The reliability of commonly used electrophysiology measures.

BACKGROUND: Electrophysiological measures can help understand brain function both in healthy individuals and in the context of a disease. Given the amount of information that can be extracted from these measures and their frequent use, it is essential to know more about their inherent reliability. OBJECTIVE/HYPOTHESIS: To understand the reliability of electrophysiology measures in healthy individuals. We hypothesized that measures of threshold and latency would be the most reliable and least susceptible to methodological differences between study sites. METHODS: Somatosensory evoked potentials from 112 control participants; long-latency reflexes, transcranial magnetic stimulation with resting and active motor thresholds, motor evoked potential latencies, input/output curves, and short-latency sensory afferent inhibition and facilitation from 84 controls were collected at 3 visits over 24 months at 4 Track-On HD study sites. Reliability was assessed using intra-class correlation coefficients for absolute agreement, and the effects of reliability on statistical power are demonstrated for different sample sizes and study designs. RESULTS: Measures quantifying latencies, thresholds, and evoked responses at high stimulator intensities had the highest reliability, and required the smallest sample sizes to adequately power a study. Very few between-site differences were detected. CONCLUSIONS: Reliability and susceptibility to between-site differences should be evaluated for electrophysiological measures before including them in study designs. Levels of reliability vary substantially across electrophysiological measures, though there are few between-site differences. To address this, reliability should be used in conjunction with theoretical calculations to inform sample size and ensure studies are adequately powered to detect true change in measures of interest.

Toward a formalization of the process to select IMIA Yearbook best papers.

BACKGROUND: Each year, the International Medical Informatics Association Yearbook recognizes significant scientific papers, labelled as "best papers", published the previous year in the subfields of biomedical informatics that correspond to the different section topics of the journal. For each section, about fifteen pre-selected "candidate" best papers are externally peer-reviewed to select the actual best papers. Although based on the available literature, little is known about the pre-selection process. OBJECTIVE: To move toward an explicit formalization of the candidate best papers selection process to reduce variability in the literature search across sections and over years. METHODS: A methodological framework is proposed to build for each section topic specific queries tailored to PubMed and Web of Science citation databases. The two sets of returned papers are merged and reviewed by two independent section editors and citations are tagged as "discarded", "pending", and "kept". A protocolized consolidation step is then jointly conducted to resolve conflicts. A bibliographic software tool, BibReview, was developed to support the whole process. RESULTS: The proposed search strategy was fully applied to the Decision Support section of the 2013 edition of the Yearbook. For this section, 1124 references were returned (689 PubMed-specific, 254 WoS-specific, 181 common to both databases) among which the 15 candidate best papers were selected. CONCLUSIONS: The search strategy for determining candidate best papers for an IMIA Yearbook's section is now explicitly specified and allows for reproducibility. However, some aspects of the whole process remain reviewer-dependent, mostly because there is no characterization of a "best paper".

[The role of skin substitutes in the surgical treatment of extensive burns covering more than 60 % of total body surface area. A review of patients over a 10-year period at the Tours University Hospital]. / Place des substituts cutanés dans le traitement chirurgical des grands brûlés sur plus de 60 % de la Surface corporelle. Revue de patients sur 11ans dans le centre des brûlés adultes du CHRU de Tours.

INTRODUCTION: Progress in intensive care and surgery has made it possible to significantly improve the survival of victims with burns over 60% of total body surface area (TBSA). Coverage of the excised areas of these patients can be difficult when there is a shortage of skin donor sites; then the role of skin substitutes can be important. MATERIALS AND METHODS: This retrospective study included patients with burns covering more than 60% TBSA and treated at the Tours University Hospital over a period of 10 years. Patients who died during the first week or who presented superficial burns were excluded. The various substitutions means to temporarily or permanently replace the cutaneous barrier are presented. The biological dressings associated with grafts expanded by six according to the sandwich technique, allografts and xenografts, widely expanded postage stamp skin grafts using a modified Meek technique (Humeca(®)), temporary cutaneous substitutes such as Biobrane(®) and skin substitutes colonized by autologous cells (Integra(®)) are presented. RESULTS: Forty-four patients were admitted. Self-immolations represented 52% of the cases. Twenty-one patients were treated with Integra(®), 5 with Biobrane(®), 17 with sandwich grafts and 4 with postage stamp skin grafts. Integra(®) was widely used when donor sites were insufficient. The mean number of surgical procedures per patient was 8.4. The mean duration of hospitalization was 155 days. Twenty-four patients survived until the end of treatment. Eighteen patients died during the first week before any surgery could be performed. Two patients died at the end of treatment. The overall survival rate was 55%. It was 92% for patients who survived the first week. The principal sequel were functional (hand, cervical, thoracic and axillary contractures) and aesthetic (face and hands). Associated treatments were pressotherapy, physical therapy, ergotherapy and thermal water therapy. CONCLUSION: By temporarily replacing the cutaneous barrier in the absence of sufficient donor sites, skin substitutes make it possible to increase the survival of patients with very extensive burns and to optimize their treatment.

