The need for an effective malaria vaccine is great, and the current lead strategy undergoing advanced testing is based on the use of the circumsporozoite protein. In this early-stage investigation, ...the authors followed a different strategy, using an attenuated
Plasmodium falciparum
sporozoite vaccine based on the NF54 strain, delivered through mosquito bites. This vaccine was found to protect against a homologous challenge.
In this early-stage investigation, the authors used an attenuated Plasmodium falciparum sporozoite vaccine based on the NF54 strain, delivered through mosquito bites. This vaccine was found to protect against a homologous challenge.
Malaria is responsible for a significant burden of morbidity and mortality in the developing world, and an effective vaccine against this disease is urgently needed.
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Despite decades of research, a licensed vaccine is still not available, largely because immunity to
Plasmodium falciparum
malaria is considered difficult to acquire, whether through natural exposure or artificially through vaccination. A further critical factor is our incomplete understanding of precisely what constitutes protective antimalarial immunity in humans.
The possibility of vaccinating humans against
P. falciparum
malaria was raised originally by the success of the radiation-attenuated sporozoite model developed several decades ago.
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Irradiation of . . .
Volunteers immunized under chloroquine chemoprophylaxis with Plasmodium falciparum sporozoites (CPS) develop complete, long-lasting protection against homologous sporozoite challenge. Chloroquine ...affects neither sporozoites nor liver-stages, but kills only asexual forms in erythrocytes once released from the liver into the circulation. Consequently, CPS immunization exposes the host to antigens from both preerythrocytic and blood stages, and induced immunity might target either of these stages. We therefore explored the life cycle stage specificity of CPS-induced protection. Twenty-five malaria-naïve volunteers were enrolled in a clinical trial, 15 of whom received CPS immunization. Five immunized subjects and five controls received a sporozoite challenge by mosquito bites, whereas nine immunized and five control subjects received an i.v. challenge with P. falciparum- infected erythrocytes. The latter approach completely bypasses preerythrocytic stages, enabling a direct comparison of protection against either life cycle stage. CPS-immunized subjects (13 of 14) developed anticircumsporozoite antibodies, whereas only one volunteer generated minimal titers against typical blood-stage antigens. IgG from CPS-immunized volunteers did not inhibit asexual blood-stage growth in vitro. All CPS-immunized subjects (5 of 5) were protected against sporozoite challenge. In contrast, nine of nine CPS-immunized subjects developed parasitemia after blood-stage challenge, with identical prepatent periods and blood-stage multiplication rates compared with controls. Intravenously challenged CPS-immunized subjects showed earlier fever and increased plasma concentrations of inflammatory markers D-dimer, IFN-γ, and monokine induced by IFN-γ than i.v. challenged controls. The complete lack of protection against blood-stage challenge indicates that CPS-induced protection is mediated by immunity against preerythrocytic stages. However, evidence is presented for immune recognition of P. falciparum -infected erythrocytes, suggesting memory responses unable to generate functional immunity.
Summary Background We have shown that immunity to infection with Plasmodium falciparum can be induced experimentally in malaria-naive volunteers through immunisation by bites of infected mosquitoes ...while simultaneously preventing disease with chloroquine prophylaxis. This immunity was associated with parasite-specific production of interferon γ and interleukin 2 by pluripotent effector memory cells in vitro. We aim to explore the persistence of protection and immune responses in the same volunteers. Methods In an open-label study at the Radboud University Nijmegen Medical Centre (Nijmegen, Netherlands), from November to December, 2009, we rechallenged previously immune volunteers (28 months after immunisation) with the bites of five mosquitoes infected with P falciparum . Newly recruited malaria-naive volunteers served as infection controls. Our primary outcome was the detection of blood-stage parasitaemia by microscopy. We assessed the kinetics of parasitaemia with real-time quantitative PCR (rtPCR) and recorded clinical signs and symptoms. In-vitro production of interferon γ and interleukin 2 by effector memory T cells was studied after stimulation with sporozoites and red blood cells infected with P falciparum . Differences in cellular immune responses between the study groups were assessed with the Mann-Whitney test. This study is registered with ClinicalTrials.gov , number NCT00757887. Findings Four of six immune volunteers were microscopically negative after rechallenge. rtPCR-based detection of blood-stage parasites in these individuals was negative throughout follow-up. Patent parasitaemia was delayed in the remaining two immunised volunteers. In-vitro assays showed the long-term persistence of parasite-specific pluripotent effector memory T-cell responses in protected volunteers. The four protected volunteers reported several mild to moderate adverse events, of which the most commonly reported symptom was headache (one to three episodes per volunteer). The two patients with delayed patency had adverse events similar to those in the control group. Interpretation Artificially induced immunity lasts longer than generally recorded after natural exposure; providing a new avenue of research into the mechanisms of malaria immunity. Funding Dioraphte Foundation.
