Attention to Color: An Analysis of Selection, Controlled Search, and Motor Activation, Using Event-Related Potentials

In this study the organization of information processing in a selective search task was examined by analyzing event-related potentials. This task consisted of searching for target letters in a relevant (attended) color. The ERPs revealed two different effects of attention: an early occipital negativity (+/- 150 ms) reflecting feature-specific attention, and a later, central N2b component (+/- 240 ms) reflecting covert orienting of attention. A later, prolonged negativity (search-related negativity) (+/- 300 ms), maximal at Cz, was related to controlled search to letters in the attended color. Detection of relevant targets resulted in a parietal P3b component. Depending on stimulus presentation conditions an earlier response to both attended and unattended targets was found: an N2 component (+/- 250 ms). In these same conditions, C'3-C'4 asymmetries (Corrected Motor Asymmetries--CMA) suggested motor activation at +/- 300 ms, in the same time range as search-related negativity. It was argued that N2 and CMA suggest the existence of a preattentive target detection system, operating in parallel with a slower serial attentive system, as reflected by N2b and search negativity.     

Characterization of monocyte maturation in adherent and suspension cultures and its application to study monocyte differentiation in Hodgkin's disease.

Monocytes purified with cell scatter monitored counterflow centrifugation were cultured in plastic (adherent) and in teflon culture bags (suspension). Sequential changes were monitored during 15 days by measuring intracellular activity of three enzymes of intermediary metabolism: glucose-6-phosphate dehydrogenase (G-6-PDH), phosphohexose isomerase (PHI) and isocitrate dehydrogenase (ICDH), and the two acid hydrolases: acid phosphatase (ACP) and N-acetyl-beta-glucosaminidase (NAG). In teflon grown macrophages a significantly lower G-6-PDH activity was seen after 15 days in comparison to plastic adherent macrophages (P less than 0.0002). For the other enzymes similar values for both culture modalities were found. The significantly, cycloheximide insensitive, higher values for G-6-PDH, PHI and ICDH in 2 h plastic adherent monocytes in comparison with plastic non-adherent monocytes, suggest a relationship between adherent capacity and the level of intermediary metabolism. The overall yield of plastic adherent macrophages after 15 days was 35% in contrast with 89% for the in suspension cultured macrophages. This corroborates the existence of adherent and non-adherent monocytes, both capable of differentiation in vitro. In 14 patients with advanced Hodgkin's disease (HD) and 14 normal controls, monocyte differentiation was studied applying both culture modalities. The enzyme levels, reflecting growth and intermediary metabolism, were similar for both groups. The adherent capacity and yield, both in teflon and in plastic, after 15 days was comparable for both groups. It was concluded that in vitro monocyte differentiation in the presence of autologous serum was qualitatively and quantitatively normal in advanced HD; this is in favour of an intrinsically normal function of monocytes in HD.     

Mental fatigue and task control: planning and preparation

The effects of mental fatigue on planning and preparation for future actions were examined, using a task switching paradigm. Fatigue was induced by "time on task," with subjects performing a switch task continuously for 2 hr. Subjects had to alternate between tasks on every second trial, so that a new task set was required on every second trial. Manipulations of response-stimulus intervals (RSIs) were used to examine whether subjects prepared themselves for the task change. Behavioral measurements, event-related potentials (ERPs), and mood questionnaires were used to assess the effects of mental fatigue. Reaction times (RTs) were faster on trials in which no change in task set was required in comparison with switch trials, requiring a new task set. Long RSIs were used efficiently to prepare for the processing of subsequent stimuli. With increasing mental fatigue, preparation processes seemed to become less adequate and the number of errors increased. A clear poststimulus parietal negativity was observed on repetition trials, which reduced with time on task. This attention-related component was less pronounced in switch trials; instead, ERPs elicited in switch trials showed a clear frontal negativity. This negativity was also diminished by time on task. ERP differences between repetition and switch trials became smaller with increasing time on task.     

GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum

The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then. This study underscores the broad phenotypic spectrum by presenting two patients with de novo GATA6 mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in/near GATA6 published to date and the associated phenotypes (n = 78). We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty‐eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss‐of‐function as the pathophysiological mechanism. In conclusion, GATA6 mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.     

Reversed diurnal variation in depression: associations with a differential antidepressant response, tryptophan: large neutral amino acid ratio and serotonin transporter polymorphisms

BACKGROUND: Although diurnal variation of mood is a widely recognized symptom of depression, the clinical, neurobiological and psychopharmacological significance of this symptom has not previously been reported. METHOD: A total of 195 depressed out-patients underwent a detailed clinical and neurobiological assessment, and were then randomized to treatment with either fluoxetine or nortriptyline. RESULTS: Of the 195 depressed patients, 62 had a pattern of reversed diurnal variation (i.e. worse in the evening). Those with reversed diurnal variation had a poorer response to a serotonergic anti-depressant, were less likely to have bipolar II disorder, had a higher tryptophan: large neutral amino acid ratio and had different allele frequencies of the polymorphisms in the promoter region of the serotonin transporter. CONCLUSIONS: These findings raise the possibility of serotonergic influence on diurnal variation, and that the symptom of reversed diurnal variation is of relevance to antidepressant prescribing.     

