Preclinical Model to Evaluate Outcomes of Amyloid Cross-Toxicity in the Rodent Brain.

The progress of neurodegenerative disorders correlates with the spread of their associated amyloidogenic proteins. Here, we investigated whether amyloid entry into nonconstitutive neurons could drive cross-toxic outcomes. Amyloid ß (Aß) was stereotaxically introduced into the rodent midbrain tegmentum, where it is not endogenously expressed. Postinfusion, rodent motor and sensorimotor capacities were assessed by standard behavioral tests at 3, 6, 9, and 12 months. The longitudinal study revealed no behavioral abnormalities. However, Aß insult provoked intraneuronal inclusions positive for phosphorylated α-synuclein in dopaminergic neurons and were seen throughout the midbrain, a pathognomonic biomarker suggesting Parkinson's pathogenesis. These findings not only underscore the cross-toxic potential of amyloid proteins but also provide a mechanism by which they disrupt homeostasis in nonconstitutive neurons and cause neuronal corruption, injury, and demise. This study may help reconcile the large incidence of neurodegenerative comorbidity observed clinically.

Gelatin-derived carbon quantum dots mitigate herbicide-induced neurotoxic effects in vitro and in vivo.

The herbicide and viologen, N, N'-dimethyl-4,4'-bipyridinium dichloride (Paraquat) is known to be toxic to neuronal cells by a multifactorial process involving an elevation in the levels of reactive oxygen species (ROS), the triggering of amyloid-protein aggregation and their accumulation, collectively leading to neuronal dyshomeostasis. We demonstrate that green-chemistry-synthesized sustainable gelatin-derived carbon quantum dots (CQDs) mitigate paraquat-induced neurotoxic outcomes and resultant compromise in organismal mortality. Gelatin-derived CQDs were found to possess antioxidant properties and ameliorated ROS elevation in paraquat-insulted neuroblastoma-derived SHSY-5Y cells, protecting them from herbicide-induced cell death. These CQDs also increased lifespan in paraquat-compromised Caenorhabditis elegans and herbicide-mediated dopamine neuron ablation. Collectively, the data underscore the ability of this sustainably synthesized, environmentally friendly biocompatible nanomaterial to protect cell lines and organisms against neurotoxic outcomes. The study findings strategically position this relatively novel nanoscopic carbon quantum framework for further testing in vertebrate trials of neurotoxic insult.

Citric Acid-Derived Carbon Quantum Dots Attenuate Paraquat-Induced Neuronal Compromise In Vitro and In Vivo.

The potent environmental herbicide and weedicide paraquat is linked to neuromotor defects and Parkinson's disease (PD). We have evaluated the neuroprotective role of citric acid-sourced carbon quantum dots (Cit-CQDs) on paraquat-insulted human neuroblastoma-derived SH-SY5Y cell lines and on a paraquat-exposed nematode (Caenorhabditis elegans). Our data reveal that Cit-CQDs are able to scavenge free radicals in test tube assays and mitigate paraquat-elevated reactive oxygen species (ROS) levels in SH-SY5Y cells. Furthermore, Cit-CQDs protect the cell line from paraquat, which otherwise elicits cell death. Cit-CQDs-challenged nematodes demonstrate enhanced survival rates 72 h post-paraquat exposure compared to controls. Paraquat ablates dopamine (DA) neurons, which results in compromised locomotor function in nematodes. However, the neurons remained intact when the nematodes were incubated with Cit-CQDs prior to neurotoxicant exposure. The collective data suggest Cit-CQDs offer neuroprotection for cell lines and organisms from xenotoxicant-associated neuronal injury and death. The study suggests Cit-CQDs as a potentially viable green chemistry-synthesized, biobased nanomaterial for intervention in neurodegenerative disorders.

Efficacy and Safety of Innovative Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review.

Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.

Potential Role of Natural Polyphenols against Protein Aggregation Toxicity: In Vitro, In Vivo, and Clinical Studies.