A 2014 medical informatics perspective on clinical decision support systems: do we hit the ceiling of effectiveness?

OBJECTIVE: To summarize recent research and propose a selection of best papers published in 2013 in the field of computer-based decision support in health care. METHOD: Two literature reviews were performed by the two section editors from bibliographic databases with a focus on clinical decision support systems (CDSSs) and computer provider order entry in order to select a list of candidate best papers to be peer-reviewed by external reviewers. RESULTS: The full review process highlighted three papers, illustrating current trends in the domain of clinical decision support. The first trend is the development of theoretical approaches for CDSSs, and is exemplified by a paper proposing the integration of family histories and pedigrees in a CDSS. The second trend is illustrated by well-designed CDSSs, showing good theoretical performances and acceptance, while failing to show a clinical impact. An example is given with a paper reporting on scorecards aiming to reduce adverse drug events. The third trend is represented by research works that try to understand the limits of CDSS use, for instance by analyzing interactions between general practitioners, patients, and a CDSS. CONCLUSIONS: CDSSs can achieve good theoretical results in terms of sensibility and specificity, as well as a good acceptance, but evaluations often fail to demonstrate a clinical impact. Future research is needed to better understand the causes of this observation and imagine new effective solutions for CDSS implementation.

A Preference-based framework for medical decision making.

Medical decision making, such as choosing which drugs to prescribe, requires to consider mandatory constraints, e.g. absolute contraindications, but also preferences that may not be satisfiable, e.g. guideline recommendations or patient preferences. The major problem is that these preferences are complex, numerous and come from various sources. The considered criteria are often conflicting and the number of decisions is too large to be explicitly handled. In this paper, we propose a framework for encoding medical preferences using a new connective, called ordered disjunction symbolized by ~×. Intuitively, the preference "Diuretic~×Betablocker means: "Prescribe a Diuretic if possible, but if this is not possible, then prescribe a Betablocker". We give an inference method for reasoning about the preferences and we show how this framework can be applied to a part of a guideline for hypertension.

Root biomass production in populations of six rooted macrophytes in response to Cu exposure: intra-specific variability versus constitutive-like tolerance.

Intra-specific variability of root biomass production (RP) of six rooted macrophytes, i.e. Juncus effusus, Phragmites australis, Schoenoplectus lacustris, Typha latifolia, Phalaris arundinacea, and Iris pseudacorus grown from clones, in response to Cu exposure was investigated. Root biomass production varied widely for all these macrophytes in control conditions (0.08 µM) according to the sampling site. Root biomass production of T. latifolia and I. pseudacorus in the 2.5-25 µM Cu range depended on the sampling location but not on the Cu dose in the growth medium. For P. australis, J. effusus, S. lacustris, and P. arundinacea, an intra-specific variability of RP depending on both the sampling location and the Cu-dose was evidenced. This intra-specific variability of RP depending on the sampling location and of Cu-tolerance for these last four species suggests that Cu constitutive tolerance for all rooted macrophytes is not a species-wide trait but it exhibits variability for some species.

A custom robot for Transcranial Magnetic Stimulation: first assessment on healthy subjects.

In this paper, a custom robotic system for Transcranial Magnetic Stimulation is assessed in clinical conditions on healthy subjects. A motor cortex mapping is performed using the robotic system with comparison to a manual approach using a neuronavigation system. Stimulation accuracy, repeatability are evaluated as well as the feeling of the system operator and the subject in terms of comfort, tiredness, stress level, ease-of-use. Very encouraging results are obtained on all these aspects, which strengthens the idea of developing robotic assistance for TMS.

A medical informatics perspective on clinical decision support systems. Findings from the yearbook 2013 section on decision support.

