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In both clinical and preclinical scenarios, 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) is the radiotracer most widely used to study brain glucose metabolism with positron emission tomography (PET). In clinical practice, there is a worldwide standardized protocol for preparing patients for [18F]FDG-PET studies, which specifies the room lighting. However, this standard is typically not observed in the preclinical field, although it is well known that animal handling affects the biodistribution of [18F]FDG. The present study aimed to evaluate the effect of ambient lighting on brain [18F]FDG uptake in mice. Two [18F]FDG-PET studies were performed on each animal, one in light and one in dark conditions. Thermal video recordings were acquired to analyse animal motor activity in both conditions. [18F]FDG-PET images were analysed with the Statistical Parametric Mapping method. The results showed that [18F]FDG uptake is higher in darkness than in light condition in mouse nucleus accumbens, hippocampus, midbrain, hindbrain, and cerebellum. The SPM analysis also showed an interaction between the illumination condition and the sex of the animal. Mouse activity was significantly different (p = 0.01) between light conditions (632 ± 215 s of movement) and dark conditions (989 ± 200 s), without significant effect of sex (p = 0.416). We concluded that room illumination conditions during [18F]FDG uptake in mice affected the brain [18F]FDG biodistribution. Therefore, we highlight the importance to control this factor to ensure more reliable and reproducible mouse brain [18F]FDG-PET results., Competing Interests: The authors have declared that no competing interests exist.

Aims: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC., Methods and Results: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs., Conclusion: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Human influenza A virus (hIAV) infection is associated with important cardiovascular complications, although cardiac infection pathophysiology is poorly understood. We aimed to study the ability of hIAV of different pathogenicity to infect the mouse heart, and establish the relationship between the infective capacity and the associated in vivo, cellular and molecular alterations., Methods and Results: We evaluated lung and heart viral titres in mice infected with either one of several hIAV strains inoculated intranasally. 3D reconstructions of infected cardiac tissue were used to identify viral proteins inside mouse cardiomyocytes, Purkinje cells, and cardiac vessels. Viral replication was measured in mouse cultured cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to confirm infection and study underlying molecular alterations associated with the in vivo electrophysiological phenotype. Pathogenic and attenuated hIAV strains infected and replicated in cardiomyocytes, Purkinje cells, and hiPSC-CMs. The infection was also present in cardiac endothelial cells. Remarkably, lung viral titres did not statistically correlate with viral titres in the mouse heart. The highly pathogenic human recombinant virus PAmut showed faster replication, higher level of inflammatory cytokines in cardiac tissue and higher viral titres in cardiac HL-1 mouse cells and hiPSC-CMs compared with PB2mut-attenuated virus. Correspondingly, cardiac conduction alterations were especially pronounced in PAmut-infected mice, associated with high mortality rates, compared with PB2mut-infected animals. Consistently, connexin43 and NaV1.5 expression decreased acutely in hiPSC-CMs infected with PAmut virus. YEM1L protease also decreased more rapidly and to lower levels in PAmut-infected hiPSC-CMs compared with PB2mut-infected cells, consistent with mitochondrial dysfunction. Human IAV infection did not increase myocardial fibrosis at 4-day post-infection, although PAmut-infected mice showed an early increase in mRNAs expression of lysyl oxidase., Conclusion: Human IAV can infect the heart and cardiac-specific conduction system, which may contribute to cardiac complications and premature death., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Mutations in the EPM2A and EPM2B genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, decreased glucose brain uptake and alterations on different brain metabolites mainly in the frontal cortex, basal ganglia and cerebellum. Mice deficient for laforin and malin present many features similar to those observed in patients, including cognitive, motor, histological and epileptic hallmarks. We describe the neuroimaging features found in two mouse models of Lafora disease. We found altered volumetric values in the cerebral cortex, hippocampus, basal ganglia and cerebellum using magnetic resonance imaging (MRI). Positron emission tomography (PET) of the cerebral cortex, hippocampus and cerebellum of Epm2a -/- mice revealed abnormal glucose uptake, although no alterations in Epm2b -/- mice were observed. Magnetic resonance spectroscopy (MRS) revealed significant changes in the concentration of several brain metabolites, including N -acetylaspartate (NAA), in agreement with previously described findings in patients. These data may provide new insights into disease mechanisms that may be of value for developing new biomarkers for diagnosis, prevention and treatment of Lafora disease using animal models.

