Audra L. Clos

Bioaccumulation and toxicity of gold nanoparticles after repeated administration in mice

Gold nanoparticles (GNPs) offer a great promise in biomedicine. Currently, there is no data available regarding the accumulation of nanoparticles in vivo after repeated administration. The purpose of the present study was to evaluate the bioaccumulation and toxic effects of different doses (40, 200, and 400 microg/kg/day) of 12.5 nm GNPs upon intraperitoneal administration in mice every day for 8 days. The gold levels in blood did not increase with the dose administered, whereas in all the organs examined there was a proportional increase on gold, indicating efficient tissue uptake. Although brain was the organ containing the lowest quantity of injected GNPs, our data suggest that GNPs are able to cross the blood-brain barrier and accumulate in the neural tissue. Importantly, no evidence of toxicity was observed in any of the diverse studies performed, including survival, behavior, animal weight, organ morphology, blood biochemistry and tissue histology. The results indicate that tissue accumulation pattern of GNPs depend on the doses administered and the accumulation of the particles does not produce sub-acute physiological damage.

Viral upper respiratory tract infection and otitis media complication in young children.

Abstract Background. The common cold or upper respiratory infection (URI) is highly prevalent among young children and often results in otitis media (OM). The incidence and characteristics of OM complicating URI due to specific viruses have not been well studied. Methods. We performed a prospective, longitudinal cohort study of 294 healthy children (age range, 6 months to 3 years). Each child was observed for 1 year to assess the occurrence of URI, acute OM (AOM), and OM with effusion (OME) complicating URI due to specific viruses. Results. We documented 1295 URI episodes (5.06 episodes per child-year) and 440 AOM episodes (1.72 episodes per child-year). Virus studies were performed for 864 URI episodes; 63% were virus positive. Rhinovirus and adenovirus were most frequently detected during URI. The overall incidence of OM that complicated URI was 61%, including a 37% incidence of AOM and a 24% incidence of OME. Young age was the most important predictor of AOM that complicated URI. AOM occurred in approximately one-half of children with URI due to adenovirus, respiratory syncytial virus, or coronavirus and in approximately one-third of those with URI due to influenza virus, parainfluenza virus, enterovirus, or rhinovirus. Conclusions. More than 60% of episodes of symptomatic URI among young children were complicated by AOM and/or OME. Young age and specific virus types were predictors of URI complicated by AOM. For young children, the strategy to prevent OM should involve prevention of viral URI. The strategy may be more effective if the priority is given to development of means to prevent URI associated with adenovirus and respiratory syncytial virus.

Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

BackgroundThe correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimers disease (AD) patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate.ResultsHere we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I), and activated caspase-9, which is related to the apoptotic mitochondrial pathway.ConclusionsThis study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.

Results of a Phase II Trial of Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and Lymphomatoid Papulosis

PURPOSE Brentuximab vedotin, a monoclonal antibody (cAC10) conjugated to monomethyl auristatin E, targets CD30(+) receptors. This phase II open-label trial was conducted to evaluate safety and efficacy in CD30(+) cutaneous T-cell lymphomas. PATIENTS AND METHODS Forty-eight patients with CD30(+) lymphoproliferative disorders or mycosis fungoides (MF) received an infusion of 1.8 mg/kg every 21 days. RESULTS Forty-eight evaluable patients (22 women and 26 men; median age, 59.5 years) had an overall response rate of 73% (95% CI, 60% to 86%; 35 of 48 patients) and complete response rate of 35% (95% CI, 22% to 49%; 17 of 48 patients). Fifteen (54%; 95% CI, 31% to 59%) of 28 patients with MF responded, independent of CD30 expression. In patients with MF/Sézary syndrome, the overall response rate was 50% (five of 10 patients) in patients with low CD30 expression (< 10%), 58% (seven of 12 patients) in patients with medium expression (10% to 50%), and 50% (three of six patients) in patients with high expression (≥ 50%). Time to response was 12 weeks (range, 3 to 39 weeks), and duration of response was 32 weeks (range, 3 to 93 weeks). All patients with lymphomatoid papulosis (n = 9) and primary cutaneous anaplastic T-cell lymphomas (n = 2) responded; time to response was 3 weeks (range, 3 to 9 weeks), and median duration of response was 26 weeks (range, 6 to 44 weeks). Soluble baseline CD30 levels were lowest in complete responders (P = .036). Grade 1 to 2 peripheral neuropathy was observed in 65% of patients (95% CI, 52% to 79%; 31 of 48 patients), is still ongoing in 55% of patients (95% CI, 41% to 69%; 17 of 31 patients), and resolved in 45% of patients (95% CI, 31% to 59%; 14 of 31 patients), with a median time to resolution of 41.5 weeks. Grade 3 to 4 events were neutropenia (n = 5), nausea (n = 2), chest pain (n = 2), deep vein thrombosis (n = 1), transaminitis (n = 1), and dehydration (n = 1). Dose reductions to 1.2 mg/kg were instituted as a result of grade 2 neuropathy (n = 6), transaminitis (n = 1), and arthralgias and fatigue (n = 2). CONCLUSION Brentuximab vedotin is both active and well tolerated in cutaneous T-cell lymphoma and lymphomatoid papulosis, with an overall response rate of 73% and complete response rate of 35%.