OBJECTIVE: To summarize excellent research and to select best papers published in 2012 in the field of computer-based decision support in healthcare. METHODS: A bibliographic search focused on clinical decision support systems (CDSSs) and computer provider order entry was performed, followed by a double-blind literature review. RESULTS: The review process yielded six papers, illustrating various aspects of clinical decision support. The first paper is a systematic review of CDSS intervention trials in real settings, and considers different types of possible outcomes. It emphasizes the heterogeneity of studies and confirms that CDSSs can improve process measures but that evidence lacks for other types of outcomes, especially clinical or economic. Four other papers tackle the safety of drug prescribing and show that CDSSs can be efficient in reducing prescription errors. The sixth paper exemplifies the growing role of ontological resources which can be used for several applications including decision support. CONCLUSIONS: CDSS research has to be continuously developed and assessed. The wide variety of systems and of interventions limits the understanding of factors of success of CDSS implementations. A standardization in the characterization of CDSSs and of intervention trial reporting will help to overcome this obstacle.

[Use of Matriderm® 1mm in reconstructive surgery. Series of 31 cases]. / Utilisation de Matriderm® 1mm en chirurgie reconstructrice. Série de 31 cas.

INTRODUCTION: Dermal substitute are used for soft-tissue defect for their functional and aesthetic advantages. Matriderm® 1mm, single layer dermal matrix, composed of collagen and elastin covered by a split thickness skin graft simultaneously to its application, has been used most often in burned surgery. This prospective series evaluates the interest of this recent dermal matrix in reconstructive surgery. PATIENTS AND METHOD: Twenty-eight patients have been treated with the substitute in our department for reconstructive surgery indication between November 2008 and May 2012. Indications were tissue losses treatment after limb or trunk sarcoma resection, melanoma, extended baso- or spinocellular carcinoma, palmoplantar keratodermy, burn sequels, or traumatic tissue losses. Indications were preferentially deep tissue losses, functional areas and the face. RESULTS: Mean treated area has been 82.4 cm(2) (10 to 600 cm(2)). Mean taken rate has been 87±19% of the area and mean day of discharge has been 4.8 days and the mean cost per patient 906.5 euros. Negative wound therapy, until D3, was used 6 times. Three patients treated for limb sarcoma had radiotherapy performed on the grafted area. Aesthetic and functional results have been encouraging. CONCLUSIONS: Matriderm® 1mm, dermal substitute commonly used in acute burn treatment can be indicated in reconstructive surgery. This series show that it permits to obtain a good graft taken rate, a quick healing with a satisfying aesthetic and functional results and permit an early discharge. However, its indications are limited by its cost.

White matter volume is decreased in the brain of patients with neuromyelitis optica.

BACKGROUND: Neuromyelitis optica (NMO) is an inflammatory disease involving predominantly the spinal cord and optic nerves. Whether patients with NMO have a loss in white or grey matter (GM) volumes remains to be determined. METHODS: Thirty patients with NMO, 30 healthy subjects matched for age and gender, 21 patients with multiple sclerosis (MS) and 20 patients with a clinically isolated syndrome (CIS) were studied. We applied a SIENAX post-treatment software. We compared white matter (WM) and GM volumes between groups and explored correlations of changes in NMO patients with age, gender, duration, disease severity, visual acuity and T2 hyperintensities. We also performed a voxel-based morphometry (VBM) analysis to identify the regions affected by loss of volume. RESULTS: White matter volume was significantly reduced in patients with NMO (764.4 ± 58.3 cm(3) ) compared to healthy subjects (843.1 ± 49.3 cm(3) ) (P < 0.001), whereas no difference was observed for the GM. Patients with CIS also presented an elective atrophy of WM and MS an atrophy of both WM and GM. We did not find any predictive factors of brain atrophy. The decrease in WM volume in NMO was noted even in the absence of visible MRI hypersignals. The VBM analysis found a few regions of WM atrophy (corpus callosum and optic radiations, P < 0.005, uncorrected) and a few regions of GM atrophy (thalamus and prefrontal cortex, P < 0.001, uncorrected). CONCLUSION: These results suggest a significant brain involvement in NMO, especially an involvement of WM which appears not to be limited to secondary degeneration after spinal cord and optic nerve damage.

Plasmodesmatal pores in the torus of bordered pit membranes affect cavitation resistance of conifer xylem.