One of the main features of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease is the amyloidogenic behavior of disease-specific proteins including amyloid ß, tau, α-synuclein, and mutant Huntingtin which participate in the formation, accumulation, and deposition of toxic misfolded aggregates. Consequently, these proteins not only associated with the progress of their respective neurodegenerative pathologies but also qualify as disease-specific biomarkers. The aim of using natural polyphenols is to target amyloid-dependent proteopathies by decreasing free radical damage and inhibiting and dissolving amyloid fibrils. We explore the effectiveness of the polyphenols epigallocatechin-3-gallate, oleuropein aglycone, and quercetin on their ability to inhibit aggregation of amyloid ß, tau, and α-synuclein and mitigate other pathological features for Alzheimer's disease and Parkinson's disease. The analysis was carried from in vitro and cell line studies to animal models and clinical trials. This Review describes the use of phytochemical compounds as prophylactic agents for Alzheimer's disease, Parkinson's disease, and other proteopathies.

Testing Amyloid Cross-Toxicity in the Vertebrate Brain.

While amyloid proteins such as amyloid ß (Aß),α-synuclein, tau, and lysozyme are known to be prion-like; emerging data have revealed that they are also able to seed the misfolding of prion-like proteins differing in sequence. In the present study, we have developed a tool designed to test neurohistochemical outcomes associated with the entry of an amyloid protein into heterotypic neurons, i.e., neurons that do not express the invading amyloid and, instead, endogenously express amyloids differing in sequence. The stereotaxic introduction of Aß into the rodent tegmental area of the mid-brain revealed that the foreign amyloid had infiltrated into nigral neurons. Furthermore, Aß was found colocalized with α-synuclein, an amyloid endogenous to the substantia nigra and differing in sequence relative to Aß. Disruption of α-synuclein status in the substantia nigra is associated with Parkinson's disease onset and progress. In addition to the study findings, a significant inroad to future neurodegenerative research was made via the stereotaxic introduction of the foreign amyloid. This technique limits the presence of confounding neurometabolic variables that may be prevalent in transgenic animal models of cross-toxicity and, thereby, better addresses the role of individual neuronal factors in cross-toxicity. Finally, the data from this work may help reconcile the high frequency of clinical comorbidity seen in neurodegenerative diseases.

Neuroprotective Effect of Brazilin on Amyloid ß (25-35)-Induced Pathology in a Human Neuroblastoma Model.

Until the recent past, the sole exemplar of proteins as infectious agents leading to neurodegenerative disorders remained the prion protein. Since then, the self-seeding mechanism characteristic of the prion protein has also been attributed to other neurodegenerative-disease-associated proteins, including amyloid-ß (Aß), tau, and α-synuclein (α-Syn). In model cell line studies, truncated Aß, viz. amyloid beta (25-35), has been found to influence cellular homeostasis through its interactions with, and via, the disruption of key housekeeping machinery. Here, we demonstrate that the incubation of human neuroblastoma (SH-SY5Y) cell line with Brazilin ((6aS,11bR)-7,11b-dihydro-6H-indeno[2,1-c]chromene-3,6a,9,10-tetrol) prior to Aß (25-35)-insult protected the cells from oxidative stress and apoptotic cell death. Furthermore, Brazilin mitigated Aß-induced alterations in protein disulfide isomerase (PDI) and α-synuclein status, both of which are important biomarkers that report on Parkinson's pathogenesis. The results obtained in this study suggest that the tetrol is neuroprotective and helps resist Aß-induced cross-pathology and amyloidogenic onset.

A Hybrid Model to Study Amyloid Cross-Toxicity.

The self-seeding mechanism characteristic of the prion-protein has also been attributed to other neurodegenerative-disease-associated proteins including amyloid beta (Aß), tau, and α-synuclein. An interesting facet of these prion-like proteins is their ability to horizontally "spread" and recruit their soluble counterparts in adjacent neurons. However, recent findings suggest a heterotoxic potential in these "seeds" whereby one neurodegeneration-associated protein can interact with another sequentially unrelated prion-like protein and influence its aggregation and drive cross-toxic outcomes and neurodegenerative co-morbidity. Yet, direct experimental evidence for amyloid cross-talk at the vertebrate level remains indirect, lacks resolution, or introduces confounding variables. Here, we discuss the need for a novel approach to resolve amyloid cross-toxicity at the neurohistochemical and organismal levels.