The development of double haploids (DHs) is a straightforward path for obtaining pure lines but has multiple bottlenecks. Among them is the determination of the optimal stage of pollen induction for androgenesis. In this work, we developed Microscan, a deep learning-based system for the detection and recognition of the stages of pollen development. In a first experiment, the algorithm was developed adapting the RetinaNet predictive model using microspores of different eggplant accessions as samples. A mean average precision of 86.30% was obtained. In a second experiment, the anther range to be cultivated in vitro was determined in three eggplant genotypes by applying the Microscan system. Subsequently, they were cultivated following two different androgenesis protocols (Cb and E6). The response was only observed in the anther size range predicted by Microscan, obtaining the best results with the E6 protocol. The plants obtained were characterized by flow cytometry and with the Single Primer Enrichment Technology high-throughput genotyping platform, obtaining a high rate of confirmed haploid and double haploid plants. Microscan has been revealed as a tool for the high-throughput efficient analysis of microspore samples, as it has been exemplified in eggplant by providing an increase in the yield of DHs production.

Nowadays, biomaterials have become a crucial element in numerous biomedical, preclinical, and clinical applications. The use of nanoparticles entails a great potential in these fields mainly because of the high ratio of surface atoms that modify the physicochemical properties and increases the chemical reactivity. Among them, carbon nanotubes (CNTs) have emerged as a powerful tool to improve biomedical approaches in the management of numerous diseases. CNTs have an excellent ability to penetrate cell membranes, and the sp 2 hybridization of all carbons enables their functionalization with almost every biomolecule or compound, allowing them to target cells and deliver drugs under the appropriate environmental stimuli. Besides, in the new promising field of artificial biomaterial generation, nanotubes are studied as the load in nanocomposite materials, improving their mechanical and electrical properties, or even for direct use as scaffolds in body tissue manufacturing. Nevertheless, despite their beneficial contributions, some major concerns need to be solved to boost the clinical development of CNTs, including poor solubility in water, low biodegradability and dispersivity, and toxicity problems associated with CNTs' interaction with biomolecules in tissues and organs, including the possible effects in the proteome and genome. This review performs a wide literature analysis to present the main and latest advances in the optimal design and characterization of carbon nanotubes with biomedical applications, and their capacities in different areas of preclinical research.

Suicide, a major public health concern, takes around 800,000 lives globally every year and is the second leading cause of death among adolescents and young adults. Despite substantial prevention efforts, between 1999 and 2017, suicide and nonfatal self-injury rates have experienced unprecedented increases across the United States - as well as in many other countries in the world. This chapter reviews the existing evidence on the causes behind increased suicide rates and critically evaluates the impact of a range of innovative approaches to suicide prevention. First, we briefly describe current trends in suicide and suicidal behaviors and relate them to recent time trends in relevant suicide risk markers. Then, we review the existing evidence in suicide prevention at the individual and the population levels, including new approaches that are currently under development. Finally, we advocate for a new generation of suicide research that examines causal factors beyond the proximal and clinical and fosters a socially conscious reimagining of suicidal prevention. To this end, we emphasize the need for the conceptualization of suicide and suicidal behaviors as complex phenomena with causes at several levels of organization. Future interdisciplinary research and interventions should be developed within a multilevel causal framework that can better capture the social, economic, and political settings where suicide, as a process, unfolds across the life course.

Iodinated contrast media (CM) are the leading cause of acute renal failure of toxic origin. Between 21% and 50% of patients that receive them develop contrast-induced nephropathy (CIN). All prophylactic measures used so far have failed to provide effective prevention. Since oxidative stress is involved in the damage, a possible preventive strategy could be the administration of antioxidant substances, such as quercetin. This compound has shown renoprotective effects in experimental studies. The aim of this study was to evaluate whether quercetin may be helpful in preventing CIN in patients undergoing coronary catheterization. A clinical phase II study was conducted. Patients were distributed in two groups, namely, CM (patients who only received contrast media) and CM+Q (patients who were pretreated with quercetin orally for 3-5 days). Results showed less incidence of CIN in the CM+Q group, possibly due to glomerular protection, evidenced by a lower increase in serum creatinine and albuminuria; and a lower decrease in the glomerular filtration rate (GFR). Furthermore, in this group, the relative risk of developing CIN observed in patients that received a high dose of contrast media was inferior. In conclusion, this is the first study that demonstrates that quercetin is a promising safe candidate in preventing CIN.

Antimicrobial resistance is increasing despite new treatments being employed. With a decrease in the discovery rate of novel antibiotics, this threatens to take humankind back to a "pre-antibiotic era" of clinical care. Bacteriophages (phages) are one of the most promising alternatives to antibiotics for clinical use. Although more than a century of mostly ad-hoc phage therapy has involved substantial clinical experimentation, a lack of both regulatory guidance standards and effective execution of clinical trials has meant that therapy for infectious bacterial diseases has yet to be widely adopted. However, several recent case studies and clinical trials show promise in addressing these concerns. With the antibiotic resistance crisis and urgent search for alternative clinical treatments for bacterial infections, phage therapy may soon fulfill its long-held promise. This review reports on the applications of phage therapy for various infectious diseases, phage pharmacology, immunological responses to phages, legal concerns, and the potential benefits and disadvantages of this novel treatment.

