A fatal case of poisoning by lormetazepam

Lormetazepam is a benzodiazepine widely used as a hypnotic for management of insomnia. It is considered to be a safe drug when not combined with alcohol or other psychoactive substances. Indeed, we could neither fi nd its toxic nor lethal concentrations in the literature. In the present article, we report a fatal case in which lormetazepam and its metabolite lorazepam were the only drugs found in body fl uids. The concentration measured in blood was more than 100 times higher than the therapeutic one. Therefore, we concluded that the death was due to the drug and that the measured levels could be regarded as lethal.     

Hb Belluno [β111(G13)Val→Gly;β133(H11)Val→Val (HBB: c.335T > G;402G > C)]: Incidental Detection of a New Clinically Silent β Chain Variant During Hb A1c Determination by High Performance Liquid Chromatography

A previously unreported β chain variant, Hb Belluno [β111(G13)Val→Gly;β133(H11)Val→Val (HBB: c.335T?>?G;402G?>?C)], was incidentally discovered in a woman suffering from diabetes, during glycated hemoglobin (Hb A_1c) assay. Its presence was suspected because of a small abnormal peak with a retention time just shorter than that of normal Hb A_1c. Standard high performance liquid chromatography (HPLC), capillary zone electrophoresis (CZE) and agarose gel electrophoresis did not allow to separate the variant from Hb A. The reversed phase HPLC of globin chains showed the presence of a heterozygous β-globin variant amounting to approximately 43.5% of the total β chains. Later, this variant was found in five other members of the same family and DNA sequencing analysis confirmed a β-globin gene mutation. The variant is clinically silent in all patients and showed a slight instability with both heat and isopropanol tests. The other three mutations at this locus also affect stability. Hemoglobin (Hb) variants may invalidate the results of Hb A_1c analysis and could result in mismanagement of diabetes. A comment alerting the requesting clinician to the presence of the Hb variant must be appended to the Hb A_1c result. Additionally, many Hb variants can be chromatographically and/or electrophoretically silent. Therefore, when the clinician suspects a variant Hb, it is not sufficient to get a negative response from an HPLC screening test to rule it out. A dialogue with the pathologist is essential, involving exchange of information and sharing a diagnostic work-up including surveys to assess Hb stability and oxygen affinity, as much as DNA sequencing.     

Nuclear EGFRvIII‐STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl‐XL promoter

Aberrant EGFR signaling strongly promotes glioma malignancy and treatment resistance. The most prevalent mutation, ΔEGFR/EGFRvIII, is an in‐frame deletion of the extracellular domain, which occurs in more than 25% of glioblastomas and enhances growth and survival of tumor cells. Paradoxically, the signaling of the potent oncogene ΔEGFR is of low intensity, raising the question of whether it exhibits preferential signaling to key downstream targets. We have observed levels of phosphorylation of STAT5 at position Y699 in cells expressing ΔEGFR that are similar or higher than in cells that overexpress EGFR and are acutely stimulated with EGF, prompting us to investigate the role of STAT5 activation in glioblastoma. Here, we show that in human glioblastoma samples, pSTAT5 levels correlated positively with EGFR expression and were associated with reduced survival. Interestingly, the activation of STAT5b downstream of ΔEGFR was dependent on SFKs, while the signal from acutely EGF‐stimulated EGFR to STAT5b involved other kinases. Phosphorylated STAT5b and ΔEGFR associated in the nucleus, bound DNA and were found on promoters known to be regulated by STAT5 including that of the Aurora A gene. ΔEGFR cooperated with STAT5b to regulate the Bcl‐XL promoter and knockdown of STAT5b suppressed anchorage independent growth, reduced the levels of Bcl‐XL and sensitized glioblastoma cells to cisplatin. Together these results delineate a novel association of nuclear ΔEGFR with STAT5b, which promotes oncogenesis and treatment resistance in glioblastoma by direct regulation of anti‐apoptotic gene, Bcl‐XL.     