Enhancing the Delivery of Chemotherapeutics: Role of Biodegradable Polymeric Nanoparticles.

While pharmaceutical drugs have revolutionized human life, there are several features that limit their full potential. This review draws attention to some of the obstacles currently facing the use of chemotherapeutic drugs including low solubility, poor bioavailability and high drug dose. Overcoming these issues will further enhance the applicability and potential of current drugs. An emerging technology that is geared towards improving overall therapeutic efficiency resides in drug delivery systems including the use of polymeric nanoparticles which have found widespread use in cancer therapeutics. These polymeric nanoparticles can provide targeted drug delivery, increase the circulation time in the body, reduce the therapeutic indices with minimal side-effects, and accumulate in cells without activating the mononuclear phagocyte system (MPS). Given the inroads made in the field of nanodelivery systems for pharmaceutical applications, it is of interest to review and emphasize the importance of Polymeric nanocarrier system for drug delivery in chemotherapy.

Looking Back, Looking Forward at Halogen Bonding in Drug Discovery.

Halogen bonding has emerged at the forefront of advances in improving ligand: receptor interactions. In particular the newfound ability of this extant non-covalent-bonding phenomena has revolutionized computational approaches to drug discovery while simultaneously reenergizing synthetic approaches to the field. Here we survey, via examples of classical applications involving halogen atoms in pharmaceutical compounds and their biological hosts, the unique advantages that halogen atoms offer as both Lewis acids and Lewis bases.

Abdominal Obesity, Race and Chronic Kidney Disease in Young Adults: Results from NHANES 1999-2010.

OBJECTIVE: Kidney dysfunction in obesity may be independent of and may precede the development of hypertension and/or diabetes mellitus. We aimed to examine if abdominal obesity is associated with early markers of CKD in a young healthy population and whether these associations differ by race and/or ethnicity. METHODS: We analyzed data from the NHANES 1999-2010 for 6918 young adults ages 20-40 years. Abdominal obesity was defined by gender criteria of waist circumference. CKD markers included estimated glomerular filtration rate and albuminuria ≥30 mg/g. Race stratified analyses were done overall and in subgroups with normal blood pressures, normoglycemia and normal insulin sensitivity. Awareness of CKD was assessed in participants with albuminuria. RESULTS: Abdominal obesity was present in over one-third of all young adults and was more prevalent among non-Hispanic blacks (45.4%) versus Mexican-Americans (40.6%) or non-Hispanic whites (37.4%) (P-value = 0.004). Mexican-American young adults with abdominal obesity had a higher odds of albuminuria even among those with normal blood pressure, normal glucose, and normal insulin sensitivity [adjusted odds ratio 4.5; 95% confidence interval (1.6-12.2), p = 0.004]. Less than 5% of young adults with albuminuria of all races and ethnicities had been told they had kidney disease. CONCLUSION: Abdominal obesity in young adults, especially in Mexican-Americans, is independently associated with albuminuria even with normal blood pressures, normoglycemia and normal insulin levels. Greater awareness of CKD is needed to protect this young population from long-standing exposure to abdominal obesity and early progressive renal disease.

Diagnóstico y manejo prenatal de un caso de bloqueo auriculo-ventricular completo / Prenatal diagnosis and management of a case of complete auricular-ventricular heart block

Se presenta un caso clínico de diagnóstico prenatal de bloqueo auricular-ventricular completo del feto, en una madre portadora de un lupus eritematoso

Diagnóstico ultrasonográfico antenatal y manejo de tumor cardíaco fetal / Antenatal ultrasonographic diagnosis and fetal cardiac tumor management

Se presenta un caso clínico de diagnóstico antenatal ultrasonográfico de tumor cardíaco y posterior manejo activo mediante seguimiento con ecocardiografía y Doppler-Color, así como el resultado perinatal y evolución posterior. Los tumores cardíacos fetales pueden ser primarios o metastásicos, siendo estos últimos más frecuentes. Si bien la frecuencia de tumores primarios es baja y en su mayoría son benignos, son capaces de causar la muerte del feto por complicaciones como arritmias, taponamiento pericárdico, obstrucción valvular o embolia