Methamphetamine (METH) is a frequent drug of abuse in U.S. populations and commonly associated with psychosis. This may be a factor in frequent criminal justice referrals and lengthy treatment required by METH users. Persecutory delusions and auditory hallucinations are the most consistent symptoms of METH-associated psychosis (MAP). MAP has largely been studied in Asian populations and risk factors have varied across studies. Duration, frequency and amount of use as well as sexual abuse, family history, other substance use, and co-occurring personality and mood disorders are risk factors for MAP. MAP may be unique with its long duration of psychosis and recurrence without relapse to METH. Seven candidate genes have been identified that may be associated with MAP. Six of these genes are also associated with susceptibility, symptoms, or treatment of schizophrenia and most are linked to glutamatergic neurotransmission. Animal studies of pre-pulse inhibition, attenuation of social interaction, and stereotypy and alterations in locomotion are used to study MAP in rodents. Employing various models, rodent studies have identified neuroanatomical and neurochemical changes associated with METH use. Throughout this review, we identify key gaps in our understanding of MAP and suggest potential directions for future research.

Although oxidative stress is known to contribute to endothelial dysfunction-associated systemic vascular disorders, its role in pulmonary vascular disorders is less clear. Our previous studies, using isolated pulmonary arteries taken from lambs with surgically created heart defect and increased pulmonary blood flow (Shunt), have suggested a role for reactive oxygen species (ROS) in the endothelial dysfunction of pulmonary hypertension, but in vivo data are lacking. Thus the initial objective of this study was to determine whether Shunt lambs had elevated levels of ROS generation and whether this was associated with alterations in antioxidant capacity. Our results indicate that superoxide, but not hydrogen peroxide, levels were significantly elevated in Shunt lambs. In addition, we found that the increase in superoxide generation was not associated with alterations in antioxidant enzyme expression or activity. These data suggested that there is an increase in superoxide generation rather than a decrease in scavenging capacity in the lung. Thus we next examined the expression of various subunits of the NADPH oxidase complex as a potential source of the superoxide production. Results indicated that the expression of Rac1 and p47(phox) is increased in Shunt lambs. We also found that the NADPH oxidase inhibitor diphenyliodonium (DPI) significantly reduced dihydroethidium (DHE) oxidation in lung sections prepared from Shunt but not Control lambs. As DPI can also inhibit endothelial nitric oxide synthase (eNOS) superoxide generation, we repeated this experiment using a more specific NADPH oxidase inhibitor (apocynin) and an inhibitor of NOS (3-ethylisothiourea). Our results indicated that both inhibitors significantly reduced DHE oxidation in lung sections prepared from Shunt but not Control lambs. To further investigate the mechanism by which eNOS becomes uncoupled in Shunt lambs, we evaluated the levels of dihydrobiopterin (BH(2)) and tetrahydrobiopterin (BH(4)) in lung tissues of Shunt and Control lambs. Our data indicated that although BH(4) levels were unchanged, BH(2) levels were significantly increased. Finally, we demonstrated that the addition of BH(2) produced an increase in superoxide generation from purified, recombinant eNOS. In conclusion our data demonstrate that the development of pulmonary hypertension in Shunt lambs is associated with increases in oxidative stress that are not explained by decreases in antioxidant expression or activity. Rather, the observed increase in oxidative stress is due, at least in part, to increased expression and activity of the NADPH oxidase complex and uncoupled eNOS due to elevated levels of BH(2).