17A, a novel non-coding RNA, regulates GABA B alternative splicing and signaling in response to inflammatory stimuli and in Alzheimer disease

Alternative splicing is a central component of human brain complexity; nonetheless, its regulatory mechanisms are still largely unclear. In this work, we describe a novel non-coding (nc) RNA (named 17A) RNA polymerase (pol) III-dependent embedded in the human G-protein-coupled receptor 51 gene (GPR51, GABA B2 receptor). The stable expression of 17A in SHSY5Y neuroblastoma cells induces the synthesis of an alternative splicing isoform that abolish GABA B2 intracellular signaling (i.e., inhibition of cAMP accumulation and activation of K(+) channels). Indeed, 17A is expressed in human brain, and we report that it is upregulated in cerebral tissues derived from Alzheimer disease patients. We demonstrate that 17A expression in neuroblastoma cells enhances the secretion of amyloid β peptide (Aβ) and the Aβ x-42/Αβ x-40 peptide ratio and that its synthesis is induced in response to inflammatory stimuli. These data correlate, for the first time, the activity of a novel pol III-dependent ncRNA to alternative splicing events and, possibly, to neurodegeneration induced by abnormal GABA B function. We anticipate that further analysis of pol III-dependent regulation of alternative splicing will disclose novel regulatory pathways associated to brain physiology and/or pathology.     

Hemodynamic Profile of Portopulmonary Hypertension

Portopulmonary hypertension (PPHTN) refers to the development of pulmonary arterial hypertension in the setting of portal hypertension with or without chronic hepatic failure. This syndrome is characterized by marked alternations of pulmonary vascular tone and obstruction of pulmonary arterial blood flow. An increased pulmonary blood flow, which is a hallmark of the hyperdynamic circulation of cirrhotic patients, seems to be present in almost all patients who develop PPHTN. The elevations of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) along with the transpulmonary gradient (TPG) have been considered in diagnosing PPHTN. Only a high TPG reflects the severity of obstruction to pulmonary blood flow and differentiates an elevated PAP with concomitant elevated PVR from the situation where the increase in PAP is due only to the hyperdynamic flow and elevated volume. A considerable risk for cardiovascular death arises when PAP increases significantly; this may occur in rapidly evolving syndromes, in very advanced disease, or during a complicated liver transplantation. The distinction between PPHTN and elevated PAP in the context of a hyperdynamic state is of great importance; a PAP increase of hyperkinetic origin, as opposed to PPHTN, is apparently not associated with a high risk for adverse effects during and following liver transplantation.     

Mechanism of the antiproliferative action of limonene on a lymphoma cell line: participation of nitric oxide. antiproliferative action of limonene on a lymphoma cell line

Previously limonene demonstrated antiproliferative action on a lymphoma cell line (BW5147). The objective of this study was to investigate the mechanism of the antiproliferative action of limonene on BW 5147 cells. The induction of apoptosis and arrest in cell cycle phases, both phenomena related to nitric oxide (NO) production, was analyzed, as well as NO production. Results showed that limonene exhibited antiproliferative action on tumoral lymphocytes exerting a decrease in cell viability that was related to apoptosis induction and to the increase in NO levels at long incubation times. At short times and depending on its concentration, limonene arrested cells in different phases of the cell cycle, related to NO production. Copyright © 2009 John Wiley & Sons, Ltd.     

Sternoclavicular physeal fracture associated with adjacent clavicle fracture in a 14-year-old boy: a case report and literature review

We report a very rare association of a physeal fracture of the medial clavicular growth plate with a fracture of the adjacent clavicle in a 14-year-old boy who fell on his shoulder while playing football. Clinical, radiographic and computed tomographic (with three-dimensional reconstruction) features are described. Open reduction, internal fixation of the lateral fracture (with a reconstructive plate) and suture of the periosteum were performed.