The relationship between trauma and beliefs about hearing voices: a study of psychiatric and non-psychiatric voice hearers.

BACKGROUND: Cognitive models suggest that distress associated with auditory hallucinations is best understood in terms of beliefs about voices. What is less clear is what factors govern such beliefs. This study aimed to explore the way in which traumatic life events contribute towards beliefs about voices and any associated distress. METHOD: The difference in the nature and prevalence of traumatic life events and associated psychological sequelae was compared in two groups of voice hearers: psychiatric voice hearers with predominantly negative beliefs about voices (PVH) and non-psychiatric voice hearers with predominantly positive beliefs about voices (NPVH). The data from the two groups were then combined in order to examine which factors could significantly account for the variance in beliefs about voices and therefore levels of distress. RESULTS: Both groups reported a high prevalence of traumatic life events although significantly more PVH reported trauma symptoms sufficient for a diagnosis of post-traumatic stress disorder (PTSD). Furthermore, significantly more PVH reported experiencing childhood sexual abuse. Current trauma symptoms (re-experiencing, avoidance and hyperarousal) were found to be a significant predictor of beliefs about voices. Trauma variables accounted for a significant proportion of the variance in anxiety and depression. CONCLUSIONS: The results suggest that beliefs about voices may be at least partially understood in the context of traumatic life events.

CDDO induces apoptosis via the intrinsic pathway in lymphoid cells.

The peroxisome-proliferator-activated receptor (PPAR) gamma agonist, CDDO, is under investigation for use in various malignancies. The mechanisms by which CDDO induces apoptosis are controversial. We have therefore sought to determine these mechanisms using primary chronic lymphocyte leukemic (CLL) cells and Jurkat cell lines with defined apoptotic abnormalities. In these cells, CDDO induced-apoptosis involved caspase-independent loss in mitochondrial membrane potential followed by caspase processing. The pattern of CDDO-induced caspase processing, defined by use of a caspase inhibitor, strongly suggested that caspase-9 was the apical caspase. Moreover, CDDO induced apoptosis in caspase-8 and FADD-deficient but not in Bcl-xL overexpressing Jurkat cells. In CLL cells, CDDO induced an early release of mitochondrial cytochrome c and Smac that preceded apoptosis. Thus, in both cell types, CDDO induced apoptosis primarily by the intrinsic pathway with caspase-9 as the apical caspase. This has important implications in the design of novel agents for the treatment of CLL and other malignancies.

Bisindolylmaleimide IX is a potent inducer of apoptosis in chronic lymphocytic leukaemic cells and activates cleavage of Mcl-1.

New agents are required for the treatment of chronic lymphocytic leukaemia (CLL). We show here that a protein kinase C inhibitor, bisindolylmaleimide IX, is a potent inducer of apoptosis in CLL cells, and investigate the mechanisms by which this is induced. Bisindolylmaleimide IX induced a conformational change and subcellular redistribution of Bax from the cytosol to the mitochondria, resulting in the release of the proapoptotic mediators cytochrome c, Smac and Omi/HtrA2 from the mitochondrial inner membrane space. This was followed by the activation of caspase-9 as the apical caspase and subsequent activation of effector caspases. CLL cells undergoing apoptosis showed a rapid caspase-mediated cleavage of Mcl-1, an antiapoptotic member of the Bcl-2 family implicated in CLL survival and poor prognosis. This cleavage was mediated primarily by caspase-3. Cleavage of Mcl-1 may provide a feed-forward amplification loop, resulting in the rapid induction of apoptosis. Bisindolylmaleimide IX or a related derivative may be of clinical use in the treatment of CLL.

Psychophysical characterisation of early functional loss in glaucoma and ocular hypertension.