Background: Colorectal cancer (CRC) is the second most common cause of cancer death worldwide. It is broadly described that cyclooxygenase-2 (COX-2) is mainly overexpressed in CRC but less is known regarding post-translational modifications of this enzyme that may regulate its activity, intracellular localization and stability. Since metabolic and proteomic profile analysis is essential for cancer prognosis and diagnosis, our hypothesis is that the analysis of correlations between these specific parameters and COX-2 state in tumors of a high number of CRC patients could be useful for the understanding of the basis of this cancer in humans., Aim: To analyze COX-2 regulation in colorectal cancer and to perform a detailed analysis of their metabolic and proteomic profile., Methods: Biopsies from both healthy and pathological colorectal tissues were taken under informed consent from patients during standard colonoscopy procedure in the University Hospital of Bellvitge (Barcelona, Spain) and Germans Trias i Pujol University Hospital (Campus Can Ruti) (Barcelona, Spain). Western blot analysis was used to determine COX-2 levels. Deglycosylation assays were performed in both cells and tumor samples incubating each sample with peptide N-glycosidase F (PNGase F). Prostaglandin E 2 (PGE 2 ) levels were determined using a specific ELISA. 1 H high resolution magic angle spinning (HRMAS) analysis was performed using a Bruker AVIII 500 MHz spectrometer and proteomic analysis was performed in a nano-liquid chromatography-tandem mass spectrometer (nano LC-MS/MS) using a QExactive HF orbitrap MS., Results: Our data show that COX-2 has a differential expression profile in tumor tissue of CRC patients vs the adjacent non-tumor area, which correspond to a glycosylated and less active state of the protein. This fact was associated to a lesser PGE 2 production in tumors. These results were corroborated in vitro performing deglycosylation assays in HT29 cell line where COX-2 protein profile was modified after PNGase F incubation, showing higher PGE 2 levels. Moreover, HRMAS analysis indicated that tumor tissue has altered metabolic features vs non-tumor counterparts, presenting increased levels of certain metabolites such as taurine and phosphocholine and lower levels of lactate. In proteomic experiments, we detected an enlarged number of proteins in tumors that are mainly implicated in basic biological functions like mitochondrial activity, DNA/RNA processing, vesicular trafficking, metabolism, cytoskeleton and splicing., Conclusion: In our colorectal cancer cohort, tumor tissue presents a differential COX-2 expression pattern with lower enzymatic activity that can be related to an altered metabolic and proteomic profile., Competing Interests: Conflict-of-interest statement: MAP is cofounder and equity holder of Aniling, a biotech company with no interests in this work. MAP lab has received research funding from Celgene. The rest of the authors declare no conflict of interest.

Magnetic resonance imaging (MRI) is a technique based on the contents and relaxation features of water in tissues. In basic MRI sequences, diffusion phenomenon of water molecules is not taken into account although it has a notable influence in the relaxation times, and therefore in the signal intensity of images. In fact, MRI techniques that take advantage of water diffusion have experienced a huge development in last years. Diffusion-weighted imaging (DWI) has spectacularly evolved reaching nowadays a great impact both in clinical and preclinical imaging-especially in the neuroimaging field-and in basic research. We present here a protocol to perform DWI studies in a high-field preclinical setup.

Clinical imaging modalities have reached a prominent role in medical diagnosis and patient management in the last decades. Different image methodologies as Positron Emission Tomography, Single Photon Emission Tomography, X-Rays, or Magnetic Resonance Imaging are in continuous evolution to satisfy the increasing demands of current medical diagnosis. Progress in these methodologies has been favored by the parallel development of increasingly more powerful contrast agents. These are molecules that enhance the intrinsic contrast of the images in the tissues where they accumulate, revealing noninvasively the presence of characteristic molecular targets or differential physiopathological microenvironments. The contrast agent field is currently moving to improve the performance of these molecules by incorporating the advantages that modern nanotechnology offers. These include, mainly, the possibilities to combine imaging and therapeutic capabilities over the same theranostic platform or improve the targeting efficiency in vivo by molecular engineering of the nanostructures. In this review, we provide an introduction to multimodal imaging methods in biomedicine, the sub-nanometric imaging agents previously used and the development of advanced multimodal and theranostic imaging agents based in nanotechnology. We conclude providing some illustrative examples from our own laboratories, including recent progress in theranostic formulations of magnetoliposomes containing ω-3 poly-unsaturated fatty acids to treat inflammatory diseases, or the use of stealth liposomes engineered with a pH-sensitive nanovalve to release their cargo specifically in the acidic extracellular pH microenvironment of tumors.

