Evaluating Mitochondrial DNA Variation in Autism Spectrum Disorders

Despite the increasing speculation that oxidative stress and abnormal energy metabolism may play a role in Autism Spectrum Disorders (ASD), and the observation that patients with mitochondrial defects have symptoms consistent with ASD, there are no comprehensive published studies examining the role of mitochondrial variation in autism. Therefore, we have sought to comprehensively examine the role of mitochondrial DNA (mtDNA) variation with regard to ASD risk, employing a multi‐phase approach. In phase 1 of our experiment, we examined 132 mtDNA single‐nucleotide polymorphisms (SNPs) genotyped as part of our genome‐wide association studies of ASD. In phase 2 we genotyped the major European mitochondrial haplogroup‐defining variants within an expanded set of autism probands and controls. Finally in phase 3, we resequenced the entire mtDNA in a subset of our Caucasian samples (～400 proband‐father pairs). In each phase we tested whether mitochondrial variation showed evidence of association to ASD. Despite a thorough interrogation of mtDNA variation, we found no evidence to suggest a major role for mtDNA variation in ASD susceptibility. Accordingly, while there may be attractive biological hints suggesting the role of mitochondria in ASD our data indicate that mtDNA variation is not a major contributing factor to the development of ASD.     

AAV8 transduction capacity is reduced by prior exposure to endosome-like pH conditions

Adeno-associated virus(AAV) is an essential instrument in the neuroscientist's toolkit, which allows delivery of DNA to provide labeling with fluorescent proteins or genetic instructions to regulate gene expression. In the field of neural regeneration, the transduction of neurons enables the observation and regulation of axon growth and regeneration, and in the future will likely be a mechanism for delivering molecular therapies to promote sprouting and regeneration after central nervous system injury. Traditional formulations of AAV preparations permit efficient viral transduction under physiologic conditions, but an improved understanding of the mechanistic limitations of AAV transduction may facilitate production of more resilient AAV strains for investigative and therapeutic purposes. We studied AAV transduction in the context of prior exposure of AAV serotype 8(AAV8) to environmental p H within the range encountered during endosomal endocytosis(p H 7.4 to p H 4.4), during which low p H-triggered structural and autoproteolytic changes to the viral capsid are believed to be necessary for endosome escape and virus uncoating. Due to the fundamental nature of these processes, we hypothesized that premature exposure of AAV8 particles to acidic p H would decrease viral transduction of HT1080 cells in vitro, as measured by fluorescent reporter gene expression using high-content imaging analysis. We found that increasingly acidic incubation conditions were associated with concomitant reductions in transduction efficiency, and that quantitative levels of reporter gene expression in transduced cells were similarly decreased. The biggest decrease in transduction occurred between p H 7.4 and p H 6.4, suggesting the possible co-occurrence of a p H-associated event and viral inactivation within that range. Taken together, these findings indicate that exposure of AAV8 to acidic p H for as little as 1 hour is deleterious to transduction ability. Future studies are necessary to understand the p H-associated causative mechanisms involved. This study was approved by the University of Miami Institutional Animal Care and Use Committee, USA(Protocol #18-108-LF) on July 12, 2018.     

Current status and future opportunities for controlling acromegaly

Growth-hormone (GH) secreting adenomas, including acromegaly, account for approximately one-sixth of all pituitary adenomas and are associated with mortality rates at least twice that of the general population. The ultimate goal of therapy for acromegaly is normalization of morbidity and mortality rates achieved through removal or reduction of the tumor mass and normalization of insulin-like growth factor I (IGF-I) levels. Previously published efficacy results of current treatment modalities (surgery, conventional radiation, and medical therapy with dopamine agonists and somatostatin analogs) are often difficult to compare because of the different criteria used to define cure (some of which are now considered inadequate). For each of these modalities, pooled data from a series of acromegaly studies were reviewed for rates of IGF-I normalization, a currently accepted definition of cure. The results showed overall cure rates of approximately 10% for bromocriptine, 34% for cabergoline, 36% for conventional radiation, 50–90% for surgery for microadenomas and less than 50% for macroadenomas, and 54–66% for octreotide. These cure rates based on IGF-I normalization are generally less than those reported for cure based solely on GH levels. Novel new therapies for acromegaly include the somatostatin analog, lanreotide, Gamma Knife radiosurgery, and pegvisomant, the first in its class of new GH receptor antagonists. Although it does not appear that Gamma Knife radiosurgery results in significantly higher cure rates or fewer complications, it does provide a notable improvement in delivery compared with conventional radiation. Early studies have reported IGF-I normalization in 48% of lanreotide-treated patients and up to 97% of pegvisomant-treated.     

