Treatment of rats with antipsychotic drugs: lack of an effect on brain N-acetyl aspartate levels

BACKGROUND: Proton magnetic resonance spectroscopy (1H-MRS) studies of schizophrenia suggest an effect of the disease or of antipsychotic medications on brain N-acetyl aspartate (NAA), a marker of neuronal viability. We studied in the rat the effect of antipsychotic drugs on NAA in several brain regions where NAA reductions have been reported in chronically medicated patients with schizophrenia. METHODS: Three groups of nine rats each were treated with haloperidol (6 mg/kg/day), clozapine (70 mg/kg/day) and vehicle for 6 weeks and were sacrificed. Concentrations of NAA were determined by high-performance liquid chromatography (HPLC) from the following brain regions: cortex, striatum, thalamus, hippocampus and cerebellum. RESULTS: Mixed-factorial ANOVA of NAA concentrations revealed no significant effect of drug group [F(2, 24) = 0.034; p = 0.966] or a group by brain region interaction [F(8, 44) = 0.841; p = 0.572]. There was a significant main effect of region [F(4, 21) = 6.104; p = 0.002] with higher NAA in the cortex. CONCLUSIONS: These results are consistent with the only other study of the effect of typical and atypical antipsychotic drugs on NAA in the rat brain. The well-documented lower NAA in chronically treated schizophrenia patients is probably not a simple effect of antipsychotic medications.     

Prevalence of non-convulsive seizure and other electroencephalographic abnormalities in ED patients with altered mental status

Four to ten percent of patients evaluated in emergency departments (ED) present with altered mental status (AMS). The prevalence of non-convulsive seizure (NCS) and other electroencephalographic (EEG) abnormalities in this population is unknown.ObjectivesTo identify the prevalence of NCS and other EEG abnormalities in ED patients with AMS.MethodsA prospective observational study at 2 urban ED. Inclusion: patients ≥ 13 years old with AMS. Exclusion: An easily correctable cause of AMS (e.g. hypoglycemia). A 30-minute standard 21-electrode EEG was performed on each subject upon presentation. Outcome: prevalence of EEG abnormalities interpreted by a board-certified epileptologist. EEGs were later reviewed by 2 blinded epileptologists. Inter-rater agreement (IRA) of the blinded EEG interpretations is summarized with κ. A multiple logistic regression model was constructed to identify variables that could predict the outcome.ResultsTwo hundred fifty-nine patients were enrolled (median age: 60, 54% female). Overall, 202/259 of EEGs were interpreted as abnormal (78%, 95% confidence interval [CI], 73-83%). The most common abnormality was background slowing (58%, 95% CI, 52-68%) indicating underlying encephalopathy. NCS (including non-convulsive status epilepticus [NCSE]) was detected in 5% (95% CI, 3-8%) of patients. The regression analysis predicting EEG abnormality showed a highly significant effect of age (P < .001, adjusted odds ratio 1.66 [95% CI, 1.36-2.02] per 10-year age increment). IRA for EEG interpretations was modest (κ: 0.45, 95% CI, 0.36-0.54).ConclusionsThe prevalence of EEG abnormalities in ED patients with undifferentiated AMS is significant. ED physicians should consider EEG in the evaluation of patients with AMS and a high suspicion of NCS/NCSE.     

Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells

The multidrug resistant (MDR) phenotype is often attributed to the activity of ATP-binding cassette (ABC) transporters such as P-glycoprotein (ABCB1). Previous work has suggested that modulation of MDR may not necessarily be a single gene trait. To identify factors that contribute to the emergence of MDR, we undertook integrative genomics analysis of the ovarian carcinoma cell line SKOV3 and a series of MDR derivatives of this line (SKVCRs). As resistance increased, comparative analysis of gene expression showed conspicuous activation of a network of genes in addition to ABCB1. Functional annotation and pathway analysis revealed that many of these genes were associated with the extracellular matrix and had previously been implicated in tumor invasion and cell proliferation. Further investigation by whole genome tiling-path array CGH suggested that changes in gene dosage were key to the activation of several of these overexpressed genes. Remarkably, alignment of whole genome profiles for SKVCR lines revealed the emergence and decline of specific segmental DNA alterations. The most prominent alteration was a novel amplicon residing at 16p13 that encompassed the ABC transporter genes ABCC1 and ABCC6. Loss of this amplicon in highly resistant SKVCR lines coincided with the emergence of a different amplicon at 7q21.12, which harbors ABCB1. Integrative analysis suggests that multiple genes are activated during escalation of drug resistance, including a succession of ABC transporter genes and genes that may act synergistically with ABCB1. These results suggest that evolution of the MDR phenotype is a dynamic, multi-genic process in the genomes of cancer cells.     