Comparison of the fertilizing capability of spermatozoa from ejaculates, epididymal aspirates and testicular biopsies using intracytoplasmic sperm injection

A prospective study was carried out to compare the fertilizing capability and pregnancy outcome following intracytoplasmic sperm injection (ICSI) using spermatozoa obtained from ejaculates, or surgically from epididymis or seminiferous tubules. A total of 77 ICSI cycles (one per patient) was included. In all, 28 patients had severe oligoasthenoteratozoospermia, 19 patients had obstructive azoospermia and 30 patients had non-obstructive azoospermia. The main outcome measures were fertilization rate per injected metaphase II oocyte and the clinical pregnancy rate per embryo transferred back to the female recipients. In patients with severe oligoasthenoteratozoospermia, the fertilization and pregnancy rates were 79 and 25 %. In patients with obstructive azoospermia, for whom epididymal spermatozoa were used, these were 75 and 28%, and in the non-obstructive group for which testicular spermatozoa were used for injection, they were 69 and 21% respectively. These rates were not significantly different in the three groups (P = 0.85 and P = 0.14 respectively), suggesting that spermatozoa from the ejaculates and epididymal or testicular biopsies are able to fertilize equally by using ICSI. Live birth per embryo transfer was significantly reduced in patients with non-obstructive azoospermia compared to the other two groups. The high abortion rate (50%) in the group in which testicular spermatozoa were used raises doubts about the developmental competence of such embryos.      

Oocyte morphology predicts outcome of intracytoplasmic sperm injection

To examine the influence of cytoplasmic morphology on the success rate of intracytoplasmic sperm injection (ICSI), the morphology of 837 metaphase II oocytes was assessed after cumulus stripping. The main abnormalities detected were excessive granularity, cytoplasmic inclusions such as vacuoles, smooth endoplasmic reticulum clustering and refractile bodies. Microinjection was performed in 538 oocytes with normal cytoplasm, 142 out of 161 with excessive granularity and 112 out of 138 with cytoplasmic inclusions. Very poor oocytes were not injected. No difference was found in fertilization rate. The embryos achieved cleaved normally and a similar number of good quality embryos among the three groups was noted. The outcome of transfer of embryos derived solely from normal oocytes (group A: 72 patients, 183 embryos) was compared with those from oocytes with cytoplasmic abnormalities (group B: 34 patients, 85 embryos). In group A, 17 clinical pregnancies (24% per patient, implantation rate 10%) were established. In group B, only one clinical pregnancy (3% per patient, implantation rate 1%) was established, from the transfer of embryos derived from oocytes with homogeneous granularity of the cytoplasm. No pregnancy resulted following the transfer of embryos from eggs with cytoplasmic inclusions. The difference was statistically significant. The outcome of ICSI is dependent on the quality of the oocytes retrieved. Normal fertilization and early embryo development were achieved in oocytes with abnormal cytoplasm morphology, but the resulting embryos failed to demonstrate the same implantation potential as those derived from oocytes with normal cytoplasm.      

Interleukin-2 activated NK cells do not use the CD95L- and TRAIL-pathways in the rapid induction of apoptosis of rat colon carcinoma CC531s cells

Natural Killer (NK) cells can induce apoptosis in target cells in at least four ways: by secretion of granzyme B/perforin (GrB/P) and via the CD95L, TRAIL and TNF-α pathways. In this study we examined the pathways used by interleukin-2 activated rat NK (A-NK) cells to induce apoptosis in the rat colon carcinoma cell line CC531s. Co-incubation of A-NK cells with CC531s cells for three hours resulted in 70% apoptosis in the latter. Addition of the GrB/P pathway-inhibitor concanamycin A reduced the number of apoptotic cells to 54%. Blockade of the CD95L, TRAIL and TNF-α pathways by specific antibodies hardly had an additional effect. However, co-incubation with transfected MEC cells that expressed CD95L or 2PK3-cells that expressed TRAIL did induce apoptosis in CC531s cells. Furthermore the A-NK cells contained CD95L and TRAIL. However, comparison of non- and permeabilized cells revealed that the majority of TRAIL was present in the cytosol of A-NK cells and was not available for induction of apoptosis. The presence of elevated levels of bcl-2 in CC531 cells reduced the sensitivity towards induction of apoptosis both by A-NK cells as well as the CD95L and TRAIL expressing cell lines. Using the caspase-inhibitors ac-IEPD-CHO, ac-DEVD-CHO and zVAD-fmk, it was shown that inhibition of the effector caspase-3 prevented A-NK cell induced apoptosis in CC531-bcl-2 cells, but not in CC531s cells. In conclusion, A-NK cells kill by secretion of GrB/P and not by the CD95L, TRAIL or TNF pathways albeit both CD95L and TRAIL are produced by the A-NK cells.