The pit membrane in bordered pits of conifer tracheids is characterized by a porous margo and central thickening (torus), which is traditionally considered to function as an impermeable safety valve against air-seeding. However, electron microscopy based on 33 conifer species, including five families and 19 genera, reveals that pores occur in the torus of 13 of the species studied. The pores have a plasmodesmatal origin with an average diameter of 51 nm and grouped arrangement. Evidence for embolism spreading via pores in tori is supported by the pore sizes, which correspond relatively well with the pressure inducing cavitation. Predictions based on earlier correlations between pit structure and cavitation resistance were only weakly supported for species with punctured tori. Moreover, species with punctured tori are significantly less resistant to cavitation than species with non-punctured tori. Nevertheless, absolute pore diameters must be treated with caution and correlations between theoretical and measured air-seeding pressures are weak. Because most pores appear not to traverse the torus but are limited to one torus pad, only complete pores would trigger air-seeding. Embolism spreading through a leaky torus is not universal across gymnosperms and unlikely to represent the only air-seeding mechanism.

Effects of afferent stimulation rate on inhibitory spinal pathways in hemiplegic spastic patients.

OBJECTIVE: It has recently been demonstrated in the cat and in healthy subjects that the effects of repetitive afferent fibre stimulation depends on the target spinal neurones. The purpose of this series of experiments was therefore to determine whether central nervous system lesions modify the behaviour of the inhibitory spinal pathways in response to repetitive activation of afferent fibres. METHODS: The H-reflex technique was used to study the effect of increasing the conditioning stimulus rate from 0.16 to 1 Hz on disynaptic inhibition and on presynaptic Ia inhibition on the affected side of 36 hemiplegic patients. RESULTS: The major finding was that, similar to results previously obtained in healthy subjects, increasing the conditioning stimulus rate in hemiplegic patients leads to an increase in the synaptic efficiency of inhibitory spinal circuits. Furthermore, a significant correlation was found between the severity of flexor carpi radialis muscle spasticity and the amount of disynaptic inhibition. CONCLUSIONS: The reinforcement of inhibitory spinal networks induced by repetitive stimulation of afferent fibres is preserved in spastic patients, whereas the mechanisms underlying this phenomena might be altered. SIGNIFICANCE: The results of these experiments open up a number of possibilities for novel spasticity therapies based on non-invasive techniques.

Adaptive responses for seed and leaf phenology in natural populations of sessile oak along an altitudinal gradient.

We assessed the adaptive potential of seed and leaf phenology in 10 natural populations of sessile oak (Quercus petraea) sampled along two altitudinal transects using common garden experiments. Population differentiation for both phenological traits was observed with high-altitude populations germinating and flushing later than low altitude ones. However, high genetic variation and heritability values were also maintained within populations, despite slightly decreasing for dates of leaf unfolding with increasing altitude. We suggest that biotic and abiotic fluctuating selection pressures within populations and high gene flow are the main mechanisms maintaining high genetic variation for these fitness related traits. Moreover, changes in selection intensity and/or selection pressures along the altitudinal gradient can explain the reduction in genetic variation observed for leaf phenology. We anticipate that the maintenance of high genetic variation will be a valuable resource for future adaptation of sessile oak populations undergoing an upslope shift caused by climate change.

Effects of galvanic mastoid stimulation in seated human subjects.

The vestibular responses evoked by transmastoid galvanic stimulation (GS) in the rectified soleus electromyogram (EMG) in freely standing human subjects disappear when seated. However, a GS-induced facilitation of the soleus monosynaptic (H and tendon jerk) reflex has been described in few experiments in subjects lying prone or seated. This study addresses the issue of whether this reflex facilitation while seated is of vestibulospinal origin. GS-induced responses in the soleus (modulation of the rectified ongoing EMG and of the monosynaptic reflexes) were compared in the same normal subjects while freely standing and sitting with back and head support. The polarity-dependent biphasic responses in the free-standing position were replaced by a non-polarity-dependent twofold facilitation while seated. The effects of GS were hardly detectable in the rectified ongoing voluntary EMG activity, weak for the H reflex, but large and constant for the tendon jerk. They were subject to habituation. Anesthesia of the skin beneath the GS electrodes markedly reduced the reflex facilitation, while a similar, although weaker, facilitation of the tendon jerk was observed when GS was replaced with purely cutaneous stimulation, a tap to the tendon of the sternomastoid muscle, or an auditory click. The stimulation polarity independence of the GS-induced reflex facilitation argues strongly against a vestibular response. However, the vestibular afferent volley, insufficient to produce a vestibular reflex response while seated, could summate with the GS-induced tactile or proprioceptive volley to produce a startle-like response responsible for the reflex facilitation.

The disynaptic group I inhibition between wrist flexor and extensor muscles revisited in humans.

