A multivariate neuromonitoring approach to neuroplasticity-based computerized cognitive training in recent onset psychosis

Two decades of studies suggest that computerized cognitive training (CCT) has an effect on cognitive improvement and the restoration of brain activity. Nevertheless, individual response to CCT remains heterogenous, and the predictive potential of neuroimaging in gauging response to CCT remains unknown. We employed multivariate pattern analysis (MVPA) on whole-brain resting-state functional connectivity (rsFC) to (neuro)monitor clinical outcome defined as psychosis-likeness change after 10-hours of CCT in recent onset psychosis (ROP) patients. Additionally, we investigated if sensory processing (SP) change during CCT is associated with individual psychosis-likeness change and cognitive gains after CCT. 26 ROP patients were divided into maintainers and improvers based on their SP change during CCT. A support vector machine (SVM) classifier separating 56 healthy controls (HC) from 35 ROP patients using rsFC (balanced accuracy of 65.5%, P < 0.01) was built in an independent sample to create a naturalistic model representing the HC-ROP hyperplane. This model was out-of-sample cross-validated in the ROP patients from the CCT trial to assess associations between rsFC pattern change, cognitive gains and SP during CCT. Patients with intact SP threshold at baseline showed improved attention despite psychosis status on the SVM hyperplane at follow-up (p < 0.05). Contrarily, the attentional gains occurred in the ROP patients who showed impaired SP at baseline only if rsfMRI diagnosis status shifted to the healthy-like side of the SVM continuum. Our results reveal the utility of MVPA for elucidating treatment response neuromarkers based on rsFC-SP change and pave the road to more personalized interventions.Subject terms: Predictive markers, Psychosis     

COMBINED RESPIRATORY EFFECTS OF COLD AIR WITH SO2 OR NO2 IN REPEATED 10-MINUTE EXPOSURES OF HYPERVENTILATING GUINEA PIGS

Previous studies in asthmatic subjects and guinea pigs have demonstrated attenuation of bronchoconstriction in repeated exposures to clean cold dry air. In the present animal study, we have simulated short-lasting human exposures to subfreezing urban air containing sulfur dioxide (SO2) and nitrogen dioxide (NO2). The anesthetized, paralyzed, and mechanically ventilated guinea pigs had 4 consecutive 10-min exposures either to clean cold dry air or to cold air with graded concentrations of SO2 (0-5 ppm) or NO2 (0-4 ppm). Peak expiratory flow (PEF) and tidal volume (V_T     

Characterization of the in vitro metabolic profile of amlodipine in rat using liquid chromatography-mass spectrometry.

In the present study, the metabolic profile of amlodipine, a well-known calcium channel blocker, was investigated employing liquid chromatography-mass spectrometric (LC/MS) techniques. Two different types of mass spectrometers - a triple-quadrupole (QqQ) and a quadrupole time-of-flight (Q-TOF) mass spectrometer - were utilized to acquire structural information on amlodipine metabolites. The metabolites were produced by incubation of amlodipine with primary cultures of rat hepatocytes. Incubations from rat hepatocytes were analyzed with LC-MS/MS, and 21 phase I and phase II metabolites were detected. Their product ion spectra were acquired and interpreted, and structures were proposed. Accurate mass measurement using LC-Q-TOF was used to determine the elemental composition of metabolites and thus to confirm the proposed structures of these metabolites. Mainly phase I metabolic changes were observed including dehydrogenation of the dihydropyridine core, as well as reactions of side chains, such as hydrolysis of ester bonds, hydroxylation, N-acetylation, oxidative deamination, and their combinations. The only phase II metabolite detected was the glucuronide of a dehydrogenated, deaminated metabolite of amlodipine. We propose several in vitro metabolic pathways of amlodipine in rat, based on our analysis of the metabolites detected and characterized.     

The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action

The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25–30 h, and high micromolar serum concentrations following ingestion of doses of ≥100 mg of the drug. The serum transport protein— 1-acid glycoprotein (AAG)—regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4. The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges similar to those of the parent mifepristone. Thus, the combined pool of mifepristone—plus its metabolites—seems to be responsible for the biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ from those needed in emergency contraception—mifepristone is effective in emergency contraception at a dose of 10 mg, which results in linear pharmacokinetics. However, the ≥200 mg doses of mifepristone needed for optimal abortifacient effects of mifepristone result in saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2–5 mg, respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical arena.     

