Population‐based case‐control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk

BACKGROUND:

Testicular germ cell tumor (TGCT) incidence increased steadily in recent decades, but causes remain elusive. Germ cell function may be influenced by cannabinoids, and 2 prior epidemiologic studies reported that the use of marijuana may be associated with nonseminomatous TGCT. Here, the authors evaluate the relation between TGCTs and exposure to marijuana and other recreational drugs using a population‐based case‐control study.

METHODS:

In total, 163 patients who were diagnosed with TGCT in Los Angeles County from December 1986 to April 1991 were enrolled, and 292 controls were matched on age, race/ethnicity, and neighborhood. Participants were asked about drug use by a structured, in‐person interview. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression analysis adjusted for history of cryptorchidism; education; religiosity; and reported use of marijuana, cocaine, and amyl nitrite.

RESULTS:

Compared with never use, ever use of marijuana had a 2‐fold increased risk (OR, 1.94; 95% CI, 1.02‐3.68), whereas ever use of cocaine had a negative association with TGCT (OR, 0.54; 95% CI, 0.32‐0.91). Stratification on tumor histology revealed a specific association of marijuana use with nonseminoma and mixed histology tumors (OR, 2.42; 95% CI, 1.08‐5.42).

CONCLUSIONS:

A specific association was observed between marijuana use and the risk of nonseminoma and mixed tumors. To the authors' knowledge, this is the first report of a negative association between cocaine use and TGCT risk. The current results warrant mechanistic studies of marijuana's effect on the endocannabinoid system and TGCT risk and caution that recreational and therapeutic use of cannabinoids by young men may confer malignant potential to testicular germ cells. Cancer 2012. © 2012 American Cancer Society.     

Role of free radicals in vascular dysfunction induced by high tidal volume ventilation

Objective  To demonstrate that increased formation of reactive oxygen (ROS) and nitrogen species (RNS) is involved in VILI-induced vascular dysfunction. Methods  Male Sprague-Dawley anesthetized rats were ventilated for 60 min using low V_T ventilation [V_T 9 ml/kg, positive end-expiratory pressure (PEEP) 5 cmH₂O, n = 18], and high V_T ventilation (V_T 35 ml/kg, zero PEEP, n = 18). Arterial pressure and respiratory system mechanics were monitored. Blood samples for the determination of arterial blood gases and lactate concentration were drawn. Vascular rings from the thoracic aortae were mounted in organ baths for isometric tension recording. We studied endothelium-dependent relaxation in norepinephrine-precontracted rings (acetylcholine, 10 nM–10 μM) and contraction induced by norepinephrine (1 nM–10 μM) in resting vessels. Vascular rings were preincubated for 30 min with Zn–Mn–SOD (100 u/ml) or tempol (10⁻⁴ M) (extracellular and intracellular superoxide scavengers, respectively) or MnTMPyP (10⁻⁵ M) (a superoxide and peroxynitrite scavenger). The presence of superoxide and nitrotyrosine in aortic rings was evaluated by immunofluorescence. Results  High V_T ventilation induced hypotension, systemic acidosis, hypoxemia and hyperlactatemia, as well as impairment in acetylcholine and norepinephrine-induced responses in vitro. Responses to acetylcholine were improved by tempol (P = 0.004) and completely corrected (P < 0.001) by MnTMPyP. Responses to norepinephrine were also improved by treatment with tempol (P < 0.001) and MnTMPyP (P < 0.001). However, Zn–Mn–SOD did not improve acetylcholine- or norepinephrine-induced responses. Immunostaining for both superoxide and nitrotyrosine was increased in aortic rings from the high V_T group. Conclusions  Our data support a role for intracellular ROS and peroxynitrite in the high V_T ventilation-induced vascular dysfunction. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

CASE REPORT: Usefulness of Magnetic Resonance Spectroscopy for Diagnosis of Hepatic Encephalopathy in a Patient with Relapsing Confusional Syndrome

Magnetic resonance spectroscopy allows the assessment of several metabolites in brain tissue. In patients with hepatic encephalopathy, this technique shows a rise in glutamine and a decrease in myoinositol in brain tissue. However, the role of magnetic resonance spectroscopy in the diagnosis of hepatic encephalopathy is not known. We report the case of a patient with a relapsing confusional syndrome who underwent magnetic resonance spectroscopy. Previously, hepatic encephalopathy was ruled out because of the negative results of a transjugular liver biopsy and normal hepatic venous pressure gradient. The results of magnetic resonance were characteristic of hepatic encephalopathy. Abdominal computed tomography demonstrated large portosystemic shunts associated with cirrhosis of the liver. This case shows that magnetic resonance spectroscopy is an useful technique for the diagnosis of hepatic encephalopathy in selected cases, such as those without clinical signs of cirrhosis and/or large portosystemic shunts.     

