Fulminant liver failure associated with T-cell non-Hodgkin's lymphoma and hepatitis C virus: a case report

Hematological malignancies can affect the liver, without producing severe hepatic involvement. We report the case of a 57-year-old man with hepatitis C virus infection and mild chronic hepatitis without antiviral treatment, who developed an aggressive T-cell non-Hodgkin's lymphoma confirmed by histological studies including liver, lymph nodes and bone marrow. The patient developed massive hepatic infiltration and acute liver failure. Rescue chemotherapy was administered but the patient died soon after with severe lactic acidosis. The immunopathological features of this association and the few reports of cases presenting with acute liver failure are reviewed.     

Naltrexone and disulfiram in patients with alcohol dependence and current depression

OBJECTIVE: Although disulfiram and naltrexone have been approved by the Food and Drug Administration for the treatment of alcoholism, no medications have been approved for individuals with alcohol dependence and comorbid psychiatric disorders. In particular, the effect of these medications on alcohol use outcomes and on specific psychiatric symptoms is still unknown in patients with the most common co-occurring disorder, major depression. METHOD: Two hundred fifty-four patients with a major Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at 3 Veterans Administration outpatient clinics. Randomization included (1) open randomization to disulfiram or no disulfiram, and (2) double-blind randomization to naltrexone or placebo. This resulted in 4 groups: (1) naltrexone alone, (2) placebo alone, (3) disulfiram and naltrexone, and (4) disulfiram and placebo. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms assessed by the Hamilton Depression Rating Scale, alcohol craving, gamma-glutamyltransferase levels, and adverse events. RESULTS: One hundred thirty-nine subjects (54.7%) met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression. There was no relationship between the diagnosis of depression and medication treatment on alcohol use outcomes, psychiatric symptoms, or the reporting of side effects for these medications. There was a significant interaction between diagnosis, medication group, and craving, where subjects with depression on disulfram reported lower craving over time than subjects with depression on naltrexone. CONCLUSIONS: The results suggest that disulfiram and naltrexone are safe pharmacotherapeutic agents for dually diagnosed individuals with depression for the treatment of alcohol use disorders.     

A novel fumarate hydratase-deficient HLRCC kidney cancer cell line, UOK268: a model of the Warburg effect in cancer

The role of energy deregulation and altered/adapted metabolism in tumor cells is an increasingly important issue in understanding cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive form of RCC characterized by germline mutation of fumarate hydratase (FH), followed by somatic loss of the remaining wild-type allele and known to be a highly metastatic and lethal malignancy compared to other RCCs. The intrinsic loss of normal tricarboxylic acid (TCA) cycle presumably aids tumorigenesis due to the necessary metabolic alterations required and the enforced dependence on glycolysis derived energy, mimicking the Warburg effect. Thus, there is considerable utility in establishing a preclinical cell model from these tumors to study energy metabolism deregulation, as well as developing new targeted therapeutic approaches for TCA cycle enzyme-deficient cancers. Here, we describe a new immortalized cell line, UOK268, derived from a patient's primary HLRCC-associated kidney cancer. This represents the first primary renal cell line to model TCA cycle gene loss and provides a perfect partner cell line to our previously described metastasis-derived HLRCC-associated cell line, UOK262. We identified a novel germline FH missense mutation, p.His192Asp, and the subsequent loss of heterozygosity in UOK268. The UOK268 cell line expressed mutant FH protein, which localized to the mitochondria, but with loss of almost all catalytic activity. The UOK268 cells had severely compromised oxidative phosphorylation and increased glycolytic flux. Ingenuity pathways analysis of human mitochondria-focused cDNA microarray (hMitChip3) gene chip data confirmed the altered mRNA expression patterns of genes involved in several important pathways, such as lipid metabolism, apoptosis, and energy production/glycolysis. UOK268 provides a unique model of a primary cell line demonstrating an enforced, irreversible Warburg effect and, combined with UOK262, provides a unique in?vitro preclinical model for studying the bioenergetics of the Warburg effect in human cancer.     

