Placenta accreta spectrum: treatment consensus in a resource-limited setting.

BACKGROUND: Management options for placenta accreta spectrum disorder are multiple, without a clear picture of which one is superior. Management guidelines describe the use of a wide range of human and technological resources that are not always available in resource-limited settings. OBJECTIVE: This consensus seeks agreement on general guidelines that facilitate the management of placenta accreta spectrum in low- and middle-income countries. STUDY DESIGN: Consensus was developed using the modified Delphi methodology, incorporating 3 successive rounds in which 6 dimensions of placenta accreta spectrum treatment were discussed: pathway for placenta accreta spectrum care, roles at different levels of care, organization of the interdisciplinary teams at the reference hospitals, training interdisciplinary teams, placenta accreta spectrum surgical treatment, and management of placenta accreta spectrum patients without prenatal diagnosis. RESULTS: Consensus was achieved on all questions on placenta accreta spectrum management. Specific low- and middle-income countries problems were addressed, trying to establish guidelines for the construction of trained placenta accreta spectrum interdisciplinary teams, as well as the rational use of the different therapeutic options available in a limited resources setting. In addition, it is highlighted the need to facilitate contact between patients affected by this disease and the interdisciplinary groups, overcoming administrative barriers typical of some health systems. CONCLUSION: We present a consensus on the treatment of placenta accreta spectrum in a low- and middle-income countries, based on local experts' opinions. Construction of high-quality scientific evidence is essential in settings with limited resources.

Performance of the INTERGROWTH-21st and World Health Organization fetal growth charts for the detection of small-for-gestational age neonates in Latin America.

OBJECTIVE: To evaluate the performance of INTERGROWTH-21st (IG-21st ) and World Health Organization (WHO) fetal growth charts to identify small-for-gestational-age (SGA) and fetal growth restriction (FGR) neonates, as well as their specific risks for adverse neonatal outcomes. METHODS: Multicenter cross-sectional study including 67 968 live births from 10 maternity units across four Latin American countries. According to each standard, neonates were classified as SGA and FGR (birth weight <10th and less than third centiles, respectively). The relative risk (RR) and diagnostic performance for a low APGAR score and low ponderal index were calculated for each standard. RESULTS: WHO charts identified more neonates as SGA than IG-21st (13.9% vs 7%, respectively). Neonates classified as having FGR by both standards had the highest RR for a low APGAR (RR, 5.57 [95% confidence interval (CI), 3.99-7.78]), followed by those who were SGA by both curves (RR, 3.27 [95% CI, 2.52-4.24]), while neonates with SGA identified by WHO alone did not have an additional risk (RR, 0.87 [95% CI, 0.55-1.39]). Furthermore, the diagnostic odds ratio for a low APGAR was higher when IG-21st was used. CONCLUSION: In a population from Latin America, the WHO charts seem to identify more SGA neonates, but the diagnostic performance of the IG-21st charts for low APGAR score and low ponderal index is better.

Recycling of Residual Polymers Reinforced with Natural Fibers as a Sustainable Alternative: A Review.

The latest advances in green alternatives are being addressed with bio-based solutions, with uses and applications in new areas due to their wide potential, low cost, lightness, renewability, biodegradability, impact toughness, fatigue resistance, and other specific properties. Natural fibers are sustainable materials that have led researchers to test their viability as alternative reinforcements in residual polymers to meet required engineering specifications; therefore, it is essential to continue making progress in replacing conventional materials. This review is expected to provide an overview of the current scopes and future prospects of biocomposites from polymers reinforced with natural fibers with a focus on the following: i. recycling of residual polymers; ii. available natural fibers and their components in the context of engineering applications; iii. the behavior of the structural modifications of the natural fibers with the physical and chemical treatments in the matrix interaction as reinforcements of the residual polymers; and iv. applications for the development of innovative, efficient, and sustainable solutions for successful, environmentally responsible products.

On-DNA Palladium-Catalyzed Hydrogenation-like Reaction Suitable for DNA-Encoded Library Synthesis.