Magnetic resonance images are obtained by a combination of different radiofrequency pulses and gradient waveforms applied to the subject inside a magnetic field. There are multiple pulse sequences used in clinical and preclinical studies adjusted to whatever physician or researches want to analyze, from basic anatomic images to accurate diagnostic techniques as diffusion, perfusion, or functional imaging. In this chapter, we present the most used radiofrequency pulse combinations of the two groups of sequences available in magnetic resonance imaging: spin-echo and gradient-echo sequences.

Background: Acquired hemophilia A (AHA) is a rare bleeding disease caused by autoantibodies against factor VIII. Spontaneous bleeding symptoms usually affect the skin and muscle, while pericardial effusion is an extremely rare manifestation. In the elderly, anticoagulant treatment is frequent and bleeding symptoms are usually associated with this., Clinical Findings: We report a hemorrhagic pericardial effusion as the AHA debut in a patient with untreated chronic lymphocytic leukemia and anticoagulated with apixaban for atrial fibrillation and chronic arterial ischemia. The patient was treated with recombinant activated factor VII to control the active bleeding and corticosteroids and cyclophosphamide to eradicate the inhibitor. In addition, a briefly review of hematological malignancies associated to acquired hemophilia was performed. PARTICULARITIES:: a) anticoagulant treatment may confuse the suspicion of AHA and its diagnosis; b) hemorrhagic pericardial effusion is an extremely rare presentation; c) bypassing agents raise the risk of thromboembolism; d) hematological malignancies rarely cause AHA (<20% of cases)., Conclusion: A multidisciplinary team is needed to diagnose and manage AHA effectively. The use of anticoagulants may lead to the misdiagnosis of clinical symptoms. Chronic lymphocytic leukemia is one of the main causes of hematological malignancies associated. The specific treatment of CLL is still recommended in the event of active disease., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The relaxivity displayed by Gd(3+) chelates immobilized onto gold nanoparticles is the result of the complex interplay between the nanoparticle size, the water exchange rate and the chelate structure. In this work we study the effect of the length of ω-thioalkyl linkers, anchoring fast water exchanging Gd(3+) chelates onto gold nanoparticles, on the relaxivity of the immobilized chelates. Gold nanoparticles functionalized with Gd(3+) chelates of mercaptoundecanoyl and lipoyl amide conjugates of the DO3A-N-(α-amino)propionate chelator were prepared and studied as potential CA for MRI. High relaxivities per chelate, of the order of magnitude 28-38 mM(-1) s(-1) (30 MHz, 25 °C), were attained thanks to simultaneous optimization of the rotational correlation time and of the water exchange rate. Fast local rotational motions of the immobilized chelates around connecting linkers (internal flexibility) still limit the attainable relaxivity. The degree of internal flexibility of the immobilized chelates seems not to be correlated with the length of the connecting linkers. Biodistribution and MRI studies in mice suggest that the in vivo behavior of the gold nanoparticles was determined mainly by size. Small nanoparticles (HD = 3.9 nm) undergo fast renal clearance and avoidance of the RES organs while larger nanoparticles (HD = 4.8 nm) undergo predominantly hepatobiliary excretion. High relaxivities, allied to chelate and nanoparticle stability and fast renal clearance in vivo suggest that functionalized gold nanoparticles hold great potential for further investigation as MRI contrast agents. This study contributes to a better understanding of the effect of linker length on the relaxivity of gold nanoparticles functionalized with Gd(3+) complexes. It is a relevant contribution towards "design rules" for nanostructures functionalized with Gd(3+) chelates as Contrast Agents for MRI and multimodal imaging.