Towards further understanding of the co-morbidity between attention deficit hyperactivity disorder and bipolar disorder: a MRI study of brain volumes

BACKGROUND: Although attention deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) co-occur frequently and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this co-morbidity is scarce. Our aim was to evaluate the morphometric magnetic resonance imaging (MRI) underpinnings of the co-morbidity of ADHD with BPD, testing the hypothesis that subjects with this co-morbidity would have neuroanatomical correlates of both disorders. METHOD: Morphometric MRI findings were compared between 31 adults with ADHD and BPD and with those of 18 with BPD, 26 with ADHD, and 23 healthy controls. The volumes (cm(3)) of our regions of interest (ROIs) were estimated as a function of ADHD status, BPD status, age, sex, and omnibus brain volume using linear regression models. RESULTS: When BPD was associated with a significantly smaller orbital prefrontal cortex and larger right thalamus, this pattern was found in co-morbid subjects with ADHD plus BPD. Likewise, when ADHD was associated with significantly less neocortical gray matter, less overall frontal lobe and superior prefrontal cortex volumes, a smaller right anterior cingulate cortex and less cerebellar gray matter, so did co-morbid ADHD plus BPD subjects. CONCLUSIONS: Our results support the hypothesis that ADHD and BPD independently contribute to volumetric alterations of selective and distinct brain structures. In the co-morbid state of ADHD plus BPD, the profile of brain volumetric abnormalities consists of structures that are altered in both disorders individually. Attention to co-morbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD.     

Hepatitis C virus RNA elimination and development of resistance in replicon cells treated with BMS-790052

BMS-790052, a first-in-class hepatitis C virus (HCV) replication complex inhibitor, targeting nonstructural protein 5A (NS5A), displays picomolar to nanomolar potency against genotypes 1 to 5. This exceptional potency translated into robust anti-HCV activity in clinical studies with HCV genotype 1-infected subjects. To date, all BMS-790052-associated resistance mutations have mapped to the N-terminal region of NS5A. To further characterize the antiviral activity of BMS-790052, HCV replicon elimination and colony formation assays were performed. Replicon was cleared from genotype 1a and 1b replicon cells in a time- and dose-dependent manner. Elimination of the genotype 1a replicon required longer treatment durations and higher concentrations of BMS-790052 than those for the genotype1b replicon. Single amino acid substitutions that conferred relatively low levels of resistance were observed at early time points and at low doses. Higher doses and longer treatment durations yielded mutations that conferred greater levels of resistance, including linked amino acid substitutions. Replicon cells that survived inhibitor treatment remained fully sensitivity to pegylated alpha interferon (pegIFN-α) and other HCV inhibitors. Moreover, genotype 1a replicon elimination was markedly enhanced when pegIFN-α and BMS-790052 were combined. Resistant variants observed in this study were very similar to those observed in a multiple ascending dose (MAD) monotherapy trial of BMS-790052, validating replicon elimination studies as a model to predict clinical resistance. Insights gained from the in vitro anti-HCV activity and resistance profiles of BMS-790052 will be used to help guide the clinical development of this novel HCV inhibitor.     

In vitro activity of BMS-790052 on hepatitis C virus genotype 4 NS5A

The antiviral profile of BMS-790052, a potent hepatitis C virus (HCV) replication complex inhibitor targeting nonstructural protein NS5A, is well characterized for HCV genotype-1. Here, we report that BMS-790052 inhibits hybrid replicons containing HCV genotype-4 NS5A genes with 50% effective concentrations (EC(50)s) ranging from 7 to 13 pM. NS5A residue 30 was an important site for BMS-790052-selected resistance in the hybrid replicons. Our results support the potential of BMS-790052 as a valuable component of combination therapy for HCV genotype-4 chronic infection.     

