Magnetic resonance angiography of the human middle meningeal artery: implications for migraine

PURPOSE: To describe a novel noninvasive method for studying middle meningeal artery (MMA) diameter changes in vivo in humans. Dilatation of the MMA has been implicated in the pathophysiology of migraine headache, but no direct evidence has been obtained in humans. MATERIALS AND METHODS: The diameter of the MMA (the extracranial part) was measured in 19 healthy volunteers before and after administration of a vasodilator (nitroglycerin (NTG), 1.2 mg sublingually) known to provoke headache. We used magnetic resonance angiography (MRA) in combination with a 47-mm microscopy coil and a semiautomatic contour detection program. RESULTS: The diameter of the MMA was 1.5+/-0.26 mm (mean+/-SD) before and 1.79+/-0.30 mm after NTG administration. This increase was 20.1% (95% CI=12.9-27.3; P<0.001). The mean increase in subjects who developed headache (N=11) was 0.34+/-0.19 mm as compared to 0.22 mm+/-0.20 mm in the eight subjects who did not (95% CI for difference=-0.07 to 0.31; P=0.188). CONCLUSION: MRA in combination with a 47-mm microscopy coil is a novel, noninvasive method to measure changes in the diameter of human meningeal vessels, with potential applications for migraine and other fields of neurovascular research.     

Tentorial artery embolization in tentorial dural arteriovenous fistulas

Introduction The tentorial artery is often involved in arterial supply to tentorial dural fistulas. The hypertrophied tentorial artery is accessible to embolization, either with glue or with particles.Methods Six patients are presented with tentorial dural fistulas, mainly supplied by the tentorial artery. Two patients presented with intracranial hemorrhage, two with pulsatile tinnitus and one with progressive tetraparesis, and in one patient the tentorial dural fistula was an incidental finding. Different endovascular techniques were used to embolize the tentorial artery in the process of endovascular occlusion of the fistulas.Results All six tentorial dural fistulas were completely occluded by endovascular techniques, confirmed at follow-up angiography. There were no complications. When direct catheterization of the tentorial artery was possible, glue injection with temporary balloon occlusion of the internal carotid artery at the level of the tentorial artery origin was effective and safe.Conclusion Different endovascular techniques may be successfully applied to embolize the tentorial artery in the treatment of tentorial dural fistulas.     

PET imaging with radiolabeled antibodies and tyrosine kinase inhibitors: immuno-PET and TKI-PET

During the last decade, the discovery of critical tumor targets has boosted the design of targeted therapeutic agents with monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) receiving most of the attention. Immuno-positron emission tomography (immuno-PET) and TKI-PET, the in vivo tracking and quantification of mAbs and TKIs biodistribution with PET, are exciting novel options for better understanding of the in vivo behavior and efficacy of these targeted drugs in individual patients and for more efficient drug development. Very recently, current good manufacturing practice compliant procedures for labeling of mAbs with positron emitters have been described, as well as the preparation of some radiolabeled TKIs, while the first proof of principle studies has been performed in patients. In this review, technical developments in immuno-PET and TKI-PET are described, and their clinical potential is discussed. An overview is provided for the most appealing preclinical immuno-PET and TKI-PET studies, as well as the first clinical achievements with these emerging technologies.     

The molecular basis of the pathogenicity of the Dutch highly pathogenic human influenza A H7N7 viruses

During the highly pathogenic avian influenza (HPAI) H7N7 virus outbreak in The Netherlands in 2003, 88 infected persons suffered from mild illnesses, and 1 died of pneumonia. Here, we studied which of the 14 amino acid substitutions observed between the fatal case (FC) virus and a conjunctivitis case (CC) virus determined the differences in virus pathogenicity. In virus-attachment experiments, the CC and FC viruses revealed marked differences in binding to the lower respiratory tract of humans. In a mouse model, the hemagglutinin (HA) gene of the FC virus was a determinant of virus tissue distribution. The lysine at position 627 of basic polymerase 2 (PB2) of the FC virus was the major determinant of pathogenicity and tissue distribution. Thus, remarkable similarities were revealed between recent HPAI H5N1 and H7N7 viruses. We conclude that the influenza virus HA and PB2 genes should be the prime targets for molecular surveillance during outbreaks of zoonotic HPAI viruses.     

