenance of the thyroid axis during diet-induced obesity in rodents is controlled at the central level.

The hypothalamic-pituitary-thyroid (HPT) axis is a major contributor in maintaining energy expenditure and body weight, and the adipocyte hormone leptin regulates this axis by increasing TRH levels in the fed state. Leptin stimulates TRH directly in the hypothalamic paraventricular nucleus (PVN; direct pathway) and indirectly by regulating proopiomelnocortin neurons in the hypothalamic arcuate nucleus (ARC; indirect pathway). Whereas the indirect pathway is fully functional in lean animals, it is inactive during diet-induced obesity (DIO) because of the establishment of leptin resistance. Despite this, the HPT axis activity in obese humans and rodents remains within the normal levels or slightly higher. Therefore, in this study, we aimed to determine the mechanism(s) by which the HPT axis is still active despite leptin resistance. With a combination of using the Sprague-Dawley rat physiological model and the Zuker rat that bears a mutation in the leptin receptor, we were able to demonstrate that under DIO conditions the HPT axis is regulated at the central level, but only through the direct pathway of leptin action on TRH neurons. Deiodinase enzymes, which are present in many tissues and responsible for converting thyroid hormones, were not statistically different between lean and DIO animals. These data suggest that the increase in T(4/3) seen in obese animals is due mostly to central leptin action. We also found that T(3) feedback inhibition on the prepro-TRH gene is controlled partially by leptin-induced pSTAT3 signaling via the TRH promoter. This interactive relationship between T(3) and pSTAT3 signaling appears essential to maintain the HPT axis at normal levels in conditions such as obesity.

GOAT: the master switch for the ghrelin system?

The ghrelin-ghrelin receptor system is one of the most important mechanisms regulating energy balance and metabolism. Among other actions, central and peripheral administration of ghrelin increases food intake and adiposity. During the last years, many efforts have been made in the investigation of the cellular and molecular mechanisms modulating the effects of ghrelin. One particularity of this peptide hormone is its acylation at serine-3 with an eight-carbon fatty acid (octanoate), which confers its biological activity. Recent reports have demonstrated that the ghrelin O-acyltransferase (GOAT) is the enzyme that catalyzes ghrelin octanoylation. Therefore, all questions concerning the posttranslational acylation of ghrelin are of great interest for the complete understanding of this system. In this review, we summarize the discovery and characterization of GOAT, and remark the importance of GOAT as a novel and potential target that regulates the biological actions of ghrelin, revealing several therapeutical possibilities for the treatment of the metabolic syndrome.

Expression of GLUT8 in mouse intestine: identification of alternative spliced variants.

GLUT8 is a facilitative glucose transporter composed of 10 exons coding for a 477 amino acids protein. It is mainly expressed in the testis, but it has also been studied in a number of tissues such as brain, adipose tissue, and liver. In this work, we have characterized the expression of GLUT8 in the small and large intestine under normal physiological conditions. Protein assay revealed low GLUT8 protein levels in the intestine compared to the testis, with higher levels in the colon than in the small intestine. Immunohistochemistry studies showed an intracellular localization of GLUT8 in enterocytes and colonocytes with a supranuclear distribution next to the apical membrane. GLUT8 immunoreactivity was also detected in the crypt cells. Interestingly, we have identified three additional transcriptional variants in mouse intestine (mGLUT-SP1, mGLUT8-SP2, and mGLUT8-SP3) produced by the deletion of one, two, and four exons, respectively, whereas only the entire mRNA was detected in the testis. Expression of these alternative variants did not have an effect on glucose consumption in 3T3-L1 cells. Although the specific function of GLUT8 in intestine remains unclear, the alternative splicing of GLUT8 could reflect a mechanism for the regulation of the gene expression in a tissue-specific manner by targeting GLUT8 mRNA for nonsense-mediated decay.

Role of a pro-sequence in the secretory pathway of prothyrotropin-releasing hormone.

