A Concise Synthesis of a BODIPY-Labeled Tetrasaccharide Related to the Antitumor PI-88

A convergent synthetic route to a tetrasaccharide related to PI-88, which allows the incorporation of a fluorescent BODIPY-label at the reducing-end, has been developed. The strategy, which features the use of 1,2-methyl orthoesters (MeOEs) as glycosyl donors, illustrates the usefulness of suitably-designed BODIPY dyes as glycosyl labels in synthetic strategies towards fluorescently-tagged oligosaccharides.This research was funded by Spanish MINISTERIO DE ECONOMIA Y COMPETITIVIDAD, GOBIERNO DE ESPAÑA (projects MAT2017–83856-C3-1-P and 3-P, PiD2020-1147555GB-C33), the MINISTERIO DE CIENCIA INNOVACION Y UNIVERSIDADES (project RTI2018-094862-B-I00), and the GOBIERNO VASCO (project IT912-16)

Oxygen dependency of mitochondrial metabolism indicates outcome of newborn brain injury

There is a need for a method of real-time assessment of brain metabolism during neonatal hypoxic-ischaemic encephalopathy (HIE). We have used broadband near-infrared spectroscopy (NIRS) to monitor cerebral oxygenation and metabolic changes in 50 neonates with HIE undergoing therapeutic hypothermia treatment. In 24 neonates, 54 episodes of spontaneous decreases in peripheral oxygen saturation (desaturations) were recorded between 6 and 81 h after birth. We observed differences in the cerebral metabolic responses to these episodes that were related to the predicted outcome of the injury, as determined by subsequent magnetic resonance spectroscopy derived lactate/N-acetyl-aspartate. We demonstrated that a strong relationship between cerebral metabolism (broadband NIRS-measured cytochrome-c-oxidase (CCO)) and cerebral oxygenation was associated with unfavourable outcome; this is likely to be due to a lower cerebral metabolic rate and mitochondrial dysfunction in severe encephalopathy. Specifically, a decrease in the brain tissue oxidation state of CCO greater than 0.06 µM per 1 µM brain haemoglobin oxygenation drop was able to predict the outcome with 64% sensitivity and 79% specificity (receiver operating characteristic area under the curve = 0.73). With further work on the implementation of this methodology, broadband NIRS has the potential to provide an early, cotside, non-invasive, clinically relevant metabolic marker of perinatal hypoxic-ischaemic injury

Guillain-Barré syndrome following the 2009 pandemic monovalent and seasonal trivalent influenza vaccination campaigns in Spain from 2009 to 2011: Outcomes from active surveillance by a neurologist network, and records from a country-wide hospital discharge database

Background: Studies have shown a slight excess risk in Guillain-Barré syndrome (GBS) incidence associated with A(H1N1)pdm09 vaccination campaign and seasonal trivalent influenza vaccine immunisations in 2009-2010. We aimed to assess the incidence of GBS as a potential adverse effect of A(H1N1)pdm09 vaccination. Methods: A neurologist-led network, active at the neurology departments of ten general hospitals serving an adult population of 4.68 million, conducted GBS surveillance in Spain in 2009-2011. The network, established in 1996, carried out a retrospective and a prospective study to estimate monthly alarm thresholds in GBS incidence and tested them in 1998-1999 in a pilot study. Such incidence thresholds additionally to observation of GBS cases with immunisation antecedent in the 42 days prior to clinical onset were taken as alarm signals for 2009-2011, since November 2009 onwards. For purpose of surveillance, in 2009 we updated both the available centres and the populations served by the network. We also did a retrospective countrywide review of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis from January 2009 to December 2011. Results: Among 141 confirmed of 148 notified cases of GBS or Miller-Fisher syndrome, Brighton 1-2 criteria in 96 %, not a single patient was identified with clinical onset during the 42-day time interval following A(H1N1)pdm09 vaccination. In contrast, seven cases were seen during a similar period after seasonal campaigns. Monthly incidence figures did not, however, exceed the upper 95 % CI limit of expected incidence. A retrospective countrywide review of the registry of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis did not suggest higher admission rates in critical months across the period December 2009-February 2010. Conclusions: Despite limited power and underlying reporting bias in 2010-2011, an increase in GBS incidence over background GBS, associated with A(H1N1)pdm09 monovalent or trivalent influenza immunisations, appears unlikely

Proton Magnetic Resonance Spectroscopy Lactate/N-Acetylaspartate within 2 weeks of birth accurately predicts 2-year motor, cognitive and language outcomes in Neonatal Encephalopathy after Therapeutic Hypothermia

OBJECTIVE: Brain proton (1H) magnetic resonance spectroscopy (MRS) lactate/N-Acetylaspartate (Lac/NAA) peak area ratio is used for prognostication in Neonatal Encephalopathy (NE). At 3-Tesla in NE babies, the objectives were to assess: (i) sensitivity and specificity of basal ganglia and thalamus (BGT) 1H MRS Lac/NAA for prediction of Bayley III outcomes at 2-years using optimized metabolite fitting (Tarquin) with threonine and total NAA; (ii) prediction of motor outcome with diffusion-weighted MRI; iii) BGT Lac/NAA correlation with the NICHD MRI score. MATERIALS AND METHODS: 55 (16 inborn, 39 outborn) NE infants at 39w+5d (35w+5d-42w+0d) admitted between February 2012 and August 2014 to UCH for therapeutic hypothermia underwent MRI and 1H MRS at 3T on day 2-14 (median day 5). MRIs were scored. Bayley III was assessed at 24 (22-26) months. RESULTS: Sixteen babies died (1 inborn, 15 outborn); 20, 19 and 21 babies had poor motor, cognitive and language outcomes. Using a threshold of 0.39, sensitivity and specificity of BGT Lac/NAA for 2-year motor outcome was 100% and 97%, cognition 90% and 97% and language 81% and 97% respectively. Sensitivity and specificity for motor outcome of mean diffusivity (MD; threshold 0.001 mm2 /s) up to day 9 was 72% and 39% and fractional anisotropy (FA; threshold 0.198) was 100%, and 94% respectively. Lac/NAA correlated with BGT injury on NICHD scores (2A, 2B, 3). CONCLUSIONS: BGT Lac/NAA on 1H MRS at 3T within 14 days accurately predicts 2-year motor, cognitive and language outcome and may be a marker directing decisions for therapies after cooling

Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia

Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue. Copyright

Recommendations for the design of therapeutic trials for neonatal seizures

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from welldesigned clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population

Reproductive cycle of the bivalves Ensis macha (Molina, 1782) (Solenidae), Tagelus dombeii (Lamarck, 1818) (Solecurtidae), and Mulinia edulis (King, 1831) (Mactridae) in southern Chile

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Comparison of the antinociceptive profiles of morphine and oxycodone in two models of inflammatory and osteoarthritic pain in rat

Oxycodone and morphine are two opioid drugs commonly used for the treatment of moderate to severe pain. However, their use in the management of noncancer pain remains a controversial issue and, in this respect, the evidence on their effectiveness and safety, particularly in osteoarthritis, is being questioned. In order to analyse their analgesic profile, two different pain models in rats were used: the formalin-induced inflammatory pain and the monosodium iodoacetate (MIA)-induced knee osteoarthritic pain. Drugs were administered systemically (i.p.) and their antinociceptive effect and potency were assessed. In the formalin test, both morphine and oxycodone produced a dose-dependent antinociceptive effect, but oxycodone outdid morphine in terms of effectiveness and potency (nearly two times) in the early (acute nociceptive) as in the late phase (inflammatory). In the osteoarthritis model, both drugs reduced movement–evoked pain (knee-bend test), mechanical allodynia (von Frey test) and heat hyperalgesia (Plantar test). Pretreatment with naloxone and naloxone methiodide reduced morphine and oxycodone effects. Peripheral mu-opioid receptors play a crucial role in the antinociceptive effect of both drugs on movement-evoked pain and heat hyperalgesia, but not on tactile allodynia. The main finding of our study is that oxycodone has a better antinociceptive profile in the inflammatory and osteoarthritic pain, being more effective than morphine at 14 days post-MIA injection (phase with neuropathic pain); it overcame the morphine effect by improving the movement-induced pain, tactile allodynia and heat hyperalgesia. Therefore, oxycodone could be an interesting option to treat patients suffering from knee osteoarthritis when opioids are required.This study was supported by Mundipharma Pharmaceuticals, S.L.Peer Reviewe

A 1-Year Cost Analysis of Spinal Surgical Procedures in Spain: Neurosurgeons Versus Orthopedic Surgeons

Objective To evaluate the direct costs of various spinal surgical procedures within 1 year of follow-up and to compare the profiles of neurosurgeons and orthopedic surgeons. Methods All spinal procedures performed within a 10-month period in patients covered by a private insurance company were included. Costs related to the spinal interventions were systematically registered in the company database. Associated costs during the 1-year follow-up were recorded. Results In total, 1,862 patients were included, with a total cost of €11,050,970, of whom 34.8% underwent noninstrumented lumbar decompression (€3,473), 27.1% dorsolumbar instrumented fusion (€6,619), 14.6% nucleoplasty (€1,323), 13.5% cervical surgery (€4,463), 3.4% kyphoplasty (€4,200), 2.9% scoliosis (€15,414), 1.2% oncologic surgery (€5,590), 0.5% traumatic compression (€7,844), and 4.7% (€1,343) other minor interventions (mainly rhizotomies). Approximately 42% of patients required reinterventions within the first year, with a global extra cost of €7,280,073; 11% were referred to the pain clinic, with a €114,663 cost; 55.5% were men; and the most common age range of patients who received an intervention was 65–75 years. Neurosurgeons performed 60% of all interventions. Noninstrumented lumbar operations were performed by neurosurgeons twice as often as instrumented operations, and they performed 76% of cervical operations. Orthopedic surgeons performed 2.5 times more instrumented than noninstrumented lumbar operations, and almost all scoliosis and rhizotomy procedures. Conclusion The direct costs of spinal surgery in Spain were generally lower than those reported in other European Union countries and the United States. Neurosurgeons and orthopedic surgeons had different spine surgical profiles and costs

A Concise Synthesis of a BODIPY-Labeled Tetrasaccharide Related to the Antitumor PI-88

12 pags., 2 figs., 1 tab., 4 schs. -- This article belongs to the Special Issue Exclusive Feature Papers in ColorantsA convergent synthetic route to a tetrasaccharide related to PI-88, which allows the incorporation of a fluorescent BODIPY-label at the reducing-end, has been developed. The strategy, which features the use of 1,2-methyl orthoesters (MeOEs) as glycosyl donors, illustrates the usefulness of suitably-designed BODIPY dyes as glycosyl labels in synthetic strategies towards fluorescently-tagged oligosaccharidesThis research was funded by Spanish MINISTERIO DE ECONOMIA Y COMPETITIVIDAD, GOBIERNO DE ESPAÑA (projects MAT2017–83856-C3-1-P and 3-P, PiD2020-1147555GB-C33), the MINISTERIO DE CIENCIA INNOVACION Y UNIVERSIDADES (project RTI2018-094862-B-I00), and the GOBIERNO VASCO (project IT912-16)Peer reviewe