A 20 year-old healthy female volunteer participated in a clinical Phase I and IIa safety and efficacy trial with candidate malaria vaccine PfLSA-3-rec adjuvanted with aluminium hydroxide. Eleven ...weeks after the third and last immunization she was experimentally infected by bites of Plasmodium falciparum-infected mosquitoes. When the thick blood smear became positive, at day 11, she was treated with artemether/lumefantrine according to protocol. On day 16 post-infection i.e. two days after completion of treatment, she woke up with retrosternal chest pain. She was diagnosed as acute coronary syndrome and treated accordingly. She recovered quickly and her follow-up was uneventful. Whether the event was related to the study procedures such as the preceding vaccinations, malaria infection or antimalarial drugs remains elusive. However, the relation in time with the experimental malaria infection and apparent absence of an underlying condition makes the infection the most probable trigger. This is in striking contrast, however, with the millions of malaria cases each year and the fact that such complication has never been reported in the literature. The rare occurrence of cardiac events with any of the preceding study procedures may even support a coincidental finding. Apart from acute coronary syndrome, myocarditis can be considered as a final diagnosis, but the true nature and patho-physiological explanation of the event remain unclear.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients with schizophrenia often experience problems regulating their emotions. Non-affected relatives show similar difficulties, although to a lesser extent, and the neural basis of such ...difficulties remains to be elucidated. In the current paper we investigated whether schizophrenia patients, non-affected siblings and healthy controls (HC) exhibit differences in brain activation during emotion regulation.
All subjects (n = 20 per group) performed an emotion regulation task while they were in an fMRI scanner. The task contained two experimental conditions for the down-regulation of emotions (reappraise and suppress), in which IAPS pictures were used to generate a negative affect. We also assessed whether the groups differed in emotion regulation strategies used in daily life by means of the emotion regulation questionnaire (ERQ).
Though the overall negative affect was higher for patients as well as for siblings compared to HC for all conditions, all groups reported decreased negative affect after both regulation conditions. Nonetheless, neuroimaging results showed hypoactivation relative to HC in VLPFC, insula, middle temporal gyrus, caudate and thalamus for patients when reappraising negative pictures. In siblings, the same pattern was evident as in patients, but only in cortical areas.