Herein we describe a method to orthogonally remove on-DNA N-Cbz, N-Alloc, N-Allyl, O-Bn, and O-Allyl protecting groups in the presence of other common protecting groups to afford free amines and carboxylic acids, respectively. The developed method uses NaBH4 as the source of hydrogen in the presence of Pd(OAc)2 under DNA aqueous conditions. In addition, under the developed conditions we were able to successfully hydrogenate triple and double bonds to totally saturated compounds. Furthermore, we introduce a new alternative procedure to reduce azides and aromatic nitro compounds to primary amines.

The synthesis of switch-off fluorescent water-stable copper nanocluster Hg2+ sensors via a simple one-pot approach by an in situ metal reduction strategy in the presence of a thiolated polymer ligand template.

The fabrication of stable fluorescent copper nanoclusters (CuNCs) in aqueous media is still challenging, despite the low price and potential biomedical applications. Herein, we report a facile and efficient strategy for assembling CuNCs using multifunctional thiolated copolymers with pH and thermoresponsive features. The new nanohybrids are formed via a simple one-pot approach through the reduction of a copper salt with hydrazine in the presence of a multithiolated polymer, which provides a template during nanocluster assembly and further efficient protection against oxidation and aggregation. Furthermore, the thermo- and pH-responsive properties of the pristine copolymers endow the nanohybrids with these stimuli-responsive features. The thiol content and the macromolecular size of the polymer ligands exert strong influences on the final photophysical properties of these new hybrid luminescent nanoclusters. The existence of stable bright greenish-yellow emission in water over long periods of time, the high photostability under UV irradiation and the strong oxidation resistance toward hydrogen peroxide of the hybrid CuNCs suggest that they have great promise for nanomedicine, bioassay and nanosensor use. Furthermore, the polymeric CuNCs obtained have been successfully tested as optical switch-off sensors for the sensitive and highly selective detection of Hg2+ in the presence of other metal ions in liquid and solid states. Finally, we demonstrate the practical application of the new hybrid to Hg2+ detection in human urine.

Mild and Efficient Palladium-Mediated C-N Cross-Coupling Reaction between DNA-Conjugated Aryl Bromides and Aromatic Amines.

DNA-encoded library technology (ELT) has emerged in the pharmaceutical industry as a powerful tool for hit and lead generation. Over the last 10 years, a number of DNA-compatible chemical reactions have been published and used to synthesize libraries. Among the most commonly used reactions in medicinal chemistry is the C-N bond formation, and its application to DNA-encoded library technology affords an alternative approach to identify high-affinity binders for biologically relevant protein targets. Herein we report a newly developed Pd-promoted C-N cross coupling reaction between DNA-conjugated aryl bromides and a wide scope of arylamines in good to excellent yields. The mild reaction conditions should facilitate the synthesis of novel DNA-encoded combinatorial libraries.

How statins could be evaluated successfully in clinical trials for Alzheimer's disease?

Over the last decade, a large number of experimental observations have suggested a relationship between alterations in cholesterol homeostasis and Alzheimer's disease (AD). Moreover, epidemiological studies have pointed an association between statin treatment and a decrease in the risk of having AD. For these reasons, a large number of clinical trials have been carried out to determine whether the statins can prevent the progression of AD. However, these studies did not provide clear evidence for the therapeutic efficacy in AD. We consider that there are a number of explanations for this failure that may provide guidance for selecting and clinically developing statins with therapeutic efficacy in AD.

Gadolinium-staining reveals amyloid plaques in the brain of Alzheimer's transgenic mice.

Detection of amyloid plaques in the brain by in vivo neuroimaging is a very promising biomarker approach for early diagnosis of Alzheimer's disease (AD) and evaluation of therapeutic efficacy. Here we describe a new method to detect amyloid plaques by in vivo magnetic resonance imaging (MRI) based on the intracerebroventricular injection of a nontargeted gadolinium (Gd)-based contrast agent, which rapidly diffuses throughout the brain and increases the signal and contrast of magnetic resonance (MR) images by shortening the T1 relaxation time. This gain in image sensitivity after in vitro and in vivo Gd staining significantly improves the detection and resolution of individual amyloid plaques in the cortex and hippocampus of AD transgenic mice. The improved image resolution is sensitive enough to demonstrate an age-dependent increase of amyloid plaque load and a good correlation between the amyloid load measured by µMRI and histology. These results provide the first demonstration that nontargeted Gd staining can enhance the detection of amyloid plaques to follow the progression of AD and to evaluate the activity of amyloid-lowering therapeutic strategies in longitudinal studies.

