Vaccination strategies to protect children against seasonal and pandemic influenza

To protect children against infection with seasonal influenza viruses, this age group is vaccinated annually in some countries. However, currently used inactivated seasonal influenza vaccines do not protect well against antigenically distinct pandemic influenza virus strains. Furthermore, annual vaccination may prevent infection with seasonal influenza viruses and subsequently the induction of heterosubtypic immunity. Therefore, the development of influenza vaccines that induce broad protective immunity should be considered a priority. In the absence of such vaccines children that are vaccinated annually against seasonal influenza should in a pandemic scenario also receive pandemic vaccines as soon as these become available. In order to protect young infant under six months of age for which no vaccines are registered at present, vaccination of pregnant women should be considered. This would afford protection through maternally derived antibodies. In addition, vaccination of close family members of young infants is recommended, to prevent transmission within the household.     

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.     

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.     

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.     

EATRIS, a Vision for Translational Research in Europe

Tremendous progress has been made in biomedical research in genomics, proteomics and metabolomics, which has led to an increasing insight into molecular mechanisms related to diseases. Yet the output of disease prevention, diagnosis and treatment solutions remains low. It is against this background that several European countries have gathered to take new actions for improving translational research from bench to bedside. Surveys were conducted to identify major bottlenecks and assess the situation of translational research in Europe. While the importance of translational research is already recognized and national governments have increased their efforts and academia more and more directs its research towards translation, there are still hurdles to overcome. Thus, a European research infrastructure—EATRIS—will be established to integrate basic and clinical research in dedicated translational centres. These EATRIS Centres will provide broad access to high-end pre-clinical and clinical facilities, including the necessary translational expertise for researchers from academia and industry.     

Facile labelling of an anti-epidermal growth factor receptor Nanobody with <Superscript>68</Superscript>Ga via a novel bifunctional desferal chelate for immuno-PET

Purpose

The ～15 kDa variable domains of camelid heavy-chain-only antibodies (called Nanobodies®) have the flexibility to be formatted as monovalent, monospecific, multivalent or multispecific single chain proteins with either fast or slow pharmacokinetics. We report the evaluation of the fast kinetic anti-epidermal growth factor receptor (EGFR) Nanobody 7D12, labelled with ⁶⁸Ga via the novel bifunctional chelate (BFC) p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS). Df-Bz-NCS has recently been introduced as the chelate of choice for ⁸⁹Zr immuno-positron emission tomography (PET).

Methods

Nanobody 7D12 was premodified with Df-Bz-NCS at pH 9. Radiolabelling with purified ⁶⁸Ga was performed at pH 5.0–6.5 for 5 min at room temperature. For in vitro stability measurements in storage buffer (0.25 M NaOAc with 5 mg ml^?1 gentisic acid, pH 5.5) at 4°C or in human serum at 37°C, a mixture of ⁶⁷Ga and ⁶⁸Ga was used. Biodistribution and immuno-PET studies of ⁶⁸Ga-Df-Bz-NCS-7D12 were performed in nude mice bearing A431 xenografts using ⁸⁹Zr-Df-Bz-NCS-7D12 as the reference conjugate.

Results

The Df-Bz-NCS chelate was conjugated to Nanobody 7D12 with a chelate to Nanobody molar substitution ratio of 0.2:1. The overall ⁶⁸Ga radiochemical yield was 55–70% (not corrected for decay); specific activity was 100–500 MBq/mg. Radiochemical purity of the conjugate was >96%, while the integrity and immunoreactivity were preserved. ^68/67Ga-Df-Bz-NCS-7D12 was stable in storage buffer as well as in human serum during a 5-h incubation period (<2% radioactivity loss). In biodistribution studies the ⁶⁸Ga-labelled Nanobody 7D12 showed high uptake in A431 tumours (ranging from 6.1?±?1.3 to 7.2?±?1.5%ID/g at 1–3 h after injection) and high tumour to blood ratios, which increased from 8.2 to 14.4 and 25.7 at 1, 2 and 3 h after injection, respectively. High uptake was also observed in the kidneys. Biodistribution was similar to that of the reference conjugate ⁸⁹Zr-Df-Bz-NCS-7D12. Tumours were clearly visualized in a PET imaging study.

Conclusion

Via a rapid procedure under mild conditions a ⁶⁸Ga-Nanobody was obtained that exhibited high tumour uptake and tumour to normal tissue ratios in nude mice bearing A431 xenografts. Fast kinetic ⁶⁸Ga-Nanobody conjugates can be promising tools for tumour detection and imaging of target expression.

     

Surgical management of primary thumb carpometacarpal osteoarthritis: a systematic review

The aim of this article is to provide an updated systematic review on the 8 most commonly used surgical procedures to treat trapeziometacarpal osteoarthritis. A thorough literature search was performed using predetermined criteria. A total of 35 articles fulfilled the inclusion criteria. Nine of these 35 articles were not included in previous systematic reviews. Systematic evaluation demonstrated the following: (1) there is no evidence that trapeziectomy or trapeziectomy with tendon interposition is superior to any of the other techniques. However, when interposition is performed, autologous tissue interposition seems to be preferable. (2) Trapeziectomy with ligament reconstruction or trapeziectomy with ligament reconstruction and tendon interposition (LRTI) is not superior to any of the other techniques. However, follow-up in the studies with a higher level of evidence was relatively short (12 mo); therefore, long-term benefits could not be assessed. In addition, trapeziectomy with LRTI seems associated with a higher complication rate. (3) Because the studies on thumb carpometacarpal (CMC) arthrodesis were of less methodological quality and had inconsistent outcomes, we are not able to conclude whether CMC arthrodesis is superior to any other technique. Therefore, high-level randomized trials comparing CMC arthrodesis with other procedures are needed. Nevertheless, findings in the newly included studies did show that nonunion rates in the literature are on average 8% to 21% and, complications and repeat surgeries are more frequent following CMC arthrodesis. (4) A study on joint replacement showed that total joint prosthesis might have better short-term results compared to trapeziectomy with LRTI. However, high-level randomized trials comparing total joint prosthesis with other procedures are needed. In addition, there is no evidence that the Artelon spacer is superior to trapeziectomy with LRTI. We conclude that, at this time, no surgical procedure is proven to be superior to another. However, based on good results of CMC arthrodesis and total joint prostheses, we postulate that there could be differences between the various surgical procedures. Therefore randomized clinical trials of CMC arthrodesis and total joint prostheses compared to trapeziectomy with long follow-up (>1 y) are warranted.     

Oral bioavailability of phenobarbital: a comparison of a solution in myvacet 9‐08, a suspension, and a tablet

Purpose: A threeway crossover study with seven healthy male volunteers was conducted to determine the relative bioavailability of phenobarbital after single dose administration of 100 mg of phenobarbital as oral solution in Myvacet 908, and as a suspension, compared with a 100 mg phenobarbital tablet. Materials and methods: At 4week intervals each subject received the solution in Myvacet 908, the suspension and the tablet in randomized order. Blood samples were collected for 48 h after each dose for analysis of phenobarbital. From the individual serum concentrationversustime curves C _maxand T _max were determined and AUC₀₄₈ was calculated. Results: All three oral dosage forms of phenobarbital are bioequivalent. No significant diffences in T _maxwere observed. Conclusion: The oral solution in Myvacet 908, and the suspension of phenobarbital proved to be bioequivalent to a tablet.