Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT2A Receptor System

Impulsivity is an important feature of multiple neuropsychiatric disorders, and individual variation in the degree of inherent impulsivity could play a role in the generation or exacerbation of problematic behaviors. Serotonin (5-HT) actions at the 5-HT_2AR receptor (5-HT_2AR) promote and 5-HT_2AR antagonists suppress impulsive action (the inability to withhold premature responses; motor impulsivity) upon systemic administration or microinfusion directly into the medial prefrontal cortex (mPFC), a node in the corticostriatal circuit that is thought to play a role in the regulation of impulsive action. We hypothesized that the functional capacity of the 5-HT_2AR, which is governed by its expression, localization, and protein/protein interactions (eg, postsynaptic density 95 (PSD95)), may drive the predisposition to inherent impulsive action. Stable high-impulsive (HI) and low-impulsive (LI) phenotypes were identified from an outbred rodent population with the 1-choice serial reaction time (1-CSRT) task. HI rats exhibited a greater head-twitch response following administration of the preferential 5-HT_2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and were more sensitive to the effects of the selective 5-HT_2AR antagonist M100907 to suppress impulsive action relative to LI rats. A positive correlation was observed between levels of premature responses and 5-HT_2AR binding density in frontal cortex ([³H]-ketanserin radioligand binding). Elevated mPFC 5-HT_2AR protein expression concomitant with augmented association of the 5-HT_2AR with PSD95 differentiated HI from LI rats. The observed differential sensitivity of HI and LI rats to 5-HT_2AR ligands and associated distinct 5-HT_2AR protein profiles provide evidence that spontaneously occurring individual differences in impulsive action reflect variation in the cortical 5-HT_2AR system.     

Pharmacokinetic Interaction of the Direct Renin Inhibitor Aliskiren with Furosemide and Extended‐Release Isosorbide‐5‐Mononitrate in Healthy Subjects

This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended‐release formulation of isosorbide‐5‐mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18–45 years) received either ISMN 40 mg or furosemide 20 mg once‐daily for 3 days followed by a 3‐day washout. Subjects then received aliskiren 300 mg once‐daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC_τ was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C_max by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC_τ by 28% (0.72 [0.64, 0.81]) and C_max by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC_τ 1.03 [0.90, 1.18]; C_max 0.94 [0.69, 1.29]) and ISMN (AUC_τ 0.88 [0.71, 1.10]; C_max 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP <90 and/or DBP <50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.     

Presence of interferon in acute- and convalescent-phase sera of humans with influenza or influenza-like illness of undetermined etiology

Interferon (IFN;titer, greater than 10 units) was present in the acute-phase sera of 30 of 40 subjects with culture and/or serologically documented, naturally acquired influenza A/Brazil/78 (H1N1) and in the acute-phase sera of five of 27 subjects with an influenza-like illness of undetermined etiology. No statistical correlation existed between the quantity of IFN in acute-phase serum and the course of the clinical illness. Antiviral activity in all of nine acute-phase sera and three of four sera obtained on the fifth to seventh days of illness was neutralized to greater than 50% by antibody to virus-induced human leukocyte IFN (HuIFN-alpha). In contrast, none of five sera collected between 21 and 23 days after the onset of illness contained IFN sensitive to neutralization by antibody to HuIFN-alpha. Resistance of IFN in convalescent-phase sera to neutralization by antibody to HuIFN-alpha suggests that multiple IFN species may evolve during viral infections.     

Induction of oviposition in the domestic hen by prostaglandins

Single intrauterine injection of prostaglandins E₁, E₂, and F₂α in this order of potency induce premature oviposition in the hen within a few minutes. Similarly, arachidonic acid, a prostaglandin precursor, was also effective in initiating egglaying. PGE₁ and PGE₂ are about 10–20 times more potent than oxytocin, suggesting a possible physiological role in the regulation of oviposition.     

Microbiology difference between colonized catheters and catheter-related bloodstream infections

BACKGROUND/AIMS: Central vein catheters for patients receiving total parenteral nutrition have a high incidence of colonized catheters and catheter-related bloodstream infections. However, the actual incidence and bacterial pattern have not been well studied. This study was undertaken to investigate the difference in bacteriology between colonized catheters and catheter-related bloodstream infections. METHODOLOGY: From January 1997 to March 1998, 354 patients receiving total parenteral nutrition were included in this study. The patients ranged in age from 49 to 80 years, 151 women and 203 men. Colonized catheters and catheter-related bloodstream infections were defined. RESULTS: The culture was performed in 249 catheter tips (249 of 614, 40.6%). Sixty tips were found to have organisms. The organisms cultured from colonized catheters were Gram(+) aerobic bacteria (34, 56.7%), fungi (14, 23.3%), and Gram(-) aerobic bacteria (12, 20%). The organisms cultured from catheter-related bloodstream infections were fungi (16, 64%), Gram(-) aerobic bacteria (5, 20%), and Gram(+) aerobic bacteria (4, 16%). Dermatogenic infection in colonized catheters should be stressed, but systemic fungal infection in catheter-related bloodstream infections should be emphasized. CONCLUSIONS: A striking difference exists in bacterial species between colonized catheters and catheter-related bloodstream infections. Further studies on different treatment strategy for colonized catheters and catheter-related bloodstream infections should be undertaken. The combined approach of a total parenteral nutrition team, sterile protocols, and early diagnosis of fungemia should be advocated for the total parenteral nutrition patients.     

Ticlopidine-associated aplastic anemia

 Serious hematologic complications associated with ticlopidine have been reported, including aplastic anemia. We report here an additional case of fatal aplastic anemia due to ticlopidine. A 66-year-old male patient developed fever and pancytopenia 2 months after ticlopidine was started. Despite the administration of granulocyte colony-stimulating factor (G-CSF) and broad-spectrum antibiotics, as well as aggressive red cell and platelet transfusions, the patient died 16 days after admission due to septic shock. Eighteen other cases of ticlopidine-induced aplastic anemia published in the English literature are also reviewed and presented here. Eight of the total 19 patients (including the one reported here) have died, mostly due to infection. Of the seven who received supportive treatment only, four had spontaneous recovery. Nine cases were treated with G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF), and response was observed in only four of them. Several other cases were treated with high-dose corticosteroids or androgens; however, it was not possible to evaluate the efficacy of these treatments because of the limited number of cases. In the absence of satisfactory treatment for ticlopidine-induced aplastic anemia at present, it may be reasonable to try antilymphocyte globulin or cyclosporine. Also, great efforts should be made in the prevention and management of infection accompanying this disease. Received: 2 November 1997 / Accepted: 12 January 1998     

Daily Life Events Influence the Results of the Dexamethasone Suppression Test in Healthy Women

Although the Dexamethasone Suppression Test (DST) plays an important role in psychosomatic research, confounding factors limit the sensitivity and specificity of the DST. The aim of this study was to investigate the relationship between the intensity of daily life stressors and DST results in healthy participants after controlling the confounding factors. The subjects of this study consisted of 75 healthy volunteers. The intensity of daily life events was assessed using the Taiwanese version of the Recent Life Change Questionnaire (RLCQ). Neuroticism was assessed using the Maudsley Personality Inventory (MPI). The Dexamethasone Suppression Test (DST) was also performed. The regression model showed that daily life events (RLCQ score) were correlated significantly with cortisol level on day 1 and D% only in women. This finding implies that daily life events should be considered as an independent variable in women in further studies when the DST is applied.