We describe the preparation, physico-chemical characterization and anti-inflammatory properties of liposomes containing the superparamagnetic nanoparticle Nanotex, the fluorescent dye Rhodamine-100 and omega-3 polyunsaturated fatty acid ethyl ester (ω-3 PUFA-EE), as theranostic anti-inflammatory agents. Liposomes were prepared after drying chloroform suspensions of egg phosphatidylcholine, hydration of the lipid film with aqueous phases containing or not Nanotex, Rhodamine-100 dye or ω-3 PUFA-EE, and eleven extrusion steps through nanometric membrane filters. This resulted in uniform preparations of liposomes of approximately 200 nm diameter. Extraliposomal contents were removed from the preparation by gel filtration chromatography. High Resolution Magic Angle Spinning (1)H NMR Spectroscopy of the liposomal preparations containing ω-3 PUFA-EE revealed well resolved (1)H resonances from highly mobile ω-3 PUFA-EE, suggesting the formation of very small (ca. 10 nm) ω-3 PUFA-EE nanogoticules, tumbling fast in the NMR timescale. Chloroform extraction of the liposomal preparations revealed additionally the incorporation of ω-3 PUFA-EE within the membrane domain. Water diffusion weighted spectra, indicated that the goticules of ω-3 PUFA-EE or its insertion in the membrane did not affect the average translational diffusion coefficient of water, suggesting an intraliposomal localization, that was confirmed by ultrafiltration. The therapeutic efficacy of these preparations was tested in two different models of inflammatory disease as inflammatory colitis or the inflammatory component associated to glioma development. Results indicate that the magnetoliposomes loaded with ω-3 PUFA-EE allowed MRI visualization in vivo and improved the outcome of inflammatory disease in both animal models, decreasing significantly colonic inflammation and delaying, or even reversing, glioma development. Together, our results indicate that magnetoliposomes loaded with ω-3 PUFA-EE may become useful anti-inflammatory agents for image guided drug delivery.

A novel synthetic methodology for preparing amide conjugates of the DO3A-N-(α-amino)propionate chelator is described, using the synthesis of the DO3A-N-(α-benzoylamido)propionate chelator as an illustrative example. The model Gd[DO3A-N-(α-benzoylamido)propionate] chelate displays accelerated water exchange, stability in a wide pH range and inertness towards transmetallation by Zn(2+). The Gd[DO3A-N-(α-benzoylamido)propionate] complex is mainly excreted via the kidneys, producing a significant increase in the kidney medulla/cortex enhancement ratio in MR images of Wistar rats, reflecting probably its higher lipophilicity compared with Gd(DTPA). The results presented suggest that Gd[DO3A-N-(α-amido)propionate] chelates can be valuable leads for preparing potentially safe high relaxivity MRI contrast agents., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background. Giardia lamblia is an important cause of diarrhoeal disease throughout the world. Giardiasis- a mild and self-limiting disease that this protozoan causes- is perceived as a harmful disease. Aim. To explore the general level of awareness about giardiasis, clinical features, mode of transmission, prevention, and consequences and describe the sources and channels of information caregivers would prefer using to be informed about this disease. Methods. A cross-sectional survey was conducted among caregivers attending to the outpatient paediatric hospital setting in Havana. Results. A total of 202 caregivers were interviewed. Nearly 73% considered giardiasis as a modern problem, and 39% considered that it could be a fatal disease. Although 76.7% were aware that small intestine is the organ affected, other localizations were cited. Abdominal pain and diarrhoea were recognized as the commonest symptoms. Around one-third could identify that giardiasis may spread through drinking unboiled water and unwashed vegetables other incorrect ways were mentioned; respondents with more than 12 years of formal education were more likely to have better knowledge. Discussion. Strategies to control giardiasis need to be through an integrated approach aiming at boosting caregivers' knowledge and encouraging healthcare workers to act as a readily available source for health information.

Objectives: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of primary progressive multiple sclerosis, differences in the evolution of clinical variables and magnetic resonance imaging results between trial arms and to investigate correlations between in-trial changes in Multiple Sclerosis Functional Composite (MSFC) score and magnetic resonance imaging variables and Expanded Disability Status Scale (EDSS) score evolution., Design: Five-year clinical trial follow-up., Setting: Clinical Neuroimmunology Unit, Multiple Sclerosis Centre of Catalonia, Autonomous University of Barcelona, Spain. Patients  Seventy-three patients received interferon beta-1b or placebo during the trial., Main Outcome Measures: After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 patients, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 patients, respectively., Results: After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (P = .02) and Word List Generation Test (P < .001) scores, and their magnetization transfer ratio measures in the normal-appearing white matter were significantly higher (P = .02, P = .009, and P = .03 for the mean, peak location, and peak height magnetic transfer ratios, respectively). During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain parenchymal fraction (P = .004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (P = .004)., Conclusions: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.