The present studies are designed to further characterise the interneuronal pathway mediating the disynaptic reciprocal group I inhibition between flexors and extensors at the wrist and the elbow levels in humans. In the first series of experiments, we compared the electrical threshold of the reciprocal group I inhibition at the wrist and the elbow level after a prolonged vibration aimed at raising the electrical threshold of the antagonistic activated Ia afferents. Prolonged vibration to the 'conditioning' tendon, which raised significantly the electrical threshold of the inhibition at the elbow level, did not alter it at the wrist level. These results suggest that the dominant input to the relevant interneurones is Ia in origin at the elbow level but Ib in origin at the wrist level. In the second series of experiments, using the spatial facilitation method, we compared the effects on the post-stimulus time histograms of single voluntarily activated motor units of two volleys delivered both separately and together to group I afferents in the nerves supplying the homonymous and antagonistic muscles. At the wrist, but not at the elbow level, the peak of homonymous monosynaptic group I excitation was reduced on combined stimulation, although the antagonistic IPSP was just at the threshold. Because the suppression did not involve the initial bins of the peak, it is argued that the suppression is not due to presynaptic inhibition of Ia terminals, but probably reflects convergence between the homonymous and antagonistic volleys onto the interneurones mediating the disynaptic inhibition. Taken together with the previously reported effects of recurrent inhibition on reciprocal inhibition, these results suggest that inhibition between flexors and extensors is differently organised at the elbow (reciprocal Ia inhibition) and the wrist (non-reciprocal group I inhibition) levels. It is argued that the particular connectivity at the wrist level might correspond to some functional requirements at this ball joint.

Post-activation depression in various group I spinal pathways in humans.

This investigation was designed to study the effects of post-activation depression in different spinal pathways fed by group I afferents available to investigation in human subjects. It was precipitated by a recent investigation in the cat showing that-contrary to the general assumption-post-activation depression is not a widespread phenomenon in the spinal cord. In 24 healthy subjects comparison was made between the effects of low and high-test stimulus rates on the monosynaptic Ia excitation, known to be subject to post-activation depression, and on oligosynaptic pathways fed by group I afferents. Both the amplitude of monosynaptic H reflexes and the amount of heteronymous monosynaptic Ia facilitation were significantly smaller at high than at low-test stimulus rates (1-2 s compared with 6-8 s between two consecutive stimuli). So was the amount of reciprocal Ia inhibition of tibialis anterior motoneurones. In contrast, the amount of other non-monosynaptic group I effects directed to the same motor nuclei (peroneal-induced excitation of quadriceps motoneurones, disynaptic non-reciprocal group I inhibition of flexor carpi radialis motoneurones, and D1 inhibition of flexor carpi radialis and soleus H reflexes) were enhanced at high stimulus rates. Results in humans confirm that post-activation depression depends on the type of group I afferents, and/or on the target neurones. The functional significance of the discrepancy between post-activation depression in pure Ia pathways and in other group I pathways is discussed with regard to the fusimotor-driven servo-assistance from Ia afferent discharges.

Evidence for recurrent inhibition of reciprocal inhibition from soleus to tibialis anterior in man.

Reciprocal inhibition between ankle flexors and extensors has been the subject of numerous studies in Man. They have demonstrated that this reciprocal inhibition is in all likelihood caused by a disynaptic pathway at least partly fed by Ia afferents. It is thus generally agreed that this reciprocally organized inhibition between ankle flexors and extensors in Man is similar to the reciprocal Ia inhibition described in the cat. This conclusion has, however, been challenged, when Jankowska and McCrea described in the cat a non-reciprocal group I inhibition involving interneurones co-excited by Ia and Ib afferents and mediating inhibition to both antagonistic and non-antagonistic motoneurones. The only way to distinguish between reciprocal Ia inhibition and non-reciprocal group I inhibition is to test if the inhibition is blocked by recurrent inhibition, since only Ia interneurones are inhibited by recurrent inhibition. In the present study, reciprocal inhibition from soleus to tibialis anterior was thus investigated following activation of soleus-coupled Renshaw cells in normal human subjects. It was found that reciprocal inhibition induced in tibialis anterior motoneurones by the activation of soleus group I afferents is deeply depressed by activation of soleus-coupled Renshaw cells. This finding provides the missing data to identify disynaptic inhibition between antagonistic ankle muscles as a reciprocal Ia inhibition.

Occurrence of two architectural types of hexagonal bilayer hemoglobin in annelids: comparison of 3D reconstruction volumes of Arenicola marina and Lumbricus terrestris hemoglobins.

