Ren: a novel, developmentally regulated gene that promotes neural cell differentiation

Expansion and fate choice of pluripotent stem cells along the neuroectodermal lineage is regulated by a number of signals, including EGF, retinoic acid, and NGF, which also control the proliferation and differentiation of central nervous system (CNS) and peripheral nervous system (PNS) neural progenitor cells. We report here the identification of a novel gene, REN, upregulated by neurogenic signals (retinoic acid, EGF, and NGF) in pluripotent embryonal stem (ES) cells and neural progenitor cell lines in association with neurotypic differentiation. Consistent with a role in neural promotion, REN overexpression induced neuronal differentiation as well as growth arrest and p27Kip1 expression in CNS and PNS neural progenitor cell lines, and its inhibition impaired retinoic acid induction of neurogenin-1 and NeuroD expression. REN expression is developmentally regulated, initially detected in the neural fold epithelium of the mouse embryo during gastrulation, and subsequently throughout the ventral neural tube, the outer layer of the ventricular encephalic neuroepithelium and in neural crest derivatives including dorsal root ganglia. We propose that REN represents a novel component of the neurogenic signaling cascade induced by retinoic acid, EGF, and NGF, and is both a marker and a regulator of neuronal differentiation

Asymptomatic esophageal squamous cell carcinoma masquerading as a rare primary pancreatic carcinoma. Diagnosis by percutaneous fine needle aspiration

An unusual case of asymptomatic squamous cell carcinoma of the esophagus metastatic to the pancreas, mimicking a rare primary pancreatic neoplasm, is reported. Percutaneous fine needle aspiration (FNA) biopsy of a pancreatic lesion showed squamous cell carcinoma, which in the pancreas is virtually always metastatic in origin. This prompted a search for an occult primary elsewhere, resulting in the discovery of an esophageal neoplasm, which in itself is one of the least likely sources of pancreatic metastases. FNA biopsy was thus a useful and accurate diagnostic tool in establishing the true nature of the pancreatic neoplasm, sparing the patient unnecessary pancreatic surgery, with its attendant morbidity and hospital costs

Neurodegeneration behind bars: from molecules to jurisprudence

The prison population is aging and developing neurodegenerative disorders at a faster pace than the general population. Hidden among this group of recidivist, career criminals, there is a subpopulation of first offenders with frontotemporal dementia behavioral variant (bvFTD). The pathological hallmark of this condition is frontotemporal lobar degeneration (FTLD), which early on spares cognition, yet predisposes to criminal violations. From the neurobiological perspective, bvFTD originates in a large-scale brain network in charge of motivation and concern, the salience network (SN). From the judiciary perspective, bvFTD is challenging because patients often retain the “appreciation” of right and wrong, yet may be organically incapable to act accordingly. Equally challenging are the dispositions in regards to bvFTD patients: return to the community, risking further violations, vs. incarceration with dismal punitive or rehabilitative benefit. In this article, we advocate for screening of all first offenders who are 55 years of age or older via neuropsychological testing and/or positron emission tomography (PET) and should bvFTD be diagnosed, their placement in, yet to be developed, palliative programs in state or private facilities

Metabotropic glutamate receptors as drug targets: what's new?

The question in the title: 'what's new?' has two facets. First, are 'clinical' expectations met with success? Second, is the number of CNS disorders targeted by mGlu drugs still increasing? The answer to the first question is 'no', because development program with promising drugs in the treatment of schizophrenia, Parkinson's disease, and Fragile X syndrome have been discontinued. Nonetheless, we continue to be optimistic because there is still the concrete hope that some of these drugs are beneficial in targeted subpopulations of patients. The answer to the second question is 'yes', because mGlu ligands are promising targets for 'new' disorders such as type-1 spinocerebellar ataxia and absence epilepsy. In addition, the increasing availability of pharmacological tools may push mGlu7 and mGlu8 receptors into the clinical scenario. After almost 30 years from their discovery, mGlu receptors are still alive. © 2014 Elsevier Ltd

Metabotropic glutamate receptors as drug targets: what's new?

The question in the title: 'what's new?' has two facets. First, are 'clinical' expectations met with success? Second, is the number of CNS disorders targeted by mGlu drugs still increasing? The answer to the first question is 'no', because development program with promising drugs in the treatment of schizophrenia, Parkinson's disease, and Fragile X syndrome have been discontinued. Nonetheless, we continue to be optimistic because there is still the concrete hope that some of these drugs are beneficial in targeted subpopulations of patients. The answer to the second question is 'yes', because mGlu ligands are promising targets for 'new' disorders such as type-1 spinocerebellar ataxia and absence epilepsy. In addition, the increasing availability of pharmacological tools may push mGlu7 and mGlu8 receptors into the clinical scenario. After almost 30 years from their discovery, mGlu receptors are still alive

Lack or Inhibition of Dopaminergic Stimulation Induces a Development Increase of Striatal Tyrosine Hydroxylase-Positive Interneurons