AIM: The psychophysical evaluation of selective cell loss in early glaucoma and ocular hypertension. METHODS: Contrast sensitivity was measured for the detection of luminance modulated gratings at a range of spatial (0.5, 2, 8 c/deg) and temporal (0, 16 Hz) frequency combinations in three groups of age matched patients (primary open angle glaucoma, ocular hypertension, normal controls; n=16). Stimuli of 5 degrees were presented foveally and at 15 degrees along the nasal horizontal meridian under photopic conditions. RESULTS: Fovea: Compared to the normal group, the thresholds for the glaucoma patients were significantly elevated at all spatial and temporal frequencies (p<0.0001), but this reduction was not significantly different at any particular spatial or temporal frequency (p>0.1). There was no difference in contrast sensitivity between the normals and OHTs (p>0.10). Periphery: The thresholds of the glaucoma patients were elevated compared to the normal controls (p<0.01). The loss of sensitivity was slightly greater at the higher spatial frequencies for both stationary and flickering patterns but this did not reach significance (p=0.09). The contrast sensitivity in normal and OHT groups was not significantly different (p>0.10). CONCLUSIONS: In early glaucoma, the reduction in contrast sensitivity to stimuli which isolate the magnocellular pathway (0.5 c/deg, 16 Hz) was not significantly different compared with the reduction in contrast sensitivity to stimuli that isolate the parvocellular pathway. These findings are not consistent with the hypothesis that the magnocellular pathway is selectively damaged in early glaucoma.

Glaucoma: squaring the psychophysics and neurobiology.

Advances in our understanding of the pathophysiology of retinal ganglion cell death in glaucoma are providing important insights into the functional changes occurring in retinal ganglion cells in the early stages of the disease. These exciting new findings may help us develop psychophysical tests to monitor early retinal ganglion cell damage, possibly before neurons are committed to the process of cell death.

Visuospatial attention: the role of target contrast and task difficulty when assessing the effects of cues.

Cueing paradigms have become popular in assessing the processes of attention. In two experiments we manipulated (i) the contrast of the target, and (ii) the similarity between the targets discriminated. We used a cue that would isolate the exogenous component of attention. Both a reduction in target contrast and an increase in target similarity raised overall reaction times by a similar amount; however, the target contrast manipulation produced a much greater cueing effect compared with the target similarity manipulation. The results suggest that manipulation of target contrast changes the attention cueing effect at a stage of attracting attention to a location of the target (the 'move' stage), rather than at a later processing stage.

Context dependent latent inhibition in adult humans.

Learning the association between one stimulus (a condition stimulus, CS) and another (unconditioned stimulus, US) can be impaired by prior exposure to the CS alone--latent inhibition (LI). Current theories attempting to elucidate the cognitive deficit in schizophrenia have used the abolition of LI in schizophrenia as an indicator of attentional dysfunction. However, it has always been unclear if human and animal LI are measuring the same psychological processes. It is obviously important to clarify this relationship so that theoretical and experimental developments in the rat do not mislead the investigation of brain-behaviour relationships in schizophrenia. LI in the rat is strongly dependent upon context. Our aim was to examine the context specificity of LI in humans and specifically to: (1) investigate whether participants' belief that they are in a different context is sufficient to abolish LI, even though there is no physical change in the environment; (2) produce a context manipulation that is immune to alternative interpretation in terms of stimulus generalization decrement; and (3) investigate whether a "tonic" change of context reduces or abolishes human LI, thus complementing previous reports using a "phasic" change of context. In two experiments we manipulated context in either the real world or a virtual world, and showed that LI is abolished by a change of context in adult humans.

Identification of visual stimuli is improved by accompanying auditory stimuli: the role of eye movements and sound location.

Can auditory signals influence the processing of visual information? The present study examined the effects of simple auditory signals (clicks and noise bursts) whose onset was simultaneous with that of the visual target, but which provided no information about the target. It was found that such a signal enhances performance in the visual task: the accessory sound reduced response times for target identification with no cost to accuracy. The spatial location of the sound (whether central to the display or at the target location) did not modify this facilitation. Furthermore, the same pattern of facilitation was evident whether the observer fixated centrally or moved their eyes to the target. The results were not altered by changes in the contrast (and therefore visibility) of the visual stimulus or by the perceived utility of the spatial location of the sound. We speculate that the auditory signal may promote attentional 'disengagement' and that, as a result, observers are able to process the visual target sooner when sound accompanies the display relative to when visual information is presented alone.

Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex.