Increased regional cerebral glucose uptake in an APP/PS1 model of Alzheimer's disease.

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by the invariant cerebral accumulation of ß-amyloid peptide. This event occurs early in the disease process. In humans, [18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) positron emission tomography (PET) is largely used to follow-up in vivo cerebral glucose utilization (CGU) and brain metabolism modifications associated with the Alzheimer's disease pathology. Here, [18F]-FDG positron emission tomography was used to study age-related changes of cerebral glucose utilization under resting conditions in 3-, 6-, and 12-month-old APP(SweLon)/PS1(M146L), a mouse model of amyloidosis. We showed an age-dependent increase of glucose uptake in several brain regions of APP/PS1 mice but not in control animals and a higher [18F]-FDG uptake in the cortex and the hippocampus of 12-month-old APP/PS1 mice as compared with age-matched control mice. We then developed a method of 3-D microscopic autoradiography to evaluate glucose uptake at the level of amyloid plaques and showed an increased glucose uptake close to the plaques rather than in amyloid-free cerebral tissues. These data suggest a macroscopic and microscopic reorganization of glucose uptake in relation to cerebral amyloidosis.

In vivo imaging of neuroinflammation in the rodent brain with [11C]SSR180575, a novel indoleacetamide radioligand of the translocator protein (18 kDa).

PURPOSE: Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects. METHODS: Here we report the radiolabelling of SSR180575 with (11)C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats. RESULTS: The image contrast and the binding of [(11)C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [(11)C]PK11195. Competition studies demonstrate that [(11)C]SSR180575 has high specific binding for the TSPO. CONCLUSION: [(11)C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic.

ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease.

Recent epidemiological, biological and genetic data indicate a relationship between cholesterol and Alzheimer's disease (AD) including the association of polymorphisms of ABCA1 (a gene that is known to participate in cholesterol and phospholipid transport) with AD prevalence. Based on these data, we postulated that genetic variation in the related and brain-specific ABCA2 gene leads to increase risk of AD. A large case-control study was conducted where the sample was randomly divided into a hypothesis-testing sample (230 cases/286 controls) and a validation sample (210 cases/233 controls). Among the 45 SNPs we tested, one synonymous SNP (rs908832) was found significantly associated with AD in both samples. Additional analyses performed on the whole sample showed a very strong association between this marker and early-onset AD (OR = 3.82, 95% C.I. = [2.00 - 7.30], P = 5 x 10(-5)). Further research is needed to understand the functional role of this polymorphism. However, together with the reported associations of AD with APOE, CYP46A1 and ABCA1, the present result adds a very significant support for the role of cholesterol and phospholipid homeostasis in AD and a rationale for testing novel cholesterol homeostasis-related therapeutic strategies in AD.

Heterologous expression of human {alpha}6{beta}4{beta}3{alpha}5 nicotinic acetylcholine receptors: binding properties consistent with their natural expression require quaternary subunit assembly including the {alpha}5 subunit.

Heterologous expression and lesioning studies were conducted to identify possible subunit assembly partners in nicotinic acetylcholine receptors (nAChR) containing alpha6 subunits (alpha6(*) nAChR). SH-EP1 human epithelial cells were transfected with the requisite subunits to achieve stable expression of human alpha6beta2, alpha6beta4, alpha6beta2beta3, alpha6beta4beta3, or alpha6beta4beta3alpha5 nAChR. Cells expressing subunits needed to form alpha6beta4beta3alpha5 nAChR exhibited saturable [(3)H]epibatidine binding (K(d) = 95.9 +/- 8.3 pM and B(max) = 84.5 +/- 1.6 fmol/mg of protein). The rank order of binding competition potency (K(i)) for prototypical nicotinic compounds was alpha-conotoxin MII (6 nM) > nicotine (156 nM) approximately methyllycaconitine (200 nM) > alpha-bungarotoxin (>10 microM), similar to that for nAChR in dopamine neurons displaying a distinctive pharmacology. 6-Hydroxydopamine lesioning studies indicated that beta3 and alpha5 subunits are likely partners of the alpha6 subunits in nAChR expressed in dopaminergic cell bodies. Similar to findings in rodents, quantitative real-time reverse transcription-polymerase chain reactions of human brain indicated that alpha6 subunit mRNA expression was 13-fold higher in the substantia nigra than in the cortex or the rest of the brain. Thus, heterologous expression studies suggest that the human alpha5 subunit makes a critical contribution to alpha6beta4beta3alpha5 nAChR assembly into a ligand-binding form with native alpha6(*)-nAChR-like pharmacology and of potential physiological and pathophysiological relevance.

Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model.

Alzheimer's disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APP(SL)PS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human beta-amyloid (Abeta) precursor protein. Abeta(x-42) is the major form of Abeta species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain. At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Abeta and thioflavine-S-positive intracellular material but not with extracellular Abeta deposits. A strong reactive astrogliosis develops together with the neuronal loss. This loss is already detectable at 6 months of age and is PS1KI gene dosage-dependent. Thus, APP(SL)PS1KI mice further confirm the critical role of intraneuronal Abeta(42) in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.

An in vitro and in vivo study of early deficits in associative learning in transgenic mice that over-express a mutant form of human APP associated with Alzheimer's disease.

Transgenic mice over-expressing a mutated form of the human amyloid precursor protein (APP, 695 isoform) bearing a mutation associated with Alzheimer's disease (V642I, so-called London mutation, hereafter APPLd2) and wild-type controls were studied at age periods (3 and 10 months) prior to the overt development of neuritic amyloid plaques. Both 3- and 10-month-old APPLd2 mice had reflex eyelid responses like those of controls, but only younger mice were able to acquire a classical conditioning of eyelid responses in a trace paradigm. In vitro studies on hippocampal slices showed that 10-month-old APPLd2 mice also presented deficits in paired-pulse facilitation and long-term potentiation, but presented a normal synaptic activation of CA1 pyramidal cells by the stimulation of Schaffer collaterals. It is proposed that definite functional changes may appear well in advance of noticeable structural alterations in this animal model of Alzheimer's disease, and that specific learning tasks could have a relevant diagnostic value.

Synthesis of a [2-pyridinyl-18F]-labelled fluoro derivative of (-)-cytisine as a candidate radioligand for brain nicotinic alpha4beta2 receptor imaging with PET.

In recent years, there has been considerable effort to design and synthesize radiotracers suitable for use in Positron Emission Tomography (PET) imaging of the alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR) subtype. A new fluoropyridinyl derivative of (-)-cytisine (1), namely (-)-9-(2-fluoropyridinyl)cytisine (3, K(i) values of 24 and 3462 nM for the alpha4beta2 and alpha7 nAChRs subtypes, respectively) has been synthesized in four chemical steps from (-)-cytisine and labelled with fluorine-18 (T(1/2): 119.8 min) using an efficient two-step radiochemical process [(a). nucleophilic heteroaromatic ortho-radiofluorination using the corresponding N-Boc-protected nitro-derivative, (b). TFA removal of the Boc protective group]. Typically, 20-45 mCi (0.74-1.67 GBq) of (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3, 2-3 Ci/micromol or 74-111 GBq/micromol) were easily obtained in 70-75 min starting from a 100 mCi (3.7 GBq) aliquot of a cyclotron-produced [18F]fluoride production batch (20-45% non decay-corrected yield based on the starting [18F]fluoride). The in vivo pharmacological profile of (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) was evaluated in rats with biodistribution studies and brain radioactivity monitoring using intracerebral radiosensitive beta-microprobes. The observed in vivo distribution of the radiotracer in brain was rather uniform, and did not match with the known regional densities of nAChRs. It was also significantly different from that of the parent compound (-)-[3H]cytisine. Moreover, competition studies with (-)-nicotine (5 mg/kg, 5 min before the radiotracer injection) did not reduce brain uptake of the radiotracer. These experiments clearly indicate that (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) does not have the required properties for imaging nAChRs using PET.

Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse.

Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. These parkin mutant mice provide a valuable tool to better understand the preclinical deficits observed in patients with PD and to characterize the mechanisms leading to the degeneration of dopamine neurons that could provide new strategies for neuroprotection.