Even though alterations in the microenvironmental properties of tissues underlie the development of the most prevalent and morbid pathologies, they are not directly observable in vivo by Magnetic Resonance Imaging (MRI) or Spectroscopy (MRS) methods. This circumstance has lead to the development of a wide variety of exogenous paramagnetic and diamagnetic MRI and MRS probes able to inform non invasively on microenvironmental variables such as pH, pO(2), ion concentration o even temperature. This review covers the fundamentals of environmental contrast and the current arsenal of endogenous and exogenous MRI and MRS contrast enhancing agents available to visualize it. We begin describing the physicochemical background necessary to understand paramagnetic and diamagnetic contrast enhancement with a special reference to novel magnetization transfer and (13)C hyperpolarization strategies. We describe then the main macrocyclic structures used to support the environmentally sensitive paramagnetic sensors, including CEST and PARACEST pH sensitive probes, temperature probes and enzyme activity or gene expression activatable probes. Finally we address the most commonly used diamagnetic contrast agents including imidazolic derivatives to reveal extracellular pH and tissue pO(2) values by MRS. The potential applications of these agents in multimodal and molecular imaging approaches are discussed.

The term "plexic hand" refers to hand and wrist involvement in traumatic brachial plexus injuries and to remaining deficits after nerve surgery has been performed. From January 2000 to March 2008, reconstructive surgery (dynamic tenodesis) was performed on seven patients with C5, 6, 7, and 8 nerve root lesions of the brachial plexus to restore wrist and finger extension. This procedure has been used in seven patients (one female). Two patients with a lesion of the brachial plexus sustained a fracture of the affected limb. Preliminary nerve repair operations were required in four cases. One hundred percent (seven) of the patients had improved function following dynamic tenodesis. The extension angle of the wrist joint on grip was 19° on average. The flexion angle of the wrist joint needed to produce MP joint extension was 24.3° on average. A new dynamic extensor tenodesis technique is proposed. The extensor digitorum communis tendons are looped through dorsal carpal retinaculum ligament and sutured to themselves. Our results demonstrate that the extensor dynamic tenodesis procedure is an effective and simple means of restoring grip function for patients with C5, 6, 7, and 8 nerve root lesions.

Background: The ideal treatment of nonunion of the scaphoid remains unresolved and controversial. It was hypothesized that scaphoid nonunion could be treated successfully using a closed-wedge osteotomy of the distal radius which reduces the inclination of the joint surface and decreases the pressure between the radial and scaphoid surfaces with a reduction of the force applied by the styloid process. We present a preliminary report in six patients with nonunion of the carpal scaphoid using this procedure. The main objective of the osteotomy is to achieve fusion, alleviate pain, and improve function., Materials and Methods: Six closed-wedge osteotomies to reduce the inclination of the distal radial surface were performed in patients with scaphoid waist nonunion and a viable proximal pole, without posttrauma osteoarthritis or with moderate posttraumatic osteoarthritis confined to the radio-scaphoid joint. The present series of six patients (all men) were followed for at least 8 months (mean follow-up 14.2 months, range 8-21 months)., Results: Solid union was achieved in five patients. Postoperatively, three patients were pain-free, two presented mild pain for heavy work, and one had moderate pain. This type of osteotomy reduced the inclination of the joint surface (radial angulation) 6.2 degrees on average. There was an improvement in joint flexion from a preoperative mean of 40 degrees to 52.5 degrees at last follow-up, in extension from 40.8 degrees to 66.7 degrees , in radial deviation from 15 degrees to 22.5 degrees , and in ulnar deviation from 30.8 degrees to 41.7 degrees ., Conclusions: This preliminary study suggests that a closed-wedge osteotomy of the distal radius could be an alternative approach for patients with scaphoid waist nonunion and a viable proximal pole, without posttrauma osteoarthritis or with moderate posttraumatic osteoarthritis confined to the radio-scaphoid joint. The number of cases was small; however, further studies with a much larger series are needed before routine use of wedge osteotomy in scaphoid nonunion can be recommended.

