Liquid-Liquid Miscibility Gaps and Hydrate Formation in Drug-Water Binary Systems: Pressure-Temperature Phase Diagram of Lidocaine and Pressure-Temperature-Composition Phase Diagram of the Lidocaine-Water System

The pressure-temperature (P–T) melting curve of lidocaine was determined (dP/dT = 3.56 MPa K^? 1), and the lidocaine–water system was investigated as a function of temperature and pressure. The lidocaine–water system exhibits a monotectic equilibrium at 321 K (ordinary pressure) whose temperature increases as the pressure increases until the two liquids become miscible. A hydrate, unstable at ordinary pressure, was shown to form, on increasing the pressure, from about 70 MPa at low temperatures (200–300 K). The thermodynamic conditions of its stability were inferred from the location of the three-phase equilibria involving the hydrate in the lidocaine–water pressure–temperature–mole fraction (P–T–x) diagram.     

Rimonabant Dimorphism and Its Pressure–Temperature Phase Diagram: A Delicate Case of Overall Monotropic Behavior

Crystalline polymorphism occurs frequently in the solid state of active pharmaceutical ingredients, and this is problematic for the development of a suitable dose form. Rimonabant, an active pharmaceutical ingredient developed by Sanofi and discontinued because of side effects, exhibits dimorphism; both solid forms have nearly the same melting temperatures, melting enthalpies, and specific volumes. Although the problem may well be academic from an industrial point of view, the present case demonstrates the usefulness of constructing pressure–temperature phase diagrams by direct measurement as well as by topological approach. The system is overall monotropic and form II is the more stable solid form. Interestingly, the more stable form does not possess any hydrogen bonds, whereas the less stable one does. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2311–2321, 2013     

Inactivation of p16 INK4a /CDKN2A gene may be a diagnostic feature of large B cell lymphoma leg type among cutaneous B cell lymphomas

The World Health Organization-European Organization for Research and Treatment of Cancer has individualized three main categories among the primary cutaneous B cell lymphoma (PCBCL): leg-type primary cutaneous large B cell lymphoma (PCLBCL leg type), primary cutaneous follicle center lymphoma (PCFCL), and primary cutaneous marginal zone lymphoma (PCMZL). The genetic features of 21 PCBCL cases (six PCLBCL leg type four PCFCL large cells, seven PCFCL small cells, and four PCMZL) were investigated by comparative genomic hybridization (CGH array). Fluorescent in situ hybridization (FISH) analysis was performed to confirm CGH array data and to detect lymphoma-associated gene rearrangements. p14 ( ARF )/p16 ( INK4a ) CDKN2A gene quantification, methylation analysis, and immunohistochemical detection were also performed. CGH array showed a higher number of recurrent genetic imbalances in PCLBCL leg type (mean 62) than in PCFCL large cells (mean 34). PCFCL small cells and PCMZL exhibited fewer chromosomal alterations (mean 24 and 9). FISH analysis provided concordant results with CGH array data in 97% (98 of 101) assays and demonstrated a t(8;14)(q24;q32) in two of six PCLBCL leg type. Recurrent deletions in 9p21 (p14 ( ARF )/p16 ( INK4a ) CDKN2A) were a constant finding in PCLBCL leg type (six of six). Conversely, PCFCL large cells exhibited recurrent 1p36 deletions (four of four) without deletion in 9p21 (zero of four). The diagnostic and prognostic impact of the p16 ( INK4a ) CDKN2A gene status in PCBCL should therefore be confirmed on a larger series.     

Low frequency of HIV-1 tropism evolution in patients successfully treated for at least 2 years

The aim of this study was to analyse tropism evolution in HIV-1 patients with at least 2 years of viral load undetectability. For this purpose, HIV-1-infected antiretroviral-treated patients (n = 128) with a viral load less than 50 copies/ml for 4 years in median were studied. No change of virus tropism was observed in 92.9% of patients. Therefore, before the use of CCR5 antagonists, genotypic viral DNA tropism determination is an available tool.     

Is there still a place for adrenal venous sampling in the diagnostic localization of pheochromocytoma?

Our objective is to outline the utility of adrenal venous sampling (AVS) with measurements of metanephrine to normetanephrine ratios for diagnostic localization of phaeochromocytoma in a patient with normal plasma levels of catecholamines. A 53-year-old-woman was referred for evaluation of recurrent pheochromocytoma following a right adrenalectomy 14 years earlier. Diagnosis of recurrent disease was established from elevations in plasma metanephrines with normal levels of catecholamines. Magnetic resonance imaging indicated two 1-2 cm masses in the right surgical bed and another 1-1.5 cm mass in the left adrenal. These masses were negative on (123)I-metaiodobenzylguanidine scintigraphy. There was no evidence of a hereditary syndrome. We, therefore, carried out two investigational approaches to identify the tumor masses. Hybrid positron emission tomography/computed tomography with (68)Ga-DOTATOC ((68)Ga-DOTATOC-PET/CT) confirmed the presence of recurrent disease in the right surgical bed and also suggested additional left adrenal involvement. Normal plasma catecholamines precluded the use of adrenal venous sampling (AVS) with catecholamine measurements. Hence, we performed AVS with measurements of plasma metanephrines, which were 4- to 7-fold higher in the left adrenal vein than in central venous plasma. We observed a reversal of the normally high metanephrine to normetanephrine ratio (mean value ± SD 5.28 ± 1.86; range 3.36-8.84, n = 13) to 0.73, establishing the presence of a left adrenal pheochromocytoma. Surgical pathology confirmed bilateral disease. This case highlights a scenario where a combination of (68)Ga-DOTATOC-PET/CT and AVS with measurement of the metanephrine to normetanephrine ratio was crucial for the preoperative assessment of a patient with bilateral pheochromocytoma.     

