Glucose modulates rat substantia nigra GABA release in vivo via ATP-sensitive potassium channels.

Glucose modulates beta cell insulin secretion via effects on ATP-sensitive potassium (KATP) channels. To test the hypothesis that glucose exerts a similar effect on neuronal function, local glucose availability was varied in awake rats using microdialysis in the substantia nigra, the brain region with the highest density of KATP channels. 10 mM glucose perfusion increased GABA release by 111 +/- 42%, whereas the sulfonylurea, glipizide, increased GABA release by 84 +/- 20%. In contrast, perfusion of the KATP channel activator, lemakalim, or depletion of ATP by perfusion of 2-deoxyglucose with oligomycin inhibited GABA release by 44 +/- 8 and 45 +/- 11%, respectively. Moreover, the inhibition of GABA release by 2-deoxyglucose and oligomycin was blocked by glipizide. During systemic insulin-induced hypoglycemia (1.8 +/- 0.3 mM), nigral dialysate GABA concentrations decreased by 49 +/- 4% whereas levels of dopamine in striatal dialysates increased by 119 +/- 18%. We conclude that both local and systemic glucose availability influences nigral GABA release via an effect on KATP channels and that inhibition of GABA release may in part mediate the hyperexcitability associated with hypoglycemia. These data support the hypothesis that glucose acts as a signaling molecule, and not simply as an energy-yielding fuel, for neurons.     

Comparative study of three methods of estimation of creatinine clearance in critically ill patients

Background

At the bedside, the reference method for creatinine clearance determination is based on the measurement of creatinine concentrations in urine and serum (mCrCl). Several models are available to calculate the creatinine clearance from the serum creatinine concentration. This observational survey aimed at testing the hypothesis that the proposed equations are unreliable to determine accurate creatinine clearance in patients admitted to intensive care unit (ICU).

Method

Creatinine clearance was determined by the use of mCrCl. Then, we compared three equations: Cockcroft-Gault (CG), Simplified Modification of Diet in Renal Disease (MDRDs), and Chronic Kidney Disease Epidemiology (CKD-EPI) in 156 consecutive patients within the first 24 hours after ICU admission. We tested the hypothesis that the three equations were equivalent. The agreement between the three equations was evaluated by linear regression and Bland and Altman analysis.

Results

Bland and Altman analysis showed similar agreement between the three equations. The biases and precisions were –4.8 ± 51, –1.3 ± 50, and 8.2 ± 44 for CG, MDRDs, and CKD-EPI equations, respectively (P > 0.05). The precisions were similar for the three equations (P > 0.05). The percentages of outliers at ± 30% were 44%, 45%, and 49% for CG, MDRDs, and CKD-EPI, respectively (P > 0.05).

Conclusion

Regarding the high percentage of outliers, the use of these equations cannot be recommended in ICU patients.     

Impact of a goal-directed therapy protocol on postoperative fluid balance in patients undergoing liver transplantation: A retrospective study

Objective

Liver transplantation carries major risks during the perioperative period. Few studies focused on the hemodynamics of patients undergoing liver transplantation. The present study was aimed to evaluate the impact of the implementation of a protocol including goal-directed therapy in patients undergoing liver transplantation. Our first goal was to determine its impact on the fluid balance. Secondarily, we evaluated possible improvements in the patient outcomes.

Study design

A before and after study.

Patients and methods

Fifty patients undergoing liver transplantation were included during two successive six-month periods. During the first period, the management of the patients was left at the discretion of the senior physicians (control group, n = 25). During the second period, the patients were treated according to a predetermined protocol including a specific hemodynamic monitoring (protocol group, n = 25).

Results

The fluid balance was negative in the protocol group and positive in the control group at 24 h (−606 mL vs. +3445 mL, P < 0.01) and 48 h (−2315 mL vs. +1170 mL, P < 0.01) after liver transplantation. The volume of the crystalloid administration was lower in the protocol group than in the control group (5000 mL vs. 8000 mL, P < 0.01, and 1500 mL vs. 6000 mL, P < 0.01, during surgery and 48 h after liver transplantation, respectively). The duration of mechanical ventilation and postoperative ileus were significantly reduced in the protocol group, as compared with the control group, 20 h vs. 94 h (P < 0.01) and 4 days vs. 6 days (P < 0.01), respectively.

Conclusion

For patients undergoing liver transplantation, the implementation of a protocol aiming to optimize hemodynamics was associated with reduced fluid balance and decreased requirement for mechanical ventilation and postoperative ileus duration.     

α1-Adrenergic receptor antagonists and gynecomastia. A case series from the Italian spontaneous reporting system and VigiBase™

Purpose

The aim of this study was to analyze the cases of gynecomastia associated with α_1A-adrenergic receptor antagonists (α₁-ARAs) in the Italian spontaneous reporting system database (Rete Nazionale di Farmacovigilanza or RNF) and in the World Health Organization ICSRs database (VigiBase^?), focusing on tamsulosin use.

Methods

We analyzed the spontaneous reports of gynecomastia related to the use of α₁-ARAs and collected from the RNF and from VigiBase^? up to December 2012. Cases of gynecomastia have been defined as reports associated with gynecomastia according with Medical Dictionary for Regulatory Activities (MedDRA). Reporting odds ratio (ROR) and Information Component (IC) were calculated as measures of disproportionality in RNF and VigiBase^?, respectively.

