Hepatic Disposition Characteristics of Electrically Charged Macromolecules in Rat in Vivo and in the Perfused Liver

The effect of electric charge on the hepatic disposition of macromolecules was studied in the rat. Charged derivatives of dextran (T-70) and bovine serum albumin (BSA), mitomycin C–dextran conjugates (MMC-D), and lactosaminated BSA (Lac-BSA) were employed as model macromolecules. After intravenous injection, cationic macromolecules were rapidly eliminated from plasma because of their extensive hepatic uptake, while anionic and neutral macromolecules were slowly eliminated. Cationic macromolecules were recovered from parenchymal and nonparenchymal hepatic cells at a cellular uptake (per unit cell number) ratio of 1.4–3.2, while that of Lac-BSA was 14. During liver perfusion using a single-pass constant infusion mode, cationic macromolecules were continuously extracted by the liver, with extraction ratios at steady-state (E _ss) ranging between 0.03 and 0.54, whereas anionic and neutral macromolecules were almost completely recovered in the outflow at steady state. The E _ss for cationized BSA (Cat-BSA) and cationic MMC-Dcat were concentration dependent and decreased at low temperatures and in the presence of colchicine and cytochalasin B. The possible participation of the internalization process in the uptake of cationic macromolecules by hepatocytes was suggested.     

Can gaze-cueing be helpful for detecting sound in autism spectrum disorder?

Autism spectrum disorder (ASD) is a developmental disorder characterized by impaired social interaction, including joint attention, but psychological studies generally have reported intact gaze-triggered joint attention in ASD. These studies used a uni-modal paradigm (i.e. visual cue–target pairs) with eyes or faces as cues and letters or dots as targets. However, it has not been determined whether joint attention is impaired under cross-modal conditions in ASD, although cross-modal impairment has been reported. This study investigated joint attention in ASD under cross-modal conditions with gaze stimuli as visual cues and two kinds of sound (social voice or non-social tone) stimuli as targets. The task for the subject was to locate the target sound and click as soon and as accurately as possible. The ASD group was impaired in joint attention when a tone was used as the target, while both groups showed joint attention to a voice. The results suggest that cross-modal joint attention is impaired in the ASD group when the cue–target relationship is weak (i.e. social cue and non-social target) while it is unimpaired when there is a strong cue–target relationship (i.e. social cue and social target).     

A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis

The potential therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL-12p40) has been established both in vitro and in vivo, warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3% body surface area involvement were enrolled in four dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75% improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.     

Facial affect recognition in pre-lingually deaf people with schizophrenia

The present study examined facial affect recognition in pre-lingually deaf individuals with schizophrenia. Affective facial-labeling task and the control task of face feature processing (the Benton facial recognition test) were performed by deaf subjects with schizophrenia using French sign language (FSL), hearing subjects with schizophrenia, and hearing healthy controls. Deaf subjects with schizophrenia performed more poorly than hearing clinical controls with schizophrenia or healthy controls on the affective facial-labeling task. No differences were found on the control task between deaf subjects with schizophrenia and hearing clinical or healthy controls. The results showed that facial affect recognition and face feature processing were differently impaired in pre-lingually deaf individuals with schizophrenia, suggesting that neurocognitive backgrounds of impaired affective facial processing may be distinct from those of general impairment in face processing.     

Frontal midline theta rhythm is correlated with cardiac autonomic activities during the performance of an attention demanding meditation procedure

Frontal midline theta rhythm (Fm theta), recognized as distinct theta activity on EEG in the frontal midline area, reflects mental concentration as well as meditative state or relief from anxiety. Attentional network in anterior frontal lobes including anterior cingulate cortex is suspected to be the generator of this activity, and the regulative function of the frontal neural network over autonomic nervous system (ANS) during cognitive process is suggested. However no studies have examined peripheral autonomic activities during Fm theta induction, and interaction of central and peripheral mechanism associated with Fm theta remains unclear. In the present study, a standard procedure of Zen meditation requiring sustained attention and breath control was employed as the task to provoke Fm theta, and simultaneous EEG and ECG recordings were performed. For the subjects in which Fm theta activities were provoked (six men, six women, 48% of the total subjects), peripheral autonomic activities were evaluated during the appearance of Fm theta as well as during control periods. Successive inter-beat intervals were measured from the ECG, and a recently developed method of analysis by Toichi et al. (J. Auton. Nerv. Syst. 62 (1997) 79-84) based on heart rate variability was used to assess cardiac sympathetic and parasympathetic functions separately. Both sympathetic and parasympathetic indices were increased during the appearance of Fm theta compared with control periods. Theta band activities in the frontal area were correlated negatively with sympathetic activation. The results suggest a close relationship between cardiac autonomic function and activity of medial frontal neural circuitry.     

Hepatic Disposition Characteristics of 111In-Labeled Lactosaminated Bovine Serum Albumin in Rats

The hepatic disposition of lactosaminated bovine serum albumin (Lac-BSA) in rats was studied at the whole body, isolated liver, and isolated parenchymal cell levels. After intravenous injection, ¹¹¹In-Lac-BSA (1 mg/kg) was rapidly eliminated from the plasma due to extensive uptake by liver parenchymal cells; however, a significant decrease in hepatic clearance was observed at high dose (50 mg/kg). In a single-pass, constant infusion experiment in the isolated liver, ¹¹¹In-Lac-BSA was continuously extracted. The extraction ratio at steady state (E_ss) for ¹¹¹In-Lac-BSA was significantly decreased by coadministrating galactose, NH₄Cl, or chloroquine, and at low temperature, suggesting that hepatic uptake of Lac-BSA proceeds via receptor-mediated endocytosis for asialoglycoprotein. Kinetic analysis of ¹¹¹In-Lac-BSA binding with isolated parenchymal cells at 4°C yielded a dissociation constant (K_d) of 2.5 ×10^–8M and a value of 3.5 × 10⁵ maximal binding sites/cell (B_max). The internalization rate constant (k_int) for ¹¹¹In-Lac-BSA was calculated to be 0.46 min^–l in liver perfusion experiments using the EDTA-wash method.     

Rapid amygdala gamma oscillations in response to fearful facial expressions

Neuroimaging studies have reported greater activation of the human amygdala in response to emotional facial expressions, especially for fear. However, little is known about how fast this activation occurs. We investigated this issue by recording the intracranial field potentials of the amygdala in subjects undergoing pre-neurosurgical assessment (n = 6). The subjects observed fearful, happy, and neutral facial expressions. Time-frequency statistical parametric mapping analyses revealed that the amygdala showed greater gamma-band activity in response to fearful compared with neutral facial expressions at 50-150 ms, with a peak at 135 ms. These results indicate that the human amygdala is able to rapidly process fearful facial expressions.     

The specific impairment of fearful expression recognition and its atypical development in pervasive developmental disorder

Several studies have examined facial expression recognition in pervasive developmental disorder (PDD), including autism and Asperger's disorder, but the results have been inconsistent. We investigated the relationship between facial expression recognition and age, face recognition, and symptom severity. Subjects were 28 individuals with mild PDD subtypes and 28 age- and gender-matched controls. Among six emotions, fearful expression recognition was specifically impaired in PDD subjects. Age had positive effects on fearful expression recognition directly and indirectly via the development of face recognition in controls, but not in PDD subjects. Furthermore, fearful expression recognition was related to the severity of PDD symptoms. We conclude that individuals with PDD show an atypical development of facial expression recognition. Moreover, impaired fearful expression recognition is closely related to social dysfunction.