Extensive non-small cell lung cancer treated with mitomycin, cisplatin, and vindesine (MiPE): a Southwest Oncology Group Study

Ninety-seven previously untreated patients with metastatic non-small cell lung cancer were treated with combination chemotherapy consisting of mitomycin (10 mg/m2) on Day 1, cisplatin (50 mg/m2) on Days 1 and 22, and vindesine (3 mg/m2) on Days 1 and 22 (MiPE). MiPE was repeated at 6-week intervals until disease progression or unacceptable toxicity. The overall response rate was 33%. There were seven complete responses (7%) and 25 partial responses (26%). The median progression-free interval for responding patients was 7 months. Median survival for all patients was 5 months, with 16% surviving 1 year. One patient died from sepsis while neutropenic. The results with MiPE treatment for patients with non-small cell lung cancer compare favorably to other mitomycin-vinca combinations previously tested in the Southwest Oncology Group.     

Assessment of Unconscious Decision Aids Applied to Complex Patient-Centered Medical Decisions

Background

To improve patient health, recent research urges for medical decision aids that are designed to enhance the effectiveness of specific medically related decisions. Many such decisions involve complex information, and decision aids that independently use deliberative (analytical and slower) or intuitive (more affective and automatic) cognitive processes for such decisions result in suboptimal decisions. Unconscious thought can arguably use both intuitive and deliberative (slow and analytic) processes, and this combination may further benefit complex patient (or practitioner) decisions as medical decision aids. Indeed, mounting research demonstrates that individuals render better decisions generally if they are distracted from thinking consciously about complex information after it is presented (but can think unconsciously), relative to thinking about that information consciously or not at all.

Objective

The current research tested whether the benefits of unconscious thought processes can be replicated using an Internet platform for a patient medical decision involving complex information. This research also explored the possibility that judgments reported after a period of unconscious thought are actually the result of a short period of conscious deliberation occurring during the decision report phase.

Methods

A total of 173 participants in a Web-based experiment received information about four medical treatments, the best (worst) associated with mostly positive (negative) side-effects/attributes and the others with equal positive-negative ratios. Next, participants were either distracted for 3 minutes (unconscious thought), instructed to think about the information for 3 minutes (conscious thought), or moved directly to the decision task (immediate decision). Finally, participants reported their choice of, and attitudes toward, the treatments while experiencing high, low, or no cognitive load, which varied their ability to think consciously while reporting judgments. Cognitive load was manipulated by having participants memorize semi-random (high), line structured (low), or no dot patterns and recall these intermittently with their decision reports. Overall then, participants were randomly assigned to the conditions of a 3 (thought condition) by 3 (cognitive-load level) between-subjects design.

Results

A logistic regression analysis indicated that the odds of participants choosing the best treatment were 2.25 times higher in the unconscious-thought condition compared to the immediate-decision condition (b=.81, Wald=4.32, P=.04, 95% CI 1.048-4.836), and 2.39 times greater compared to the conscious-thought condition (b=.87, Wald=4.87, P=.027, 95% CI 1.103-5.186). No difference was observed between the conscious-thought condition compared to the immediate-decision condition, and cognitive load manipulations did not affect choices or alter the above finding.

Conclusions

This research demonstrates a plausible benefit of unconscious thinking as a decision aid for complex medical decisions, and represents the first use of unconscious thought processes as a patient-centered medical decision aid. Further, the quality of decisions reached unconsciously does not appear to be affected by the amount of cognitive load participants experienced.