Results

Up to December 2012, about 186,000 reports were recorded in the RNF. Among these, 902 reports of adverse drug reaction (ADR) have been associated with the use of at least one α₁-ARAs. Of these, in 15 cases, gynecomastia was a listed ADR: in 10, the suspected drug was tamsulosin (in eight, it was the sole suspect); in two, doxazosin and alfuzosin, respectively; and in one, terazosin. ROR for tamsulosin was 5.3 (95 % CI 1.8, 15.7). In VigiBase^?, 84 reports of gynecomastia indicated tamsulosin as suspected drug. Tamsulosin-associated gynecomastia showed the highest IC value within this class of drugs (IC 95 % 2.43).

Conclusion

In this study, we highlight a possible association between gynecomastia and tamsulosin use. To our knowledge, this association has not been described before and could represent a potential signal.     

Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants

Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression. In the present study, liver RNA samples from drug-treated rats from more recent experiments were examined for statistical fit to the OS/RM signature. Of all 97 drugs examined, in addition to the nine drugs noted above, 19 more were identified as OS/RM-producing compounds—chlorpromazine, clozapine, cyproterone acetate, dantrolene, dipyridamole, glibenclamide, isoniazid, ketoconazole, methapyrilene, naltrexone, nifedipine, sulfamethoxazole, tamoxifen, coumarin, ritonavir, amitriptyline, valproic acid, enalapril, and chloramphenicol. Importantly, all of the OS/RM drugs listed above have been linked to idiosyncratic hepatotoxicity, excepting chloramphenicol, which does not have a package label for hepatotoxicity, but does have a black box warning for idiosyncratic bone marrow suppression. Most of these drugs are not acutely toxic in the rat. The OS/RM signature should be useful to avoid idiosyncratic hepatotoxicity of drug candidates.     

The Influence of Early Life Nutrition on Epigenetic Regulatory Mechanisms of the Immune System

The immune system is exquisitely sensitive to environmental changes. Diet constitutes one of the major environmental factors that exerts a profound effect on immune system development and function. Epigenetics is the study of mitotically heritable, yet potentially reversible, molecular modifications to DNA and chromatin without alteration to the underlying DNA sequence. Nutriepigenomics is an emerging discipline examining the role of dietary influences on gene expression. There is increasing evidence that the epigenetic mechanisms that regulate gene expression during immune differentiation are directly affected by dietary factors or indirectly through modifications in gut microbiota induced by different dietary habits. Short-chain fatty acids, in particular butyrate, produced by selected bacteria stains within gut microbiota, are crucial players in this network.     

Lymph node blast crisis in chronic myeloid leukemia mimicking T-immunoblastic lymphoma.

BACKGROUND: Chronic myeloid leukemia arises from a somatic mutation in a pluripotent stem cell. It generally terminates with a blastic crisis (BC). One third of BC are lymphoid, and most have a pre-B phenotype. Few cases of T-lymphoid BC have been reported. Here we describe a lymph node blast crisis mimicking T-immunoblastic lymphoma. METHODS: Bone marrow and lymph nodes were histologically examined by standard methods and by an immunoperoxidase technique. Cytogenetic studies were also performed on lymph node and blood cells. Analysis of T-cell receptor genes and BCR rearrangements were performed on DNA extracted from both frozen bone marrow and lymph-node cells. RESULTS: Lymph-node histology showed an infiltration by large lymphoid blasts, consistent with a diagnosis of immunoblastic lymphoma. Blast cells were CD2, CD7, TDT positive, and negative for myeloid and mature lymphoid antigens. The Ph1 chromosome was found in both bone marrow and lymph-node cells. BCR rearrangement was found in the DNA from both bone marrow and lymph-node cells. TCR genes were not rearranged. DISCUSSION: The present study provides strong evidence that the lymph-node blast crisis of CML can assume the morphological appearance of immunoblastic lymphoma and may retain the immunological phenotype and genetic features of early T cells with BCR rearrangements.     

Monocyte-derived tissue factor contributes to stent thrombosis in an in vitro system

OBJECTIVES: This study evaluated the role of circulating tissue factor (TF) in mediating thrombus formation on stents in an in vitro model of stent perfusion. BACKGROUND: The traditional view of coagulation has recently been challenged by the demonstration that TF is present in circulating blood. The potential contribution of this intravascular pool of TF to thrombus formation on stents is not known. METHODS: Coronary stents were placed in parallel silicone tubes connected to a roller pump that was set to pump blood at a flow rate of 10 ml/min. Stents were then exposed to heparinized blood from healthy volunteers for 120 min. RESULTS: The presence of the stent in the circuit caused a significant increase in monocyte TF expression, but only monocytes with attached platelets stained positive for TF. Thrombi formed on stents and the thrombi stained positive for TF. Pretreatment of blood with a monoclonal antibody against TF (cH36) caused a 56% reduction in (125)I-fibrin(ogen) deposition on stents compared with controls (p = 0.002). Monocyte depletion of blood reduced (125)I-fibrin(ogen) deposition by 45% (p = 0.01) and TF staining in the thrombus by 83% (p = 0.01). Pretreatment of blood with a monoclonal antibody against P-selectin reduced (125)I-fibrin(ogen) deposition by 24% (p = 0.04). Perfusion of stents with leukocyte-reduced platelet-rich plasma (PRP) produced small thrombi and treatment of PRP with cH36 reduced (125)I-fibrin(ogen) deposition by 43% (p = 0.01). CONCLUSIONS: Circulating TF plays a pivotal role in thrombus formation on stents. Monocytes appear to be the main, but not only, source of TF depositing in the thrombus.