Proteasome inhibitors, including lactacystin and MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal), potently induce apoptosis in leukaemic B cells from patients with B cell chronic lymphocytic leukaemia (B-CLL). This pro-apoptotic effect occurs in cells from patients at all stages of the disease, including those resistant to conventional chemotherapy, suggesting that proteasome inhibitors may be useful for treatment of B-CLL. Following initial inhibition of proteasomal activity, these agents induce mitochondrial cytochrome c release and caspase-dependent apoptosis, involving cleavage/activation of caspases -2, -3, -7, -8 and -9. Pre-treatment with the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe)fluoromethyl ketone (Z-VAD.fmk), did not prevent the release of cytochrome c or partial processing of caspase-9 but prevented activation of effector caspases and the induction of apoptosis. These results suggest that the release of cytochrome c is caspase independent and that caspase-9 is the initiator caspase in proteasome inhibitor-induced apoptosis of B-CLL cells. Activation of B-CLL lysates with dATP results in the formation of an approximately 700 kDa caspase-activating apoptosome complex containing Apaf-1. We describe for the first time the formation of a similar approximately 700 kDa caspase-activating apoptosome complex in B-CLL cells induced to undergo apoptosis by proteasome inhibitors.

Superficial leiomyosarcoma of the head and neck: case report and review of the literature.

Superficial leiomyosarcomas are rare in the head and neck region. Because of the infrequent nature of soft tissue sarcomas in general, superficial leiomyosarcomas are often misdiagnosed on clinical grounds. Immunohistochemistry is essential for an accurate histologic diagnosis, and it should include a broad panel of antibody studies. With respect to differences in clinical appearance and biologic behavior, superficial leiomyosarcomas can be broadly classified as either cutaneous or subcutaneous; local control and overall survival are significantly more favorable in patients with the former. The primary treatment of a leiomyosarcoma is a wide surgical excision with an emphasis on negative margins. Treatment failures are usually attributable to a local recurrence. Systemic metastasis occurs in about one-third of patients with subcutaneous involvement. Although cutaneous leiomyosarcoma is considered a relatively more benign process with minimal metastatic potential, systemic metastasis is still possible. This was demonstrated in our case, as a recurrent cutaneous leiomyosarcoma metastasized to the lung. Proper management requires inclusion of this entity in the differential diagnosis, as well as familiarity with its clinical behavior. In this article, we review the literature on superficial leiomyosarcoma and discuss its epidemiology, presentation, clinical behavior, evaluation, tissue diagnosis, staging, and treatment.

Contrast gain mechanism or transient channel? Why the effects of a background pattern alter over time.

If a brief test pulse is presented on a prolonged background pedestal, it is strongly masked if presented at the start of the pedestal, and is only weakly masked if presented 200 ms after the start. This has been suggested to occur due to contrast gain mechanisms that reduce the representation of the pedestal and therefore reduce its masking effects. We show here that the effect is due to the large transient in contrast that accompanies the onset of the pedestal. We find similar masking at pedestal offset, when the pedestal is continually flickered, or when pedestal and test have a high spatial frequency. These results were all predicted on the basis of sustained and transient channels.

The predictive value of serum interleukins in recurrent respiratory papillomatosis: a preliminary study.

OBJECTIVE: IL-2 is the primary interleukin responsible for activation of the cell-mediated (Th1) arm of the immune response. Our objective was to determine whether a correlation existed between circulating levels of interleukin-2 as well as its soluble receptor (sIL-2R) and the clinical course of recurrent respiratory papillomatosis. METHODS AND MATERIALS: Fifteen children with a histological diagnosis of RRP were recruited. Age at the time of study, time since first diagnosis, and number of surgical interventions were recorded. The number of surgically treated recurrences per year was then calculated. We obtained serum samples from each of these 15 children and from 10 normal control subjects. We then performed in vitro determination of serum IL-2 and soluble IL-2 receptor levels using enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: IL-2 was significantly lower (136.6 vs. 199.9 pg/mL, P =.035) in papilloma patients than in control subjects. IL-2R was also lower in papilloma patients (531.7 vs. 785.8 U/mL, P =.025). There was no statistical age difference between the papilloma and control groups. Among patients with papillomatosis, IL-2 and sIL-2R levels were significantly higher in those with aggressive disease (>4 surgically treated recurrences per year) versus non-aggressive disease (179.2 vs. 99.2 pg/mL, P =.024; and 697 vs. 387 U/mL, P =.022). Age was also significantly lower in the aggressive papilloma group (P =.002). CONCLUSIONS: Levels of interleukin-2 and IL-2 receptor were significantly lower in patients with recurrent respiratory papillomatosis compared with normal children. These data support the presence of an aberrant cell-mediated immune response in children with recurrent respiratory papillomatosis.