Traumatic brachial plexus injuries are a devastating injury that results in partial or total denervation of the muscles of the upper extremity. Treatment options that include neurolysis, nerve grafting, or neurotization (nerve transfer) has become an important procedure in the restoration of function in patients with irreparable preganglionic lesions. Restoration of elbow flexion is the primary goal in treating patients with severe brachial plexus injuries. Nerve transfers are used when spinal roots are avulsed, and proximal stumps are not available. In the present study, we analyze the results obtained in 20 patients treated with phrenic-musculocutaneous nerve transfer to restore elbow flexion after brachial plexus injuries. A consecutive series of 25 adult patients (21 men and 4 women) with a brachial plexus traction/crush lesion were treated with phrenic-musculocutaneous nerve transfer, but only 20 patients (18 men and 2 women) were followed and evaluated for at least 2 years postoperatively. All patients had been referred from other institutions. At the initial evaluation, eight patients received a diagnosis of C5-6 brachial plexus nerve injury, and in the other 12 patients, a complete brachial plexus injury was identified. Reconstruction was undertaken if no clinical or electrical evidence of biceps muscle function was seen by 3 months post injury. Functional elbow flexion was obtained in the majority of cases by phrenic-musculocutaneous nerve transfer (14/20, 70%). At the final follow-up evaluation, elbow flexion strength was a Medical Research Council Grade 5 in two patients, Grade 4 in four patients, Grade 3 in eight patients, and Grade 2 or less in six patients. Transfer involving the phrenic nerve to restore elbow flexion seems to be an appropriate approach for the treatment of brachial plexus root avulsion. Traumatic brachial plexus injury is a devastating injury that result in partial or total denervation of the muscles of the upper extremity. Treatment options include neurolysis, nerve grafting, or neurotization (nerve transfer). Neurotization is the transfer of a functional but less important nerve to a denervated more important nerve. It has become an important procedure in the restoration of function in patients with irreparable preganglionic lesions. Restoration of elbow flexion is the primary goal in treating patients with severe brachial plexus injuries. Nerve transfers are used when spinal roots are avulsed, and proximal stumps are not available. Newer extraplexal sources include the ipsilateral phrenic nerve as reported by Gu et al. (Chin Med J 103:267-270, 1990) and contralateral C7 as reported by Gu et al. (J Hand Surg [Br] 17(B):518-521, 1992) and Songcharoen et al. (J Hand Surg [Am] 26(A):1058-1064, 2001). These nerve transfers have been introduced to expand on the limited donors. The phrenic nerve and its anatomic position directly within the surgical field makes it a tempting source for nerve transfer. Although not always, in cases of complete brachial plexus avulsion, the phrenic nerve is functioning as a result of its C3 and C4 major contributions. In the present study, we analyze the results obtained in 20 patients treated with phrenic-musculocutaneous nerve transfer to restore elbow flexion after brachial plexus injuries.

Background: Loss of elbow flexion due to traumatic palsy of the brachial plexus represents a major functional handicap.Then, the first goal in the treatment of the flail arm is to restore the elbow flexion by primary direct nerve surgery or secondary reconstructive surgery. There are various methods to restore elbow flexion which are well documented in the medical literature but the most known and used is Steindler flexorplasty.This review is intended to detail the author's experience with Steindler flexorplasty to restore elbow flexion in patients with brachial plexus palsy C5-C6-C7 where wrist extensors are paralyzed or weakened., Methods: We conducted a retrospective follow-up study of 12 patients with absent or extremely weak elbow flexion (motor grade 2 or less), wrist/finger extensor and triceps palsy associated; who had undergone surgical reconstruction of the flail upper limb by tendon transfer (Steindler flexorplasty) and wrist arthrodesis to restore elbow flexion. The aetiology of elbow weakness was in all patients brachial plexus palsy (C5-C6-C7 deficit). Data were collected from medical records and from the information obtained during follow-up visits.Age, sex, preoperative strength (rated on a 0 to 5 scale for the flexors of the elbow, wrist flexors, pronator and triceps), previous surgery, length of follow-up, other associated operative procedures, results and complications were recorded., Results: The results are the follows: Eleven patients were found to have very good or good function of the transferred muscles. One patient had mild active flexion of the elbow despite the reconstructive procedure. There were no major intraoperative complications. Two patients experienced transient, intermittent nocturnal ulnar paresthesias postoperatively. In both patients these symptoms subsided without further surgery., Conclusion: Our study suggests that in patients with C5-C6-C7 palsy where the wrist and finger extensors are paralyzed or weaked, the flexor-pronators muscles of the forearm are strong but the triceps is not available for transfer; Steindler flexorplasty to restore elbow flexion should be complemented with wrist arthrodesis.

Background: After severe brachial palsy involving the shoulder, many different muscle transfers have been advocated to restore movement and stability of the shoulder. Paralysis of the deltoid and supraspinatus muscles can be treated by transfer of the trapezius., Methods: We treated 10 patients, 8 males and 2 females, by transfer of the trapezius to the proximal humerus. In 6 patients the C5 and C6 roots had been injured; in one C5, C6 and C7 roots; and 3 there were complete brachial plexus injuries. Eight of the 10 had had neurosurgical repairs before muscle transfer. Their average age was 28.3 years (range 17 to 41), the mean delay between injury and transfer was 3.1 years (range 14 months to 6.3 years) and the average follow-up was 17.5 months (range 6 to 52), reporting the clinical and radiological results. Evaluation included physical and radiographic examinations. A modification of Mayer's transfer of the trapezius muscle was performed. The principal goal of this work was to evaluate the results of the trapezius transfer for flail shoulder after brachial plexus injury., Results: All 10 patients had improved function with a decrease in instability of the shoulder. The average gain in shoulder abduction was 46.2 degrees; the gain in shoulder flexion average 37.4 degrees. All patients had stable shoulder (no subluxation of the humeral head on radiographs)., Conclusion: Trapezius transfer for a flail shoulder after brachial plexus palsy can provide satisfactory function and stability.