The biogenesis of rat thyrotropin releasing hormone (TRH) involves the processing of its precursor (proTRH) into five biologically active TRH peptides and several non-TRH peptides where two of them had been attributed potential biological functions. This process implicates 1) proper folding of proTRH in the endoplasmic reticulum after its biosynthesis and exit to the Golgi apparatus and beyond, 2) initial processing of proTRH in the trans Golgi network and, 3) sorting of proTRH-derived peptides to the regulated secretory pathway. Previous studies have focused on elucidating the processing and sorting determinants of proTRH. However, the role of protein folding in the sorting of proTRH remains unexplored. Here we have investigated the role in the secretion of proTRH of a sequence comprising 22 amino acid residues, located at the N-terminal region of proTRH, residues 31-52. Complete deletion of these 22 amino acids dramatically compromised the biosynthesis of proTRH, manifested as a severe reduction in the steady state level of proTRH in the endoplasmic reticulum. This effect was largely reproduced by the deletion of only three amino acid residues, 40PGL42, within the proTRH31-52 sequence. The decreased steady state level of the mutant DeltaPGL was due to enhanced endoplasmic reticulum-associated protein degradation. However, the remnant of DeltaPGL that escaped degradation was properly processed and sorted to secretory granules. Thus, these results suggest that the N-terminal domain within the prohormone sequence does not act as "sorting signal" in late secretion; instead, it seems to play a key role determining the proper folding pathway of the precursor and, thus, its stability.

Yellowish lesions of the oral cavity. Suggestion for a classification.

The colour of a lesion is due to its nature and to its histological substratum. In order to ease diagnosis, oral cavity lesions have been classified according to their colour in: white, red, white and red, bluish and/or purple, brown, grey and/or black lesions. To the best of our knowledge, there is no such a classification for yellow lesions. So, a suggestion for a classification of yellowish lesions according to their semiology is made with the following headings: diffuse macular lesions, papular, hypertrophic, or pustular lesions, together with cysts and nodes. This interpretation of the lesions by its colour is the first step to diagnosis. It should be taken into account that, as happens with any other classification, the yellowish group of lesions includes items with different prognosis as well as possible markers of systemic disorders.

Yellowish lesions of the oral cavity. Suggestion for a classification

Para facilitar el diagnóstico de las lesiones de la cavidad oral estas han sido clasificadas atendiendo a su color en: blancas, rojas, blancas y rojas, azules y/o púrpura, marrones, grises y/o negras. El color de la lesión se debe a su naturaleza y al sustrato histológico. Debido a que no existe ninguna clasificación de las lesiones, según nuestro conocimiento, atendiendo a su color amarillo, proponemos aquí esta clasificación desde una perspectiva semiológica, agrupándolas en lesiones maculares difusas, lesiones papulares, lesiones hipertróficas, lesiones pustulosas, quistes y nódulos. Esta lectura de las lesiones según su color constituye el primer paso para ayudar a su diagnóstico. Finalmente, debemos considerar que al igual que ocurre con las lesiones que se clasifican en cualquier grupo de color, el grupo de lesiones amarillas incluirá lesiones con diferente pronóstico y además lesiones que pueden indicar una patología sistémica de base

The colour of a lesion is due to its nature and to its histological substratum. In order to ease diagnosis, oral cavity lesions have been classified according to their colour in: white, red, white and red, bluish and/or purple, brown, grey and/or black lesions. To the best of our knowledge, there is no such a classification for yellow lesions. So, a suggestion for a classification of yellowish lesions according to their semiology is made with the following headings: diffuse macular lesions, papular, hypertrophic, or pustular lesions, together with cysts and nodes. This interpretation of the lesions by its colour is the first step to diagnosis. It should be taken into account that, as happens with any other classification, the yellowish group of lesions includes items with different prognosis as well as possible markers of systemic disorders

Differential expression of glucose transporter GLUT8 during mouse spermatogenesis.

GLUT8 is a facilitative glucose transporter expressed at high levels in the testis. In this study, we analyzed the GLUT8 expression in mouse testis during spermatogenesis by RT-PCR, Western blot and immunohistochemistry methods. Our results show that GLUT8 expression is limited to spermatids and spermatozoa in the testis. Expression begins when round spermatids are formed at postnatal day 24. The expression persists throughout spermiogenesis, and it is also detected in spermatozoa, but it is absent in more immature germ cells, Sertoli cells and interstitial tissue. GLUT8 immunoreactivity is always restricted to the acrosomic system in a manner that matches the acrosome system formation. The GLUT8 expression is mainly associated with the acrosomic membrane in the acrosome, although significant immunoreactivity is also found inside the acrosomic lumen. The specific GLUT8 location suggests that this transporter plays a pivotal role in the fuel supply of spermatozoa, and in the traffic of sugars during the capacitation and fertilization processes.