Textured backgrounds alter perceived speed.

Both the luminance contrast of an object, and the nature of the background texture over which it moves, are known to influence its perceived speed. In this study the effect of object contrast upon perceived speed was investigated for targets moving across textured patterns of various contrasts. Experiment 1 showed a strong effect of contrast for objects moving over homogenous backgrounds, that was reduced or abolished if the object moved over a textured background. A further experiment suggested that this reduction may be the result of an increase in target visibility, perhaps as a result of additional 'second order' motion signals produced by motion over texture backgrounds. A final experiment suggested that two processes were occurring: (1) higher contrast backgrounds appeared to increase the perceived speeds of all objects; and (2) that higher contrast backgrounds eliminated the contrast induced changes in perceived speed.

Attention to overlapping objects: detection and discrimination of luminance changes.

Selective attention to 1 of 2 overlapping objects was assessed in a cuing paradigm. Participants detected or identified targets that appeared in 1 of 6 possible target locations (3 on each object). Significant cuing effects for the simple detection of such targets using both reaction time and sensitivity measures of performance were found. Cuing effects were consistently greater when the participants were required to identify some aspect of the target even when the tasks (detection vs. identification) were equated for overall performance level. These differences in cuing effects between tasks were much reduced if the target locations were no longer grouped into 2 objects. It is suggested that identical stimuli can elicit differing attentional mechanisms depending on task type (rather than task difficulty) and that these mechanisms differ in the nature of the representation of the visual world.

Can one pay attention to a particular color?

In an array of elements whose colors vary can we selectively choose to process all the items of a particular color preferentially in relation to those of another color? We addressed this question by presenting subjects with arrays containing many elements, and recording reaction times to a luminance change of one of the elements. Half the elements had one color and the other half another color--the spatial distribution being random. In two tasks--a simple detection of this change or a choice reaction time to the polarity of the change--we found that reaction times were independent of the number of items in the array. Cuing the subjects as to the color of the target item had no significant influence on the detection task, but subjects were faster if cued for the discrimination task. A further experiment replicated these findings and examined possible costs and benefits. Our final experiment separated the roles of attentional guidance and postattentional processes by having subjects judge the orientation of the target element and varying the magnitude of the target flash that defined which element was the target. We found that this judgment was also affected by color cuing, and that the size of the effect interacted with the flash strength, suggesting that color cuing has its influence at the stage of attentional guidance. We conclude that subjects can selectively attend to items on the basis of color given the appropriate task and stimulus dynamics.

Caspases-3 and -7 are activated in goniothalamin-induced apoptosis in human Jurkat T-cells.

Goniothalamin, a plant styrylpyrone derivative isolated from Goniothalamus andersonii, induced apoptosis in Jurkat T-cells as assessed by the externalisation of phosphatidylserine. Immunoblotting showed processing of caspases-3 and -7 with the appearance of their catalytically active large subunits of 17 and 19 kDa, respectively. Activation of these caspases was further evidenced by detection of poly(ADP-ribose) polymerase cleavage (PARP). Pre-treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD.FMK) blocked apoptosis and the resultant cleavage of these caspases and PARP. Our results demonstrate that activation of at least two effector caspases is a key feature of goniothalamin-induced apoptosis in Jurkat T-cells.

Impact of acute epinephrine removal on hepatic glucose metabolism during stress hormone infusion.

We examined the effect of acute discontinuation of an epinephrine (EPI) infusion on hepatic glucose metabolism during stress hormone infusion (SHI). Glucose metabolism was assessed in 11 conscious, 20-hour fasted dogs using tracer and arteriovenous techniques after a 3-day exposure to SHI. SHI increased EPI, norepinephrine, cortisol, and glucagon levels (approximately sixfold to 10-fold), which led to marked hyperglycemia, hyperinsulinemia, and accelerated glucose metabolism. On day 3, EPI infusion was acutely discontinued for 180 minutes in five dogs while infusion of the other hormones was continued (SHI - EPI). In the remaining six dogs, all hormones were continued for the duration of the study (SHI + EPI). In SHI - EPI, EPI levels decreased from 1,678+/-191 to 161+/-47 pg/mL. Isoglycemia (183+/-10 to 185+/-15 mg/dL) was maintained with an exogenous glucose infusion. Arterial insulin levels increased from 41+/-8 to 64+/-8 microU/mL. Whole-body glucose utilization increased from 3.5+/-0.5 to 9.4+/-1.9 mg/kg/min. Nonesterified fatty acids ([NEFAs] 763+/-292 to 147+/-32 micromol/L) decreased. Net hepatic glucose output decreased (2.6+/-0.6 to 0.1+/-0.3 mg/kg/min). In SHI + EPI, hepatic glucose metabolism remained unaltered. In summary, EPI plays a pivotal role during SHI by stimulating glucose production and inhibiting glucose utilization. In part, these effects are mediated by restraining pancreatic insulin secretion.