Distinct Temporal Expression of 5-HT1A and 5-HT2A Receptors on Cerebellar Granule Cells in Mice

Serotonin plays an important role of controlling the physiology of the cerebellum. However, serotonin receptor expression has not been fully studied in the developing cerebellum. We have recently shown that cerebellar granule cells transiently express 5-HT₃ receptors. In the present study, we investigate expression of 5-HT₁ and 5-HT₂ receptors in the mouse cerebellum both during postnatal development and in juvenile mice. Here, we show for the first time that 5-HT_1A and 5-HT_2A receptors are present on cerebellar granule cells with a distinct temporal expression pattern: 5-HT_1A receptors are expressed only during the first 2 weeks, while 5-HT_2A receptor expression persists until at least 8 weeks after birth. Because of its prolonged expression pattern, we investigated the electrophysiological properties of the 5-HT_2A receptor. 5-HT_2A receptors expressed by cerebellar granule cells promote stability by reducing variability of the synaptic response, and they modulate the paired-pulse ratio of the parallel fibre–Purkinje cell synapse. Furthermore, pharmacological block of 5-HT_2A receptors enhances short-term synaptic plasticity at the parallel fibre–Purkinje cell synapse. We thus show a novel role for serotonin in controlling function of the cerebellum via 5-HT_2A receptors expressed by cerebellar granule cells.     

Novel G3/DT adjuvant promotes the induction of protective T cells responses after vaccination with a seasonal trivalent inactivated split-virion influenza vaccine

Vaccines used against seasonal influenza are poorly effective against influenza A viruses of novel subtypes that may have pandemic potential. Furthermore, pre(pandemic) influenza vaccines are poorly immunogenic, which can be overcome by the use of adjuvants. A limited number of adjuvants has been approved for use in humans, however there is a need for alternative safe and effective adjuvants that can enhance the immunogenicity of influenza vaccines and that promote the induction of broad-protective T cell responses. Here we evaluated a novel nanoparticle, G3, as an adjuvant for a seasonal trivalent inactivated influenza vaccine in a mouse model. The G3 adjuvant was formulated with or without steviol glycosides (DT, for diterpenoid). The use of both formulations enhanced the virus-specific antibody response to all three vaccine strains considerably. The adjuvants were well tolerated without any signs of discomfort. To assess the protective potential of the vaccine-induced immune responses, an antigenically distinct influenza virus strain, A/Puerto Rico/8/34 (A/PR/8/34), was used for challenge infection. The vaccine-induced antibodies did not cross-react with strain A/PR/8/34 in HI and VN assays. However, mice immunized with the G3/DT-adjuvanted vaccine were partially protected against A/PR/8/34 infection, which correlated with the induction of anamnestic virus-specific CD8⁺ T cell responses that were not observed with the use of G3 without DT. Both formulations induced maturation of human dendritic cells and promoted antigen presentation to a similar extent. In conclusion, G3/DT is a promising adjuvant formulation that not only potentiates the antibody response induced by influenza vaccines, but also induces T cell immunity which could afford broader protection against antigenically distinct influenza viruses.     

PAR1 contributes to influenza A virus pathogenicity in mice

Influenza causes substantial morbidity and mortality, and highly pathogenic and drug-resistant strains are likely to emerge in the future. Protease-activated receptor 1 (PAR1) is a thrombin-activated receptor that contributes to inflammatory responses at mucosal surfaces. The role of PAR1 in pathogenesis of virus infections is unknown. Here, we demonstrate that PAR1 contributed to the deleterious inflammatory response after influenza virus infection in mice. Activating PAR1 by administering the agonist TFLLR-NH₂ decreased survival and increased lung inflammation after influenza infection. Importantly, both administration of a PAR1 antagonist and PAR1 deficiency protected mice from infection with influenza A viruses (IAVs). Treatment with the PAR1 agonist did not alter survival of mice deficient in plasminogen (PLG), which suggests that PLG permits and/or interacts with a PAR1 function in this model. PAR1 antagonists are in human trials for other indications. Our findings suggest that PAR1 antagonism might be explored as a treatment for influenza, including that caused by highly pathogenic H5N1 and oseltamivir-resistant H1N1 viruses.     

The relationship between stress and quality of life in psychiatric outpatients

Stress is the subjective feeling produced by events that are uncontrollable or threatening. Stress factors are coded on a separate axis of the DSM‐IV classification system when they influence the diagnosis, treatment, and prognosis of psychiatric disorders. The relationship between stress and the psychosocial outcome measure quality of life (QOL), that has become a topic of growing interest in medical and psychiatric practice, is hardly examined in psychiatric outpatients. Therefore, in the present study, this relationship was investigated in a population of psychiatric outpatients (n = 410) with a broad spectrum of psychiatric disorders. Stress was assessed with the Everyday Problem Checklist (EPCL). QOL was measured with the World Health Organization (WHO) QOL Assessment Instrument (WHOQOL‐100). The study population experienced considerable rates and intensities of stress, that were significantly higher compared with normative groups derived from a random sample of the Dutch population. Even after a correction for the presence of psychopathology, stress explained an amount of the variance of all aspects of QOL. It is concluded that in addition to the presence of psychopathology, stress plays a significant role in determining QOL. This justifies the classification of stress on a separate axis of DSM‐IV. It is advisable to consider stress more systematically in psychiatric assessment and treatment. Copyright © 2006 John Wiley & Sons, Ltd.