We examined the role of endogenous dopamine (DA) in regulating the number of intrinsic tyrosine hydroxylase-positive (TH +) striatal neurons using mice at postnatal day (PND) 4 to 8, a period that corresponds to the developmental peak in the number of these neurons. We adopted the strategy of depleting endogenous DA by a 2-day treatment with α-methyl-p-tyrosine (αMpT, 150 mg/kg, i.p.). This treatment markedly increased the number of striatal TH + neurons, assessed by stereological counting, and the increase was highly correlated to the extent of DA loss. Interestingly, TH + neurons were found closer to the clusters of DA fibers after DA depletion, indicating that the concentration gradient of extracellular DA critically regulates the distribution of striatal TH + neurons. A single i.p. injection of the D1 receptor antagonist, SCH23390 (0.1 mg/kg), the D2/D3 receptor antagonist, raclopride (0.1 mg/kg), or the D4 receptor antagonist, L-745,870 (5 mg/kg) in mice at PND4 also increased the number of TH + neurons after 4 days. Treatment with the D1-like receptor agonist SKF38393 (10 mg/kg) or with the D2-like receptor agonist, quinpirole (1 mg/kg) did not change the number of TH + neurons. At least the effects of SCH23390 were prevented by a combined treatment with SKF38393. Immunohistochemical analysis indicated that striatal TH + neurons expressed D2 and D4 receptors, but not D1 receptors. Moreover, treatment with the α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) (3.2 mg/kg) also increased the number of TH + neurons. The evidence that DHβE mimicked the action of SCH23390 in increasing the number of TH + neurons supports the hypothesis that activation of D1 receptors controls the number of striatal TH + neurons by enhancing the release of acetylcholine. These data demonstrate for the first time that endogenous DA negatively regulates the number of striatal TH + neurons by direct and indirect mechanisms mediated by multiple DA receptor subtypes. © 2012 Busceti et al.Peer Reviewe

Serum 25-hydroxy vitamin D levels in essential hypertension

For decades 25(OH) vitamin D has been considered a dynamic steroid hormone exerting its action as a transcription factor regulating the expression of various genes (1). Vitamin D is a cluster of fat-soluble molecules analogous to steroids. Numerous forms of vitamin D exist; cholecalciferol (or vitamin D3) is synthesized in reaction to ultraviolet (UV) irradiation of the skin consequential to the photochemical cleavage of 7-dehydrocholesterol, a precursor of cholesterol in the skin. A second form of vitamin D, ergocalciferol (or vitamin D2) is formed by irradiation of ergosterol, a membrane sterol found in the Ergot fungus. Nutritional sources of vitamin D comprise fish oils (D3), egg yolks (D3), and mushrooms (D2) as well as unnaturally prepared cereals and dairy products (D2 or D3). Epidemiological studies then established improved risks of chronic morbid disorders with lower levels of serum 25-OH D. More recently, 25(OH) vitamin D deficiency has been considered as an independent risk factor for cardiovascular disease and mortality in general population. Biologic effects of 25(OH) vitamin D result largely from its binding to the nuclear steroid hormone 25(OH) vitamin D receptor (VDR), which is found in almost all tissues and is moreover closely related to the thyroid, retinoid, and peroxisome proliferator-activator receptors. While all 25(OH) vitamin D metabolites bind the VDR, most biological effects are probable mediated by calcitriol because of its greater receptor similarity (2). Vitamin D plays a considerable function in the physiology of the cardiovascular system and its insufficiency has been allied to extensive complications, such as cardiovascular events, hypertension, obesity, metabolic syndrome, type 2 diabetes, immune disorders and numerous types of cancer (3,4). The indisputable potential inverse relationship between vitamin D deficiency and elevated blood pressure (BP) suggests involvement of vitamin D metabolism in the pathogenesis of hypertension

ErbB2 associates with GM3 in lipid rafts in mammary epithelial HC11 cells

We analyzed the role of gangliosides in the association of the ErbB2 receptor tyrosine-kinase (RTK) with lipid rafts in mammary epithelial HC11 cells. Scanning confocal microscopy experiments revealed a strict ErbB2-GM3 colocalization in wild-type cells. In addition, analysis of membrane fractions obtained using a linear sucrose gradient showed that ErbB2, epidermal growth factor receptor (EGFR) and Shc-p66 (proteins correlated with the ErbB2 signal transduction pathway) were preferentially enriched in lipid rafts together with gangliosides. Blocking of endogenous ganglioside synthesis by (+/-)-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol hydrochloride ([D]-PDMP) induced a drastic cell-surface redistribution of ErbB2, EGFR and Shc-p66, within the Triton-soluble fractions, as revealed by linear sucrose-gradient analysis. This redistribution was partially reverted when exogenous GM3 was added to ganglioside-depleted HC11 cells. The results point out the key role of ganglioside GM3 in retaining ErbB2 and signal-transduction-correlated proteins in lipid rafts