Colour and polarity contributions to global motion perception.

The influence of the image segmentation cues based on colour and polarity on a motion coherence task were examined. In line with previous reports, when the signal and noise were given unique identities thresholds were much lower than when they were the same, suggesting a strong influence of segmentation. In another paradigm extra noise elements that differed in colour or polarity interfered despite this perceptual segmentation. We suggest that the results when signal and noise have unique identities are attributable to the subjects' ability to attend to a particular location(s) in space. When this strategy was eliminated by presenting the stimuli in the near-periphery or very briefly the effect of the colour or polarity information disappears.

Visual perception: here's mud in your mind's eye.

We appear to be unaware of large changes in our visual scene if our attention is temporarily diverted. This suggests that the rich, complete visual scene that we appear to have may be just an illusion.

Personal hormone monitoring for contraception.

OBJECTIVE: To determine the effectiveness and acceptability of personal hormone monitoring for contraception. DESIGN: A large prospective study was carried out on personal hormone monitoring for contraception when used with abstinence during the identified fertile days. SETTING: Three country study under the auspices of the departments of Obstetrics and Gynaecology of the Universities of Birmingham, Dublin and Dusseldorf SUBJECTS: Seven hundred and ten women, median age 30, were recruited from the general population. They were required to have regular menstrual cycles (23-35 days) and to be delaying their next pregnancy. INTERVENTIONS: Personal hormone monitoring consists of a hand held monitor and disposable test sticks which measure changes in urinary concentrations of oestrone-3-glucuronide and luteinising hormone. An algorithm estimated the fertile days which were displayed by a red light. OUTCOME MEASURES AND RESULTS: One hundred and sixty two pregnancies occurred in 7209 cycles of use, of which 67 were method related pregnancies. The 13 cycle life-table method pregnancy rate (95 per cent CI) was 12. 1 per cent (9.3-14.8). The system allowed analysis of the effect of changes to the algorithm to modify the defined fertile period. As a result the algorithm was changed to increase the median warning of the luteinising hormone surge to six days. With the revised algorithm, half of the method pregnancies would have been prevented giving a calculated method pregnancy rate of 6.2 per cent (4.2-8.3) and method efficacy of 93.8 per cent. The continuation rate after 13 cycles was 78 per cent. CONCLUSION: Personal hormone monitoring proved simple to use and will be of value to women who do not want to use other methods of contraception.

PIP: A newly developed personal system of hormone monitoring allows the rapid assay of estrone-3-glucuronide (EG) and luteinizing hormone (LH) in urine to determine the fertile period. The Persona system consists of disposable test sticks to measure EG and LH concentrations in early morning urine and a hand-held monitor that indicates by the use of red and green lights the fertile and infertile phases of the cycle. The monitor stores information for the previous 6 cycles and adapts to the individual user's patterns. The effectiveness of this regimen when used with abstinence during the identified fertile period was investigated in a prospective population-based study conducted in the UK, Ireland, and Germany. 710 women (median age, 30 years) with regular menstrual cycles were enrolled. The continuation rate after 13 cycles was 78%. 162 pregnancies occurred in 7209 cycles of use, 67 of which were method-related. The 13-cycle life-table method pregnancy rate was 12.1% (95% confidence interval (CI), 9.3-14.8%). As a result of these findings, the algorithm was changed to increase the median warning of the LH surge from 4 to 6 days. Had this revised algorithm been used, the method pregnancy rate would have been reduced to 6.2% (95% CI, 4.2-8.3%) and method efficacy increased to 93.8%. The total efficacy rate compares favorably with pregnancy rates in women using other nonhormonal methods of fertility control. Women with cycle lengths of 23-35 days can expect to be required to abstain from intercourse for 6-12 days each cycle.