Lithocholate glucuronide is a cholestatic agent

Lithocholic acid and its taurine, glycine, and sulfate derivatives are potent cholestatic agents. Lithocholate glucuronide is present in the plasma and urine of patients with cholestatic syndromes, but little is known of its metabolism, excretion, and cholestatic potential. [3 beta-3H]lithocholate 3-O-beta-D-glucuronide was synthesized, and chemical and radiochemical purity were established. The aqueous solubility of lithocholate glucuronide was determined and found to be greater than that of lithocholic acid or several of its derivatives. In the range of concentrations examined, calcium ions precipitated lithocholate glucuronide stoichiometrically. The material was administered to rats prepared with an external biliary fistula. When 17-25 micrograms quantities were administered, 89.1 +/- 4.5% (mean +/- SEM) of the radiolabel was secreted in bile within the first 20 h after administration, the major fraction being secreted in less than 20 min. Four-fifths of the radiolabeled material in bile was the administered unaltered parent compound, while a minor fraction consisted of a more polar derivative(s). We showed that increasing biliary concentrations of more polar derivatives were observed with milligram doses of [3H]lithocholate glucuronide, and with time after the administration of these loading doses. Milligram doses of [3H]lithocholate glucuronide resulted in partial or complete cholestasis. When induced cholestasis was partial, secretion in bile remained the primary excretory route (82.5-105.6% recovery in bile), while, when complete cholestasis was induced, wide tissue distribution of radiolabel was observed. Cholestasis developed rapidly during infusion of [3H]lithocholate glucuronide. Bile flow was diminished within 10-20 min of the start of an infusion of 0.05 mumol, 100 g-1 body weight, minute-1, administered concomitantly with an equimolar infusion of taurocholate. The results establish that lithocholate glucuronide exerts cholestatic effects comparable to those exerted by unconjugated lithocholic acid.     

Pre-operative Assessment of Anatomical Position of Inferior Alveolar Nerve and Its Significance in Bilateral Sagittal Split Osteotomy

The aim of this study is to investigate the position and course of the mandibular canal through the ramus, angle and body of mandible using computed tomographic (CT) imaging pre-operatively and to relate these predetermined values intra-operatively to perform sagittal split ramus osteotomies. Pre-operative CT scans were taken and four points were marked at mandibular foramen, mandibular angle, mandibular body and midpoint and different dimensions of IAN were measured to localize the inferior alveolar nerve. With the obtained values, precise osteotomy cuts were made intra-operatively and intra-operative measurements for position of IAN were noted. Based on the preoperative CT measurements, the chance to encounter IAN bundle, during surgery was evaluated. The present study proved that pre-operative CT imaging prior to BSSO surgical procedure is an effective way to investigate the position and course of the IAN canal through the framework of the mandible and by interpolating these dimensions intra operatively, reduces the risk of direct injury to the IAN bundle.     

Combining clinicopathological predictors and molecular biomarkers in the oncogenic K-RAS/Ki67/HIF-1α pathway to predict survival in resectable pancreatic cancer

Background:

The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS hyperactivation is virtually universal in pancreatic cancer, that confers drug resistance, drives aggressive tumorigenesis and rapid metastasis. Pancreatic tumours are often marked by hypovascularity, increased hypoxia and ineffective drug delivery. Thus, biomarker discovery and developing innovative means of countervailing oncogenic K-RAS activation are urgently needed.

Methods:

Tumour specimens from 147 pancreatic cancer patients were analysed by immunohistochemical (IHC) staining and tissue microarray (TMA). Statistical correlations between selected biomarkers and clinicopathological predictors were examined to predict survival.

Results:

We find that heightened hypoxia response predicts poor clinical outcome in resectable pancreatic cancer. SIAH is a tumour-specific biomarker. The combination of five biomarkers (EGFR, phospho-ERK, SIAH, Ki67 and HIF-1α) and four clinicopathological predictors (tumour size, pathological grade, margin and lymph node status) predict patient survival post surgery in pancreatic cancer.

Conclusions:

Combining five biomarkers in the K-RAS/Ki67/HIF-1α pathways with four clinicopathological predictors may assist to better predict survival in resectable pancreatic cancer.     

Health-related quality of life in patients with dual diagnosis: clinical correlates

ABSTRACT: BACKGROUND: Although the studies published so far have found an affectation in the Health Related Quality of Life (HRQOL) in both psychiatric and substance use dependence disorders, very few studies have applied HRQOL as an assessment measure in patients suffering both comorbid conditions, or Dual Diagnosis. The aim of the current study was to assess HRQOL in a group of patients with Dual Diagnosis compared to two other non-comorbid groups and to determine what clinical factors are related to HRQOL. METHODS: Cross-sectional assessment of three experimental groups was made through the Short Form -- 36 Item Health Survey (SF-36). The sample consisted of a group with Dual Diagnosis (DD; N = 35), one with Severe Mental Illness alone (SMI; N = 35) and another one with Substance Use Dependence alone (SUD; N = 35). The sample was composed only by males. To assess the clinical correlates of SF-36 HRQOL, lineal regression analyses were carried out. RESULTS: The DD group showed lower scores in most of the subscales, and in the mental health domain. The group with SUD showed in general a better state in the HRQOL while the group with SMI held an intermediate position with respect to the other two groups. Daily medication, suicidal attempts and daily number of coffees were significantly associated to HRQOL, especially in the DD group. CONCLUSIONS: The DD group showed lower self-reported mental health quality of life. Assessment of HRQOL in dual patients allows to identify specific needs in this population, and may help to establish therapeutic goals to improve interventions.