Reproductive anatomy and fecundity estimation of the haematophagous ectoparasite <Emphasis Type="Italic">Carnus hemapterus</Emphasis>

The dynamics of host–parasite interactions depends to a large extent on the effect of host responses on parasite fitness. An increased research effort is currently being invested in the study of host influence on parasite fitness both at a population and at an individual level even though basic information (e.g. the reproductive anatomy of parasites) is frequently missing. Here, we study for the first time the reproductive system of the diptera Carnus hemapterus, a 2-mm long, highly mobile haematophagous fly parasitizing nestlings of a broad variety of bird species. Although this species is poorly known, it is being increasingly used for the study of host–parasite interactions. We also assess the reliability of a method to estimate fecundity based on the number of laid eggs per gravid female and analyse the effect of body size on fecundity estimates. Our results show that carnid flies are synovigenic, so that both the number of laid eggs at a given moment and the egg load represent only a fraction of the true potential fecundity. Moreover, laid eggs are probably a fraction of the number of mature eggs ready to be laid since females withheld seemingly mature eggs at oviposition. A high proportion of pregnant females did not lay eggs, and the number of eggs laid per pregnant female varied remarkably. The latter is explained partly by a positive relationship with body size (thorax length and abdomen width). Caution is needed when using the number of laid eggs as a shortcut estimation of fecundity in C. hemapterus. We propose some improvements to the method for assessing Carnus fertility.     

Impact of mercury exposure on blood pressure and cardiac autonomic activity among Cree adults (James Bay, Quebec, Canada)

Aboriginal populations from Quebec (Canada) are exposed to higher mercury levels than southern regions since these populations consume high quantities of fish. Epidemiological evidence suggests a detrimental impact of mercury on cardiovascular risk factors such as heart rate variability (HRV) and blood pressure (BP). The objective of this study was to assess the impact of mercury exposure on BP, resting heart rate (HR) and HRV among Cree adults. Data were collected among 791 adults ≥18 years old living in seven communities of the James Bay. Blood mercury and hair levels were used as biomarkers of recent and long-term exposure. BP was measured through a standardised protocol while HRV was derived from a 2-h Holter monitoring assessment. The relationship between mercury and the outcomes was studied using ANOVA and ANCOVA analysis. Geometric mean of blood mercury and hair mercury concentration was 17.0 nmol/L (95%CI: 6.1–44.0) and 2.36 nmol/g (95%CI: 2.09–2.65); respectively. After adjusting for confounders, blood mercury was associated with HRV parameters such as LF (β=0.21, P=0.0002), HF (β=0.15, P=0.004) and LF/HF (β=0.06, P=0.003). Similar associations were observed with hair mercury. In contrast, no significant association was observed between blood mercury or hair mercury and BP after adjusting for confounders. In conclusion, mercury exposure seems to affect HRV among Cree adults even after considering fish nutrients (n-3 fatty acids and selenium) and other contaminants (lead and polychlorinated biphenyls) that are also present in the traditional diet of this population.     

Chest trauma

Chest trauma is a frequent problem arising from lesions caused by domestic and occupational activities and especially road traffic accidents. These injuries can be analyzed from distinct points of view, ranging from consideration of the most severe injuries, especially in the context of multiple trauma, to the specific characteristics of blunt and open trauma. In the present article, these injuries are discussed according to the involvement of the various thoracic structures. Rib fractures are the most frequent chest injuries and their diagnosis and treatment is straightforward, although these injuries can be severe if more than three ribs are affected and when there is major associated morbidity. Lung contusion is the most common visceral lesion. These injuries are usually found in severe chest trauma and are often associated with other thoracic and intrathoracic lesions. Treatment is based on general support measures. Pleural complications, such as hemothorax and pneumothorax, are also frequent. Their diagnosis is also straightforward and treatment is based on pleural drainage. This article also analyzes other complex situations, notably airway trauma, which is usually very severe in blunt chest trauma and less severe and even suitable for conservative treatment in iatrogenic injury due to tracheal intubation. Rupture of the diaphragm usually causes a diaphragmatic hernia. Treatment is always surgical. Myocardial contusions should be suspected in anterior chest trauma and in sternal fractures. Treatment is conservative. Other chest injuries, such as those of the great thoracic and esophageal vessels, are less frequent but are especially severe.