Disruption of Conscious Access in Psychosis Is Associated with Altered Structural Brain Connectivity

According to global neuronal workspace (GNW) theory, conscious access relies on long-distance cerebral connectivity to allow a global neuronal ignition coding for conscious content. In patients with schizophrenia and bipolar disorder, both alterations in cerebral connectivity and an increased threshold for conscious perception have been reported. The implications of abnormal structural connectivity for disrupted conscious access and the relationship between these two deficits and psychopathology remain unclear. The aim of this study was to determine the extent to which structural connectivity is correlated with consciousness threshold, particularly in psychosis. We used a visual masking paradigm to measure consciousness threshold, and diffusion MRI tractography to assess structural connectivity in 97 humans of either sex with varying degrees of psychosis: healthy control subjects (n = 46), schizophrenia patients (n = 25), and bipolar disorder patients with (n = 17) and without (n = 9) a history of psychosis. Patients with psychosis (schizophrenia and bipolar disorder with psychotic features) had an elevated masking threshold compared with control subjects and bipolar disorder patients without psychotic features. Masking threshold correlated negatively with the mean general fractional anisotropy of white matter tracts exclusively within the GNW network (inferior frontal-occipital fasciculus, cingulum, and corpus callosum). Mediation analysis demonstrated that alterations in long-distance connectivity were associated with an increased masking threshold, which in turn was linked to psychotic symptoms. Our findings support the hypothesis that long-distance structural connectivity within the GNW plays a crucial role in conscious access, and that conscious access may mediate the association between impaired structural connectivity and psychosis.     

Five-year follow-up of clinical and radiological outcomes of LP-ESP elastomeric lumbar total disc replacement in active patients

Background context

The surgical treatment of degenerative disc disease at the lumbar spine may involve fusion. Total disc replacement (TDR) is an alternative treatment to avoid fusion-related adverse events, specifically adjacent segment disease. New generation of elastomeric non-articulating devices has been developed to more effectively replicate the shock absorption and flexural stiffness of native disc.

Risk of venous thromboembolism in the course of acute medical illness. Part 1: Basic research, clinical models, descriptive and analytic epidemiology

PURPOSE: Some acute medical illnesses are associated with an increased risk of venous thromboembolism. This risk is difficult to assess in medical patients on account of the multiplicity of their pathologies, leading to potential interactions between numerous risk factors. CURRENT KNOWLEDGE AND KEY POINTS: A rational analysis of the risk of venous thrombosis in acute medical setting may be derived from pathogenic models and be based on elementary risk factors for venous thromboembolism classified as transient, permanent, major and intermediate factors. The systematic study of pathophysiological mechanisms in process, in each medical patient could guide the physician attitude toward still non-evaluated situations. FUTURE PROSPECTS AND PROJECTS: A synthesis of the last epidemiological and pathophysiological data is developed in the first part of this literature review, whereas the risk linked to specific situations in ambulatory, hospital or internal medicine settings will be described in the second part.     

Risk of venous thromboembolism in acute medical illnesses. Part 2: Situations at risk in ambulatory, hospital and internal medicine settings

PURPOSE: The increased risk of thromboembolism in acute medical illnesses (AMI) is difficult to assess because of the diversity of medical conditions. The first part of this review of the literature was dedicated to methods of risk analysis based on our current pathophysiological knowledge. This second part describes more specifically the risk of venous thrombosis linked to AMI in hospital, ambulatory and internal medicine settings. CURRENT KNOWLEDGE AND KEY POINTS: The incidence of venous thromboembolism is higher in hospital than in ambulatory setting, albeit the latter remains significant. Stroke and affections leading to intensive care management represent conditions at great risk. Several mechanisms leading to a prothrombotic state have been identified, explaining the increased risk observed during relapses of pathologies specifically treated in internal medicine such as lupus erythematosus, Wegener granulomatosis, inflammatory bowel diseases and Behcet's disease. FUTURE PROSPECTS AND PROJECTS: Next to the pathophysiological understanding of venous thrombosis, the assessment of the specific thrombogenic burden of an AMI is an additive tool to screen medical patients at high risk. This systematic review of the literature shows uncertainties towards some risk factors as bedrest or acute inflammatory response. Taking into account the methodological difficulties inherent to prospective and epidemiological studies, a meta-analysis focusing on these factors would be useful to refine prevention guidelines for venous thromboembolism in medical setting.