Given that all groups performed similarly on the emotion regulation task, but differed in overall negative affect ratings and brain activation, our findings suggest reduced levels of emotion regulation processing in neural circuits in patients with schizophrenia. Notably, this also holds for siblings, albeit to a lesser extent, indicating that it may be part and parcel of a vulnerability for psychosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alexithymia is a personality construct denoting emotion processing problems. It has been suggested to encompass two dimensions: a cognitive and affective dimension. The cognitive dimension is ...characterized by difficulties in identifying, verbalizing and analyzing emotions, while the affective dimension reflects the level of emotional arousal and imagination. Alexithymia has been previously proposed as a risk factor for developing psychosis. More specifically, the two alexithymia dimensions might be differentially related to the vulnerability for psychosis. Therefore, we examined the two dimensions of alexithymia, measured with the BVAQ in 94 siblings of patients with schizophrenia, 52 subjects at ultra-high risk (UHR) for developing psychosis, 38 patients with schizophrenia and 109 healthy controls. The results revealed that siblings and patients had higher levels of cognitive alexithymia compared to controls. In addition, subjects at UHR for psychosis had even higher levels of cognitive alexithymia compared to the siblings. The levels of affective alexithymia in siblings and patients were equal to controls. However, UHR individuals had significantly lower levels of affective alexithymia (i.e. higher levels of emotional arousal and fantasizing) compared to controls. Alexithymia was further related to subclinical levels of negative and depressive symptoms. These findings indicate that alexithymia varies parametrically with the degree of risk for psychosis. More specifically, a type-II alexithymia pattern, with high levels of cognitive alexithymia and normal or low levels of affective alexithymia, might be a vulnerability factor for psychosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alexithymia is a psychological construct that can be divided into a cognitive and affective dimension. The cognitive dimension is characterized by difficulties in identifying, verbalizing and ...analysing feelings. The affective dimension comprises reduced levels of emotional experience and imagination. Alexithymia is widely regarded to arise from an impairment of emotion regulation. This is the first functional magnetic resonance imaging (fMRI) study to critically evaluate this by investigating the neural correlates of emotion regulation as a function of alexithymia levels. The aim of the current study was to investigate the neural correlates underlying the two alexithymia dimensions during emotion perception and emotion regulation. Using fMRI, we scanned 51 healthy subjects while viewing, reappraising or suppressing negative emotional pictures. The results support the idea that cognitive alexithymia, but not affective alexithymia, is associated with lower activation in emotional attention and recognition networks during emotion perception. However, in contrast with several theories, no alexithymia-related differences were found during emotion regulation (neither reappraisal nor suppression). These findings suggest that alexithymia may result from an early emotion processing deficit rather than compromised frontal circuits subserving higher-order emotion regulation processes.
Alexithymia (“no words for feelings”) is a psychological construct that can be divided in a cognitive and affective dimension. The cognitive dimension reflects the ability to identify, verbalize and ...analyze feelings, whereas the affective dimension reflects the degree to which individuals get aroused by emotional stimuli and their ability to fantasize. These two alexithymia dimensions may differentially put individuals at risk to develop psychopathology. However, their neural correlates have rarely been investigated. The aim of the current study was to investigate whether the cognitive and affective alexithymia dimension are associated with unique anatomical profiles. Structural MRI scans of 57 participants (29 males; mean age: 34) were processed using a voxel-based morphometry (VBM) – Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL) approach. Multiple regression analyses were performed to examine the common and specific associations between gray and white matter volume and alexithymia subdimensions. The results revealed that the cognitive dimension was related to lower dorsal anterior cingulate volume. In contrast, the affective alexithymia was associated with lower gray matter volume in the medial orbitofrontal cortex (OFC) and lower white matter volume in the superior longitudinal fasciculus (SLF) near the angular gyrus. No relationship between corpus callosum volume and alexithymia was observed. These results are consistent with the idea that there are two separable neural systems underlying alexithymia. This finding might encourage future research into the link between specific alexithymia subtypes and the development of psychopathology.
Background Grey matter, both volume and concentration, has been proposed as an endophenotype for schizophrenia given a number of reports of grey matter abnormalities in relatives of patients with ...schizophrenia. However, previous studies on grey matter abnormalities in relatives have produced inconsistent results. The aim of the present study was to examine grey matter differences between controls and siblings of patients with schizophrenia and to examine whether the age, genetic loading or subclinical psychotic symptoms of selected individuals could explain the previously reported inconsistencies. Methods We compared the grey matter volume and grey matter concentration of healthy siblings of patients with schizophrenia and healthy controls matched for age, sex and education using voxel-based morphometry (VBM). Furthermore, we selected subsamples based on age (< 30 yr), genetic loading and subclinical psychotic symptoms to examine whether this would lead to different results. Results We included 89 siblings and 69 controls in our study. The results showed that siblings and controls did not differ significantly on grey matter volume or concentration. Furthermore, specifically selecting participants based on age, genetic loading or subclinical psychotic symptoms did not alter these findings. Limitations The main limitation was that subdividing the sample resulted in smaller samples for the subanalyses. Furthermore, we used MRI data from 2 different scanner sites. Conclusion These results indicate that grey matter measured through VBM might not be a suitable endophenotype for schizophrenia.
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