Three-year follow-up of protease inhibitor-based regimen simplification in HIV-infected patients

Patients with sustained virological suppression on protease inhibitor (PI)-based therapy were randomly assigned to switch the PI to nevirapine (n = 155), efavirenz (n = 156), or abacavir (n = 149) and were followed for at least 3 years regardless of the discontinuation of assigned therapy. There was a higher probability of maintaining virological suppression after 3 years of follow-up with nevirapine or efavirenz than with abacavir. In contrast, abacavir showed a lower incidence of adverse effects leading to drug discontinuation.     

Neuronal nitric oxide synthase immunoreactivity in the guinea-pig liver: distribution and colocalization with neuropeptide Y and calcitonin gene-related peptide

AIMS/BACKGROUND: The innervation pattern of the guinea-pig liver is similar to that of the human liver. However, many aspects of the distribution of the neuronal isoform of the enzyme nitric oxide synthase (nNOS) in the guinea-pig liver and its colocalization with neuropeptides remain to be elucidated. METHODS: The distribution of nNOS was studied in fixed guinea-pig liver by light microscopic immunohistochemistry. Confocal analysis was used to determine its colocalization with neuropeptide Y (NPY) or calcitonin gene-related peptide (CGRP). RESULTS: nNOS-immunoreactive (nNOS-IR) nerves were observed in relation to hilar and interlobar vessels and in Glisson's capsule. A few nNOS-IR ganglia were observed in the extrahepatic bile duct and close to the interlobar portal triads. In addition, nNOS-IR fibers were located in the interlobular portal triads and pervading the parenchyma. Moreover, nNOS-IR nerves were demonstrated for the first time in the larger central veins and in the hepatic vein. nNOS-NPY and nNOS-CGRP colocalizations were detected in the fibromuscular layer of the bile duct and periductal plexus, respectively. CONCLUSIONS: These results support the phylogenetic conservation of the nNOS-IR hepatic innervation and its possible contribution to the regulation of hepatic blood flow and certain hepatic functions.     

The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation.

BACKGROUND/AIMS: Liver failure may cause brain edema through an increase in brain glutamine. However, usually standard neuroimaging techniques do not detect brain edema in cirrhosis. We assessed magnetization transfer ratio and (1)H-magnetic resonance (MR) spectroscopy before and after liver transplantation to investigate changes in brain water content in cirrhosis. METHODS: Non-alcoholic cirrhotics without overt hepatic encephalopathy (n=24) underwent (1)H-MR of the brain and neuropsychological tests. (1)H-MR results were compared with those of healthy controls (n=10). In a subgroup of patients (n=11), the study was repeated after liver transplantation. RESULTS: Cirrhotic patients showed a decrease in magnetization transfer ratio (31.5+/-3.1 vs. 37.1+/-1.1, P<0.01) and an increase in glutamine/glutamate signal (2.22+/-0.47 vs. 1.46+/-0.26, P<0.01). The increase in glutamine/glutamate signal was correlated to the decrease in magnetization transfer ratio and to neuropsychological function. Following liver transplantation, there was a progressive normalization of magnetization transfer ratio, glutamine/glutamate signal and neuropsychological function. Accordingly, correlations between these variables were lost after liver transplantation. CONCLUSIONS: Cirrhotic patients show reversible changes in magnetization transfer ratio that are compatible with the development of low-grade cerebral edema. Minimal hepatic encephalopathy and low-grade cerebral edema appear to be the consequences of the metabolism of ammonia in the brain.     

