Nicotine discrimination and self-administration in humans as a function of smoking status

Nicotine’s discriminative stimulus effects may be critical to understanding reinforcement of tobacco smoking. It is not known whether regular nicotine exposure produces tolerance or sensitivity to these effects. In this study, male and female smokers (n = 11) and never-smokers (n = 10) were trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0) on day 1. On day 2, both groups were tested on generalization of this discrimination across intermittent presentations of 0, 3, 6, 12, and 20 μg/kg nicotine in random order. Quantitative and quantal behavioral discrimination tasks, used in previous research, were employed. On day 3, subjects were instructed to self-administer sprays from the 20 μg/kg nicotine versus 0 bottles in a concurrent-choice procedure. All but one subject (female smoker) learned reliably to discriminate 20 μg/kg nicotine from placebo (≥ 80% correct) on day 1. Nicotine-appropriate responding on day 2 was attenuated in smokers versus never-smokers at 20 μg/kg on the quantitative task and at 12 μg/kg on the quantal task, suggesting tolerance. There was no difference in responding at other doses. Smokers also showed attenuated responses on the subjective measure of “head rush”, which was associated with discrimination responding in both groups. Nicotine self-administration was significantly greater in smokers versus never-smokers, who self-administered nicotine below chance levels, and was inversely related to discrimination behavior in never-smokers but unrelated in smokers. Women smokers showed less change in nicotine-appropriate responding across generalization doses, reported less confidence in discriminating training doses during acquisition on day 1, and tended to self-administer less nicotine on day 3. These results indicate that smokers may become tolerant to the discriminative stimulus effects of nicotine, perhaps promoting increased use. Received: 1 October 1996/Final version: 28 January 1997     

Relevance of HIV-1-specific CD4+ helper T-cell responses during structured treatment interruptions in patients with CD4+ T-cell nadir above 400/mm3

OBJECTIVES: To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved. METHODS: Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years. RESULTS: VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P < 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P < 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88). CONCLUSIONS: STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.     

Current perspectives on HER2 testing: a review of national testing guidelines.

Knowledge of HER2 status is a prerequisite when considering a patient's eligibility for Herceptin (trastuzumab) therapy. Accurate assessment of HER2 status is essential to ensure that all patients who may benefit from Herceptin are correctly identified. There are several assays available to determine HER2 status: the most common in routine clinical practice are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Various factors can affect the results achieved with these assays, including the assay antibody/probe, the methodology and the experience of personnel. Many countries have implemented national testing guidelines in an attempt to standardize testing procedures and make results more accurate. These guidelines vary in the level of detail and the number of recommendations. This review looks at areas of consensus between the different national testing guidelines and highlights where errors may arise during the testing procedure. The key point underlined by this review is that whatever method is used to test for HER2 status, the technology must be validated first, and there must be regular internal and external quality control and quality assurance procedures.     

Human recombinant neutralizing antibodies against hantaan virus G2 protein

Old world hantaviruses, causing hemorrhagic fever with renal syndrome (HFRS), still present a public health problem in Asia and Eastern Europe. The majority of cases has been recorded in China. The aim of our study was to generate human recombinant neutralizing antibodies to a hantavirus by phage display technology. To preserve the structural identity of viral protein, the panning procedure was performed on native Hantaan (HTN) (76-118) virus propagated in Vero-E6 cells. In total, five complete human recombinant IgG antibodies were produced in a baculovirus expression system. All of them were able to completely neutralize HTN, and Seoul (SEO) virus in a plaque reduction neutralization test (PRNT). Three of these antibodies could also completely neutralize Dobrava (DOB) virus but not Puumala (PUU) virus. All antibodies bind to Hantaan virus G2 protein localized in the virus envelope. The sequence areas within the HTN (76-118)-G2 protein detected by five selected antibodies were mapped using peptide scans. Two partial epitopes, 916-KVMATIDSF-924 and 954-LVTKDIDFD-963, were recognized, which presumably are of paramount importance for docking of the virus to host cell receptors. A consensus motif 916-KVXATIXSF-924 could be identified by mutational analysis. The neutralizing antibodies to the most widely distributed hantaviruses causing HFRS might be promising candidates for the development of an agent for prevention and treatment of HFRS in patients.     

Does the beneficial effect of HRT on endothelial function depend on lipid changes

OBJECTIVES: To determine whether improvement in endothelial function of the brachial artery observed in women treated with hormone replacement therapy (HRT) may be explained by changes in lipid profile or blood pressure, information was used obtained in a single-centre, randomised, double blind, placebo-controlled trial. METHODS: Hundred-and-five healthy postmenopausal women, aged 50-65 years, were treated with 0.625 mg conjugated equine estrogens (CEE) combined with 2.5 mg medroxyprogesterone acetate (MPA) (CEE+MPA), 2.5 mg tibolone or placebo for 3 months. At baseline and after 3 months, endothelial function was assessed using flow-mediated dilatation (FMD) and nitro glycerine-mediated dilatation (NMD). Furthermore, lipids were measured. Multivariate linear regression analysis was applied to address the research question. RESULTS: Treatment with CEE+MPA resulted in an improvement in FMD of 2.0% (95% CI: -0.1; 4.1). CEE/MPA reduced total cholesterol with 13% (95% CI: -18%; -7%), LDL-cholesterol with 23% (95% CI: -30%; -15%) and lipoprotein(a) (Lp(a)) with 14% (95% CI: -26%; -2%). The magnitude of the relation of CEE/MPA with endothelial function was attenuated to from 2.0 to 1.6% when change in Lp(a) was taken into account. Adjustments for other lipids or blood pressure did not attenuate the association. CONCLUSIONS: The improvement in endothelial function in postmenopausal women treated with CEE+MPA appears to be partially mediated by change in Lp(a), and apparently not by changes in other lipids.     