Mitotic-like tau phosphorylation by p25-Cdk5 kinase complex.

Among tau phosphorylation sites, some phosphoepitopes referred to as abnormal ones are exclusively found on tau aggregated into filaments in Alzheimer's disease. Recent data suggested that molecular mechanisms similar to those encountered during mitosis may play a role in abnormal tau phosphorylation. In particular, TG-3 phosphoepitope is associated with early stages of neurofibrillary tangles (NFTs). In this study, we reported a suitable cell model consisting of SH-SY5Y cells stably transfected with an inducible p25 expression vector. It allows investigation of tau phosphorylation by p25-Cdk5 kinase complex in a neuronal context and avoiding p25-induced cytotoxicity. Immunoblotting analyses showed that p25-Cdk5 strongly phosphorylates tau protein not only at the AT8 epitope but also at the AT180 epitope and at the Alzheimer's mitotic epitope TG-3. Further biochemical analyses showed that abnormal phosphorylated tau accumulated in cytosol as a microtubule-free form, suggesting its impact on tau biological activity. Since tau abnormal phosphorylation occurred in dividing cells, TG-3 immunoreactivity was also investigated in differentiated neuronal ones, and both TG-3-immunoreactive tau and nucleolin, another early marker for NFT, were also generated. These data suggest that p25-Cdk5 is responsible for the mitotic-like phosphoepitopes present in NFT and argue for a critical role of Cdk5 in neurodegenerative mechanisms.

A risk for early-onset Alzheimer's disease associated with the APBB1 gene (FE65) intron 13 polymorphism.

Alzheimer's disease (AD) is a genetically complex neurodegenerative disorder and the leading cause of dementia of the elderly. Recently, Hu et al. suggested that a trinucleotide deletion in intron 13 of the APBB1 gene was a factor protecting against late-onset AD. We report here the results of a case/control study aimed at replicating this association. Our study included 461 AD patients and 397 matched controls. We compared the allele and genotype frequencies of the polymorphism between the two groups but did not find any statistically significant difference (P=0.08 and P=0.09, respectively). By contrast, adjusting for age and sex, we found a slight risk associated with the deletion (odds ratio=1.47, 95% confidence interval=1.05-2.04). Stratification by age showed that the risk effect associated with the deletion concerned subjects aged less than 65 years.

SSR180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), a peripheral benzodiazepine receptor ligand, promotes neuronal survival and repair.

In the present study, we have investigated the potential neuroprotective effects of a novel peripheral benzodiazepine binding site (PBR) ligand, 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575), in models of central and peripheral neurodegeneration in vivo and its effect on steroid concentrations in plasma and nervous tissue. SSR180575 shows high affinity (IC(50), 2.5-3.5 nM) and selectivity for the rat and human PBR and potently inhibits the in vivo binding of [(3)H]alpidem to PBR in the rat brain and spleen after oral or i.p. administration (ID(50), 0.1-0.3 mg/kg). In an experimental model of motoneuron degeneration induced by facial nerve axotomy in the immature rat, SSR180575 given i.p. or orally for 8 days rescued facial motoneurons, increasing their survival by 40 to 72% at 6 and 10 mg/kg p.o. b.i.d. Moreover, in this model, SSR180575 (10 mg/kg p.o. b.i.d.) increased by 87% the number of motoneurons immunoreactive to peripherin, a type III intermediate filament, whose expression is up-regulated during nerve regeneration. SSR180575 also improved functional recovery in acrylamide-induced neuropathy in the rat when given therapeutically at 2.5 to 10 mg/kg/day p.o. Furthermore, SSR180575 (3 mg/kg i.p. b.i.d.) accelerated functional recovery of the blink reflex after local injury of the facial nerve in the rat. SSR180575 increased pregnenolone accumulation in the brain and sciatic nerve (+100% at 3 mg/kg i.p.), suggesting that its neuroprotective effects are steroid-mediated. These results indicate that PBR ligands (e.g., SSR180575) promote neuronal survival and repair in axotomy and neuropathy models and have potential for the treatment of neurodegenerative diseases (e.g., peripheral neuropathies or amyotrophic lateral sclerosis).