The use of pedicled vascularised bone grafts from the distal radius makes it possible to transfer bone with a preserved circulation and viable osteoclasts and osteoblasts. Experiments performed at the basic science level has provided substantial evidence that low-intensity ultrasound can accelerate and augment the fracture healing process. Only an adequate double-blind trial comparing treatment by ultrasound stimulation in patients treated by similar surgical techniques can provide evidence of the true effect of ultrasound. This paper describes the results of such a trial. From 1999 to 2004, 21 fractures of the scaphoid with established non-union treated with vascularised pedicle bone graft were selected for inclusion in a double-blind trial. All patients were males, with an average age of 26.7 years (range 17-42 years) and an average interval between injury and surgery of 38.4 months (range 3 months-10 years). Low-intensity ultrasound was delivered using a TheraMed 101-B bone-growth stimulator (30 mW/cm2, 20 min/day), which was modified to accomplish double-blinding. These modifications did not affect the designated active units. The placebo units were adjusted to give no ultrasound signal output across the transducer. Externally, all units appeared identical but were marked with individual code numbers. Patients were randomly allocated to either an active or placebo stimulation. Follow-up averaged 2.3 years (range 1-4 years). All patients achieved fracture union (active and placebo groups), but compared with the placebo device (11 patients), the active device (ten patients) accelerated healing by 38 days (56+/-3.2 days compared with 94+/-4.8 days, p<0.0001, analysis of variance).

We carried out a retrospective review of 32 consecutive patients (30 adults and two children) with total or partial lesions of the brachial plexus who had surgical repair using nerve grafting, neurotisation, and neurolysis between January 1991 and December 2003. The outcome measures of muscular strength were correlated with the type of lesion, age, preoperative time, length and number of grafts, and time to reinnervation of the biceps. The function of the upper limb was also evaluated. There was a significant correlation between muscular strength after surgical repair and both the preoperative time and the length of the nerve graft. There was also a significant correlation between muscular strength and the number of grafts. Muscular strength was better when the neurolysis was done before six months. When neurosurgical repair and reconstructive procedures were performed, the function of the upper limb was improved.

Paracoccidioidomycosis (PCM) is a primary pulmonary infection that often disseminates to other organs and systems. Involvement of the central nervous system (CNS) is rare and due to the fact that both clinical alertness and establishment of the diagnosis are delayed, the disease progresses causing serious problems. We report here a case of neuroparacoccidioidomycosis (NPCM), observed in a 55 year-old male, who consulted due to neurological symptoms (left hemiparesis, paresthesias, right palpebral ptosis, headache, vomiting and tonic clonic seizures) of a month duration. Upon physical examination, an ulcerated granulomatous lesion was observed in the abdomen. To confirm the diagnosis a stereotactic biopsy was taken; additionally, mycological tests from the ulcerated lesion and a bronchoalveolar lavage were performed. In the latter specimens, P. brasiliensis yeast cells were visualized and later on, the brain biopsy revealed the presence of the fungus. Treatment with itraconazole (ITZ) was initiated but clinical improvement was unremarkable; due to the fact that the patient was taking sodium valproate for seizure control, drug interactions were suspected and confirmed by absence of ITZ plasma levels. The latter medication was changed to clonazepam and after several weeks, clinical improvement began to be noticed and was accompanied by diminishing P. brasiliensis antigen and antibody titers. In the PCM endemic areas, CNS involvement should be considered more often and the efficacy of itraconazole therapy should also be taken into consideration.

The Flemish Information System for Drugfree Therapeutic Programs (VLIS-DC) is a computerised information system designed for residential treatment programs for drug addicts. The input is data from the therapeutic centers and the output is information for management, research and treatment. The system was installed in 1988. The final report for this first year has not yet been published, except for some preliminary results presented here. VLIS-DC generates information from clients admitted during 1988 in 8 departments in 6 centers for the whole Flemish region. Data of 623 admissions in these centers can be analysed. 411 were drug addicts (opiates, cocaine, amphetamines, cannabis, hallucinogens, solvents), 119 alcohol addicts and 75 addicted to medication. Of the total, 478 were daily users. The VLIS-DC is well functioning because all centers take part. Within a short time, more detailed information will become available from these centers.