Brief report: cognitive functioning in children with Tourette's syndrome with and without comorbid ADHD

OBJECTIVE: To examine whether patients with Tourette's syndrome (TS) with and without comorbid attention deficit and hyperactivity disorder (ADHD) differ in cognitive functioning and whether a higher level of cognitive functioning is associated with severity of TS symptoms and psychosocial functioning. METHODS: Cognitive functioning, symptom severity, and psychosocial functioning were examined in 40 patients (33 boys, 7 girls; age range 6-18 years) with TS, of whom 17 had the comorbid diagnosis of ADHD. RESULTS: Patients with a comorbid ADHD diagnosis evidenced poorer performance than those with TS alone with respect to severity of TS symptoms, psychosocial functioning, verbal and performance intelligence, and word fluency, but not on tests of cognitive flexibility. Psychosocial functioning was predicted by symptom severity, but not by intelligence or fluency. CONCLUSIONS: Results confirm prior findings that comorbid ADHD is associated with more TS symptoms and worse psychosocial and cognitive functioning, and motivate whether cognitive flexibility plays a role in moderating the deleterious psychosocial effects of Tourette's syndrome and ADHD.     

Evaluation of a single-tube multiplex polymerase chain reaction screen for detection of common alpha-thalassemia genotypes in a clinical laboratory

We prospectively compared a single-tube multiplex polymerase chain reaction (PCR) for detecting alpha-thalassemia with our current approach using 452 blood samples. Initial evaluation of 89 specimens revealed sensitivity and specificity, respectively, for the hemoglobin H inclusion body test (HbH prep) vs PCR for detecting alpha0-thalassemia carriers of 0.79 and 0.96 and for a mean corpuscular volume (MCV) of 82 microm3 (82 fL) or less, 1.0 and 0.45. Detection of all alpha-thalassemia genotypes was significantly lower for HbH prep and MCV (sensitivity and specificity, respectively: HbH prep, 0.48 and 0.96; MCV, 0.87 and 0.47). In a follow-up evaluation of patients with positive HbH prep results or suspected alpha-thalassemia prescreened by low MCV, the sensitivity and specificity, respectively, of HbH prep vs PCR increased to 0.97 and 0.93 for alpha0-thalassemia and 0.83 and 0.92 for any alpha-thalassemia. PCR detected alpha-thalassemia in 37.2% of 298 suspected alpha-thalassemia cases with suggestive indices but negative HbH prep results and no detectable hemoglobinopathy. This multiplex approach was more sensitive than the HbH prep for detecting all alpha-thalassemia genotypes, particularly alpha+-thalassemia; was particularly valuable for identifying carriers of alpha0-thalassemia at risk for offspring with hemoglobin Bart hydropsfetalis, regardless of other diagnosed hemoglobinopathies; and is an ideal adjunct to standard clinical screening protocols for detecting alpha-globin deletions.     

Postextrasystolic regulation patterns of blood pressure and heart rate in patients with idiopathic dilated cardiomyopathy

Assessment of fluctuations in heart rate (HR) following a premature ventricular complex (PVC) is valuable for identifying patients at high risk of sudden cardiac death. We hypothesised that postextrasystolic potentiation is the main determinant of the regulation patterns of blood pressure (BP) and HR following a PVC. Twelve patients with idiopathic dilated cardiomyopathy (IDC) and 13 control subjects with single PVCs (comparable coupling intervals) were investigated. Non-invasive finger arterial BP and ECGs were analysed. Regulation patterns following a single PVC were quantified using the indices postextrasystolic amplitude potentiation (PEAP) and maximum turbulence slope of five consecutive mean BP values (MBP-TS), and compared with the HR turbulence parameters turbulence slope (HR-TS) and turbulence onset (HR-TO). PEAP was significantly higher in IDC patients compared to controls (48.7 ± 32.6 vs. 9.8 ± 5.4 %, P < 0.01), whereas MBP-TS was lower (0.97 ± 0.60 vs. 2.07 ± 1.04 mmHg BBI⁻¹ (BBI, beat-to-beat interval), P < 0.05), as was HR-TS (8.46 ± 7.90 vs. 30.73 ± 22.90 ms BBI⁻¹, P < 0.01). HR-TO was significantly higher in IDC patients (−0.56 ± 2.19 vs. −5.52 ± 4.13 %, P < 0.01). In addition, the regulation patterns of BP and HR following a single PVC differed significantly between IDC patients and controls. Specifically, we observed pronounced PEAPs in IDC patients. The baroreflex response initiated by the low pressure amplitude of the PVC was suppressed in IDC patients due to the augmented potentiation of the first postextrasystolic blood pressure. Furthermore, IDC patients displayed impressive postextrasystolic pulsus alternans phenomena, whereas healthy subjects exhibited a typical baroreflex pattern. The pulsus alternans phenomenon seems to be triggered by a PVC.