Inhaled Insulin Forms Toxic Pulmonary Amyloid Aggregates

It is well known that interfaces, such as polar-nonpolar or liquid-air, play a key role in triggering protein aggregation in vitro, in particular the aggregation of peptides and proteins with the predisposition of misfolding and aggregation. Here we show that the interface present in the lungs predisposes the lungs to form aggregation of inhaled insulin. Insulin inhalers were introduced, and a large number of diabetic patients have used them. Although inhalers were safe and effective, decreases in pulmonary capacity have been reported in response to inhaled insulin. We hypothesize that the lung air-tissue interface provides a template for the aggregation of inhaled insulin. Our studies were designed to investigate the harmful potential that inhaled insulin has in pulmonary tissue in vivo, through an amyloid formation mechanism. Our data demonstrate that inhaled insulin rapidly forms amyloid in the lungs causing a significant reduction in pulmonary air flow. Our studies exemplify the importance that interfaces play in protein aggregation in vivo, illustrating the potential aggregation of inhaled proteins and the formation of amyloid deposits in the lungs. These insulin deposits resemble the amyloid structures implicated in protein misfolding disorders, such as Alzheimers and Parkinsons diseases, and could as well be deleterious in nature.

Formation of immunoglobulin light chain amyloid oligomers in primary cutaneous nodular amyloidosis

Background  Primary cutaneous nodular amyloidosis (PCNA) is thought to be a plasma cell dyscrasia. The amyloid deposits are found in the dermis and subcutis, and they contain clonal immunoglobulin light chains, produced by a local proliferation of plasma cells. New insights into amyloid diseases have revealed that the pathology is due more to the presence of small, misfolded protein species termed oligomers than to the deposition of fibrillar material.

Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra-lesional injections of anti-amyloid antibodies

Please cite this paper as: Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra‐lesional injections of anti‐amyloid antibodies. Experimental Dermatology 2010; 19: 904–911.

Association of Skin with the Pathogenesis and Treatment of Neurodegenerative Amyloidosis

Amyloidosis are a large group of conformational diseases characterized by abnormal protein folding and assembly which results in the accumulation of insoluble protein aggregates that may accumulate systemically or locally in certain organs or tissue. In local amyloidosis, amyloid deposits are restricted to a particular organ or tissue. Alzheimer’s, Parkinson’s disease, and amyotrophic lateral sclerosis are some examples of neurodegenerative amyloidosis. Local manifestation of protein aggregation in the skin has also been reported. Brain and skin are highly connected at a physiological and pathological level. Recently several studies demonstrated a strong connection between brain and skin in different amyloid diseases. In the present review, we discuss the relevance of the “brain–skin connection” in different neurodegenerative amyloidosis, not only at the pathological level, but also as a strategy for the treatment of these diseases.

Role of oligomers in the amyloidogenesis of primary cutaneous amyloidosis

BACKGROUND Primary cutaneous amyloidosis (PCA) describes a heterogeneous group of cutaneous diseases characterized by amyloid deposition; this may manifest as macules, papules, or nodules, depending on the subtype involved. To date, relatively little is known about the process of amyloidogenesis in the skin; however, investigators recently have identified small amyloid species, known as oligomers, which give rise to large amyloid fibrillar aggregates. OBJECTIVE The purpose of the current study was to identify small oligomers in patients with PCA using novel immunohistochemical techniques and to examine our findings in light of previous hypotheses of amyloid formation in these diseases. METHODS Six cases of PCA were analyzed using Congo red, thioflavin S, and hematoxylin-eosin. We also analyzed these samples with the novel oligomer-specific conformational antibody I-11 to detect the small, misfolded protein oligomers. Semiquantitative analysis was performed on these samples to grade the amount of amyloid aggregates and oligomers detected in the skin samples with light and polarized microscopy. RESULTS In the cases examined, we detected intracellular oligomers in the basal cell layer of the epidermis and the surrounding cells in the dermis. We also were able to detect large aggregates of amyloid in our samples and to correlate the relationship of oligomers to amyloid aggregates in accordance with previous studies on cutaneous amyloidosis and other amyloid-related diseases. LIMITATIONS Small sample size is a limitation. CONCLUSIONS PCA is an amyloid-related disease that likely follows a similar mechanism as other more intensively studied amyloid diseases.