A strong initial systemic inflammatory response is associated with higher corticosteroid requirements and longer duration of therapy in patients with giant-cell arteritis

OBJECTIVE: To assess whether the intensity of the initial systemic inflammatory response is able to predict response to therapy in patients with giant cell arteritis (GCA). METHODS: Retrospective review of 75 patients (49 women and 26 men) with biopsy-proven GCA who had regular followup and were treated according to uniform criteria. Four parameters were used to evaluate the baseline inflammatory response at diagnosis: fever, weight loss, erythrocyte sedimentation rate > or = 85 mm/hour, and hemoglobin < 110 gm/liter. Patients were considered to have a weak inflammatory response if they had 2 or fewer inflammatory parameters (group 1) and a strong inflammatory response if 3 or 4 parameters were present (group 2). Time required to achieve a maintenance dose of less than 10 mg prednisone/day was recorded and analyzed by the Kaplan-Meier survival analysis method. Tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) serum levels were also determined in 62 patients and 15 controls. RESULTS: Forty patients had a weak (group 1) and 35 had a strong (group 2) initial inflammatory response. Patients in group 2 had significantly higher levels of circulating TNFalpha (31.9 +/- 16.8 versus 22.3 +/- 9 pg/ml; P = 0.01) and IL-6 (28.2 +/- 17.4 versus 16.6 +/- 13 pg/ml; P = 0.004) than patients in group 1. In group 1, 50% of patients required a median of 40 weeks (95% CI 37-43) to reach a maintenance dose of <10 mg, whereas in group 2 a median of 62 weeks (95% CI 42-82) was necessary (P = 0.0062). Patients in group 2 experienced more flares than patients in group 1 (P = 0.01) and received higher cumulative steroid doses (8.974 +/- 3.939 gm versus 6.893 +/- 3.075 gm; P = 0.01). CONCLUSION: GCA patients with a strong initial systemic inflammatory reaction have more elevated circulating levels of IL-6 and TNFalpha, have higher and more prolonged corticosteroid requirements, and experience more disease flares during corticosteroid therapy than patients with a weak systemic acute phase response.     

A B lymphocyte mitogen is a Brucella abortus virulence factor required for persistent infection

Microbial pathogens with the ability to establish chronic infections have evolved strategies to actively modulate the host immune response. Brucellosis is a disease caused by a Gram-negative intracellular pathogen that if not treated during the initial phase of the infection becomes chronic as the bacteria persist for the lifespan of the host. How this pathogen and others achieve this action is a largely unanswered question. We report here the identification of a Brucella abortus gene (prpA) directly involved in the immune modulation of the host. PrpA belongs to the proline-racemase family and elicits a B lymphocyte polyclonal activation that depends on the integrity of its proline-racemase catalytic site. Stimulation of splenocytes with PrpA also results in IL-10 secretion. Construction of a B. abortus-prpA mutant allowed us to assess the contribution of PrpA to the infection process. Mice infected with B. abortus induced an early and transient nonresponsive status of splenocytes to both Escherichia coli LPS and ConA. This phenomenon was not observed when mice were infected with a B. abortus-prpA mutant. Moreover, the B. abortus-prpA mutant had a reduced capacity to establish a chronic infection in mice. We propose that an early and transient nonresponsive immune condition of the host mediated by this B cell polyclonal activator is required for establishing a successful chronic infection by Brucella.     

A study of intestinal permeability in relation to the inflammatory response and plasma endocab IgM levels in patients with acute pancreatitis

BACKGROUND: There is scarce information regarding intestinal permeability (IP) in patients with acute pancreatitis (AP) and its relationship with systemic inflammatory response and bacterial translocation (BT). AIMS: To study IP in patients with mild and severe forms of AP as compared with controls and the presumed correlations between IP, the inflammatory response, and endotoxin. PATIENTS AND METHODS: Sixty-eight patients with AP and 13 healthy controls were included. IP was assessed by means of the lactulose/mannitol (L/M) test, at admission (LMR1), and at the 15th day (LMR2). The presence of endotoxin was assessed by means of endotoxin-core antibodies type IgM (EndoCab IgM), at admission and 15 days later in patients with severe AP. Plasma levels of interleukins 6, 8, 10, and tumor necrosis factor alpha were tested within the first 72 hours from the onset of pain. RESULTS: Both LMR1 and LMR2 were significantly higher in patients than in controls, and in patients with severe versus mild forms of AP. Plasma levels of Endocab IgM increased significantly in patients with severe AP. Basal plasma levels of pro- and anti-inflammatory cytokines were significantly higher in patients with severe AP. A significant correlation was found between LMR2 and Endocab IgM levels in patients with severe AP (r = 0.73, P = 0.02). CONCLUSIONS: Patients with AP show an increased IP when compared with controls, being more relevant and persistent in severe cases. This seems related to an increase of endotoxemia late in the course of the disease, but not with an exacerbation of the systemic immune response.