Reactive oxygen species (ROS) and reactive nitrogen species (RNS)produced؊ production as measured by dihydroethidium oxidation. Furthermore, using dihydrorhodamine to monitor ONOO ؊ formation, ADMA caused a dose-dependent increase in ONOO ؊ after treatment for 24 h. Similar effects of ADMA were seen using purified iNOS protein in a cell-free system. Together, these data indicate that elevated ADMA may contribute to the production of ROS and RNS in airway inflammation. Keywords: ADMA; epithelial cells; LA-4 cells; NOS; oxidative stressEndogenous nitric oxide (NO) plays a key beneficial role in the physiologic regulation of airway functions including the control of vascular and bronchial tone and neuroendocrine regulation of airway mediator release (1, 2). However, overproduction of NO has also been shown to contribute to tissue injury in inflammatory and ischemic conditions (3). One mechanism by which NO can contribute to tissue injury is by its diffusion-controlled reaction with superoxide (O 2 Ϫ ) to produce peroxynitrite (ONOO Ϫ ), a potent oxidant thought to be a key mediator of NO-mediated (Received in original form August 14, 2006 and in final form November 22, 2006 ) This work was supported by Grant Number P20RR017670 (A.H.) from the National Center for Research Resources (NCRR), and Grant Number 1F32HL086154 (S.M.W.) from the National Heart, Lung, and Blood Institute (NHLBI), both components of the National Institutes of Health (NIH). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NCRR, NHLBI, or NIH.Correspondence and requests for reprints should be addressed to Sandra Wells, Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Skaggs Building, Room 155, Missoula, MT 59812. E-mail: sandra.wells@umontana.edu CLINICAL RELEVANCEThis study demonstrates that elevated levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) may contribute to the production of reactive oxygen species and reactive nitrogen species in airway inflammation. These findings suggest that ADMA may play a role in airway diseases including asthma.tissue injury in atherosclerosis, congestive heart failure, glutamate excitotoxicity, and other disease states involving inflammatory oxidative stress (4). NO is formed from the semi-essential amino acid L-arginine by the action of three isoforms of the enzyme nitric oxide synthase (NOS) (5). The constitutive isoforms (cNOS) are expressed mainly in nonadrenergic noncholinergic nerves (neuronal NOS [nNOS]), endothelial cells (endothelial NOS [eNOS]), and airway epithelium (nNOS and eNOS) (5-8), and are involved in the physiologic regulation of the airway by the local production of small amounts of NO. The third isoform is induced after exposure to proinflammatory cytokines (inducible NOS [iNOS]) and is expressed in epithelial cells and inflammatory cells of the airway including macrophages (9). In addition to...

We have previously reported on the ex vivo generation of cytotoxic effector cells, termed cytokine-induced killer (CIK) cells, that have both in vitro and in vivo antitumor activity in murine models. We now report on our efforts for the large-scale expansion of CIK cells and also present preliminary results from a phase I clinical trial. Nine patients with advanced Hodgkin disease (n = 7) and non-Hodgkin lymphoma (n = 2), all of whom had relapsed after an autologous transplantation, were treated with escalating doses of CIK cells (3 patients at each dose level of 1 x 10(9) , 5 x 10(9) , or 1 x 10(10) cells). The CIK cells were produced by culturing unselected cells from steady-state apheresis products with interferon gamma, OKT3, and interleukin 2. After 21 days in culture, with the addition of fresh media and interleukin 2 every 3 to 4 days, the median culture was 97% viable (range, 61%-100%), 98% CD3 + (range, 66%-99%), 76% CD8 + (range, 27%-96%), 23% CD4 + (range, 6%-78%), 20% CD3 + CD56 + (range, 8%-58%), and <1% CD16 + 56 + (range, 0.2%-7.7%). The CD3 + CD56 + cells have previously been shown to exhibit the most cytotoxic activity. The absolute number of CD3 + CD56 + cells typically expanded 290-fold (range, 3- to 4000-fold) under these culture conditions. In vitro cytotoxic activity was measured against a human B-cell tumor line (OCI-Ly8). At a 40:1 effector-target cell ratio, CIK cells killed 32% (range, 2%-69%) of the target cells. A total of 21 infusions were administered to 9 patients. The number of CIK cells infused ranged from 1.0 x 10(9) to 1.0 x 10(10) per treatment. Toxicity was minimal, and there were no immediate adverse reactions to the infusions. Two patients had partial responses, and 2 patients had stabilization of disease: 1 for more than 18 months. Considering that these were heavily pretreated patients with advanced hematologic malignancies, we believe that CIK cells expanded in this fashion may have utility for the treatment of high-risk patients with evidence of minimal residual disease after autologous transplantation.