Health-related quality of life of coronary artery bypass grafting and percutaneous transluminal coronary artery angioplasty patients: 1-year follow-up

OBJECTIVES: The aim of the study was to compare the health-related quality of life (HRQoL) of patients undergoing coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) before the interventions and 6 and 12 months afterward, and to compare their HRQoL also with that of the general population. METHODS: The sample (n = 615) consisted of consecutive coronary artery disease patients treated with elective CABG (n=432) or PTCA (n=183). The baseline data before the treatments were collected by structured interview, the follow-up data mainly by mailed self-administered questionnaires. HRQoL was measured by the 15D. For comparisons, the groups were standardized for differences in socioeconomic and clinical characteristics with a regression analysis. RESULTS: At baseline, the average 15D scores of the patient groups were 0.752 (95 percent confidence interval [CI], 0.743-0.761) in CABG and 0.730 (95 percent CI, 0.716-0.744) in PTCA. After standardization, the difference between the groups was statistically significant but not clinically important. These scores were significantly worse (statistically and clinically) than the score of 0.883 (95 percent CI, 0.871-0.879) in the general population sample matched with the gender and age distribution of the patients. By 6 months, the CABG and PTCA patients had experienced a statistically significant and clinically important improvement to 0.858 (95 percent CI, 0.844-0.872) and 0.824 (95 percent CI, 0.806-0.842), respectively. No significant change took place in either group from 6 to 12 months. CONCLUSIONS: Both CABG and PTCA produces an approximately similar, clinically important improvement in HRQoL in 1-year follow-up.     

Characterization of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-provoked strong and rapid aversion to unfamiliar foodstuffs in rats

A conspicuous but scantly studied feature of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity is avoidance of unfamiliar foodstuffs, which seems to be one of the very few exquisitely sensitive behavioural effects in adult laboratory animals. Here we characterized this peculiar response further after low doses of TCDD. The time-course of the novelty avoidance, the role of nutriment form and dependence of the aversion on the time lag between TCDD exposure and the presentation of a novel food item was determined using rats with different sensitivities to lethality of TCDD. Rats were offered chocolate, liquid nutriment or familiar feed with an unfamiliar texture and the consumptions were measured for varying periods. Aversion to a novel food item (chocolate) emerged within 5.5h after TCDD exposure. A lag of a week or more between TCDD exposure and the presentation of chocolate abolished the avoidance whereas simultaneous presentation of chocolate with TCDD treatment rendered the rats oblivious to the chocolate's presence for over 40 days. Rats avoided also liquid nutriments when these were coupled with TCDD administration but this faded much sooner than chocolate aversion. Even a change in feed texture at the exposure was able to elicit the response. However, habituation was found to interfere with the aversion. These findings indicate that temporal proximity to TCDD exposure is a requisite for the avoidance response which emerges rapidly and may linger on for extended periods, but is not strictly confined to any specific food type. The molecular mechanisms of this tantalizing behavioural alteration remain to be determined.     

Physical ill health and risk of psychosis

Patients with psychosis have been found to suffer from physical illnesses more commonly than the general population. In this report, self-reported physical ill health and its correlates among subjects with and without vulnerability to psychosis in a sample of first-degree relatives, help-seekers and controls were investigated. Perceived physical health was statistically significantly poorer among subjects with minor symptoms on the Structured Interview for Prodromal Symptoms and those vulnerable to psychosis than among those without symptoms measured by 13 somatoform symptom sum scores of the Symptom Checklist-90. Those at current risk of psychosis had a significantly higher mean sum score on the 13 somatic items (mean=21.1) than others (mean=9.6). Having physical symptoms or a self-reported physician-diagnosed illness was significantly associated with vulnerability to psychosis (odds ratio=3.05). The subjects with a mood disorder (odds ratio=4.33) had significantly more commonly physician-diagnosed illnesses than those who had no diagnosis or any other diagnosis. Physical ill health seems to be common among those vulnerable to psychosis.     

Recruitment and treatment practices for help-seeking "prodromal" patients

The prodrome of psychosis has become a target for early identification and for treatments that address both symptoms and risk for future psychosis. Interest and activity in this realm is now worldwide. Clinical trials with rigorous methodology have only just begun, making treatment guidelines premature. Despite the sparse evidence base, treatments are currently applied to patients in the new prodromal clinics, usually treatments developed for established psychosis and modified for the prodromal phase. This communication will describe representative samplings of how treatment-seeking prodromal patients are currently recruited and treated in prodromal clinics worldwide. Recruitment includes how prodromal patients are sought, initially evaluated, apprised of their high-risk status, and informed of the risks and benefits of prodromal treatments and how their mental state is monitored over time. The treatment modalities offered (and described) include engagement, supportive therapy, case management, stress management, cognitive behavioral treatment, family-based treatment, antipsychotic pharmacotherapy, and non-antipsychotic pharmacotherapy. References for details are noted.