A 3D reconstruction at 25 A resolution of native hemoglobin of the polychaete worm Arenicola marina was carried out from frozen-hydrated specimens examined in the electron microscope. The reconstruction volume of this large extracellular multimeric respiratory pigment appears as a hexagonal bilayer structure with eclipsed vertices in its upper and lower hexagonal layers. Conversely, in hemoglobins of oligochaetes, achaetes, and vestimentiferans and in chlorocruorins of the Sabellidae (polychaete) family, the vertices of the upper layer are 16 degrees clockwise rotated with respect to those of the lower layer. The fact that two other polychaete hemoglobins (Alvinella pompejana and Tylorrhynchus heterochaetus) have the same architecture as Arenicola led us to define two types of hexagonal bilayer hemoglobins/chlorocruorins: (i) type-I present in oligochaete, achaete, and vestimentiferan hemoglobins and in Sabellidae chlorocruorins; and (ii) type-II present in polychaete hemoglobins. A comparative study of the hemoglobins of Lumbricus terrestris (type-I) and Arenicola marina (type-II) showed that only two small differences located in the c4 and c5 linking units are responsible of the important architectural difference present in oligomers. A likely scheme proposed to explain the phylogenic distribution of the two types suggests that Clitellata, Sabellida (polychaete), and vestimentiferan hemoglobins and chlorocruorins derive from a type-I ancestral molecule, while Terebellida (Alvinella), Phyllodocida (Tylorrhynchus), and Scolecida (Arenicola) and possibly other polychaetes derive from an ancestor molecule with type-II hemoglobin. The architectures of the hollow globular substructures are highly similar in Arenicola and Lumbricus hemoglobins, with 12 globin chains and three linking units (c3a, c3b, and c4). The central piece of Arenicola hemoglobin is an ellipsoid while that of Lumbricus is a toroid. No phylogenic correlation could be found between the structure of the central pieces and the architecture type.

Reassembly of Lumbricus terrestris hemoglobin: a study by matrix-assisted laser desorption/ionization mass spectrometry and 3D reconstruction from frozen-hydrated specimens.

Dodecamers and four types of linker chains (L1-L4) were purified from dissociated hemoglobin of the earthworm Lumbricus terrestris. Various preparations comprising dodecamer of globin chains and linker chains were allowed to reassemble at neutral pH. They produced various oligomers that were purified by gel filtration, analyzed in matrix-assisted laser desorption/ionization mass spectrometry and submitted to 3D reconstruction from isolated particles observed in cryoelectron microscopy. Despite the impossibility to completely free the L2, L3, and L4 preparations from L1, the following conclusions were obtained. First, hemoglobin molecules indistinguishable from native hemoglobin at 25 A resolution were obtained in the absence of linker chains L2, L3, or L4. Second, the 3D reconstruction volumes of reassembled hemoglobins containing dodecamers and L1+L3 or dodecamers and L1+L4 demonstrate that reassembly of native-like structures can be obtained from at most two linker chains and dodecamers. Third, the 3D reconstruction volumes of native and reassembled hemoglobins containing dodecamers and (1) L1, L2, and L4, (2) L1, L3, and L4, (3) L1 and L4, and (4) L1 and L3 were highly similar. Since these structures comprise two types of substructures (one involved in the c3a, c3b, and c4 linking units of the hollow globular substructure and the other in the c5 connection and the toroid), it seems highly probable that the minimal number of linker chains required to reassemble native-like hemoglobin is at most two.

Octamerization enables soluble CD46 receptor to neutralize measles virus in vitro and in vivo.

A chimeric fusion protein encompassing the CD46 ectodomain linked to the C-terminal part of the C4b binding protein (C4bp) alpha chain (sCD46-C4bpalpha) was produced in eukaryotic cells. This protein, secreted as a disulfide-linked homo-octamer, was recognized by a panel of anti-CD46 antibodies with varying avidities. Unlike monomeric sCD46, the octameric sCD46-C4bpalpha protein was devoid of complement regulatory activity. However, sCD46-C4bpalpha was able to bind to the measles virus hemagglutinin protein expressed on murine cells with a higher avidity than soluble monomeric sCD46. Moreover, the octameric sCD46-C4bpalpha protein was significantly more efficient than monomeric sCD46 in inhibiting virus binding to CD46, in blocking virus induced cell-cell fusion, and in neutralizing measles virus in vitro. In addition, the octameric sCD46-C4bpalpha protein, but not the monomeric sCD46, fully protected CD46 transgenic mice against a lethal intracranial measles virus challenge.