Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat

Inhibition of mitochondrial complex I is one of the leading hypotheses for dopaminergic neuron death associated with Parkinson's disease (PD). To test this hypothesis genetically, we used a mouse strain lacking functional Ndufs4, a gene encoding a subunit required for complete assembly and function of complex I. Deletion of the Ndufs4 gene abolished complex I activity in midbrain mesencephalic neurons cultured from embryonic day (E) 14 mice, but did not affect the survival of dopaminergic neurons in culture. Although dopaminergic neurons were more sensitive than other neurons in these cultures to cell death induced by rotenone, MPP⁺, or paraquat treatments, the absence of complex I activity did not protect the dopaminergic neurons, as would be expected if these compounds act by inhibiting complex 1. In fact, the dopaminergic neurons were more sensitive to rotenone. These data suggest that dopaminergic neuron death induced by treatment with rotenone, MPP⁺, or paraquat is independent of complex I inhibition.     

ULTRASOUND IMAGING MEASUREMENT OF THE TRANSVERSUS ABDOMINIS IN SUPINE,STANDING, AND UNDER LOADING: A RELIABILITY STUDY OF NOVICE EXAMINERS

Background

Military personnel and first responders (police and firefighters) often carry large amounts of gear. This increased load can negatively affect posture and lead to back pain. The ability to quantitatively measure muscle thickness under loading would be valuable to clinicians to assess the effectiveness of core stabilization treatment programs and could aid in return to work decisions. Ultrasound imaging (USI) has the potential to provide such a measure, but to be useful it must be reliable.

Purpose

To assess the intrarater and interrater reliability of measurements of transversus abdominis (TrA) and internal oblique (IO) muscle thickness conducted by novice examiners using USI in supine, standing, and with an axial load.

Study Design

Prospective, test‐retest study

Methods

Healthy, active duty military (N=33) personnel were examined by two physical therapy doctoral students (primary and secondary ultrasound technicians) without prior experience in USI. Thickness measurements of the TrA and IO muscles were performed at rest and during a contraction to preferentially activate the TrA in three positions (hook‐lying, standing, and standing with body armor). Percent thickness changes and intraclass correlation coefficients (ICC) were calculated.

Results

Using the mean of three measurements for each of the three positions in resting and contracted muscle states, the intrarater ICC (3,3) values ranged from 0.90 to 0.98. The interrater ICC (2,1) values ranged from 0.39 to 0.79. The ICC values of percent thickness changes were lower than the individual ICC values for all positions and muscle states.

Conclusion

There is excellent intrarater reliability of novice ultrasound technicians measuring abdominal muscle thickness using USI in three positions during the resting and contracted muscle states. However, interrater reliability of two novice technicians was poor to fair, so additional training and experience may be necessary to improve reliability.

Level of Evidence

2b     

Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials

Background

Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes.

Radiographic Anatomy of the Native Anterior Cruciate Ligament: a Systematic Review

BackgroundIn an attempt to improve the accuracy and reproducibility of tunnel positioning, radiographs are being analyzed in an attempt to recreate the native anatomy of the ACL. Understanding the native ACL radiographic anatomy is an essential prerequisite to understand the relevance of postoperative tunnel position.Questions/PurposesWe performed a systematic review of the literature to delineate the radiographic location of the native ACL femoral and tibial footprints.MethodsA search was performed in March 2014 in PubMed, the Cochrane Collaboration Library, and EMBASE to identify all studies that evaluated the native anterior cruciate ligament (ACL) anatomy on radiographs. Various measurement methods were used in each study, and averages were obtained of the data from studies with the same measurement methods.ResultsFifteen papers were identified (which included data on 177 femora and 207 tibiae in total). Evaluation of the femoral footprint using the quadrant method on lateral knee radiographs showed that the average percent distance location of the anteromedial (AM) bundle and posterolateral (PL) bundle was 22.8% (95% confidence interval (CI) 16.59–28.90) and 32.5% (95% CI 27.71–37.26) from the posterior condyle, respectively, and 23.2% (95% CI 19.52–26.94) and 50.0% (95% CI 46.16–53.76) from Blumensaat’s line, respectively. Using the Amis and Jacob method, the tibial footprint on the lateral knee radiograph average percent distances was 35.1% (95% CI 34.46–35.72) for the center of the AM bundle and 47.3% (95% CI 41.69–52.95) for the center of the PL bundle of the ACL. The femoral and tibial ACL footprints on the anteroposterior (AP) views of the knee were not well delineated by these studies.ConclusionThe information presented in this systematic review offers surgeons another important tool for accurate ACL footprint identification.

Electronic supplementary material

The online version of this article (doi:10.1007/s11420-014-9417-5) contains supplementary material, which is available to authorized users.     

Benznidazole-resistance in Trypanosoma cruzi is a readily acquired trait that can arise independently in a single population

Benznidazole is the frontline drug used against Trypanosoma cruzi, the causative agent of Chagas disease. However, treatment failures are often reported. Here, we demonstrate that independently acquired mutations in the gene encoding a mitochondrial nitroreductase (TcNTR) can give rise to distinct drug-resistant clones within a single population. Following selection of benznidazole-resistant parasites, all clones examined had lost one of the chromosomes containing the TcNTR gene. Sequence analysis of the remaining TcNTR allele revealed 3 distinct mutant genes in different resistant clones. Expression studies showed that these mutant proteins were unable to activate benznidazole. This correlated with loss of flavin mononucleotide binding. The drug-resistant phenotype could be reversed by transfection with wild-type TcNTR. These results identify TcNTR as a central player in acquired resistance to benznidazole. They also demonstrate that T. cruzi has a propensity to undergo genetic changes that can lead to drug resistance, a finding that has implications for future therapeutic strategies.     

Practice Effects and Longitudinal Cognitive Change in Normal Aging vs. Incident Mild Cognitive Impairment and Dementia in The Mayo Clinic Study of Aging

The objective of this study was to examine practice effects and longitudinal cognitive change in a population-based cohort classified as clinically normal at their initial evaluation. We examined 1390 individuals with a median age of 78.1 years and re-evaluated them up to four times at approximate 15-month intervals, with an average follow-up time of 5 years. Of the 1390 participants, 947 (69%) individuals remained cognitively normal, 397 (29%) progressed to mild cognitive impairment (MCI), and 46 (3%) to dementia. The stable normal group showed an initial practice effect in all domains which was sustained in memory and visuospatial reasoning. There was only a slight decline in attention and language after visit 3. We combined individuals with incident MCI and dementia to form one group representing those who declined. The incident MCI/dementia group showed an unexpected practice effect in memory from baseline to visit 2, with a significant decline thereafter. This group did not demonstrate practice effects in any other domain and showed a downward trajectory in all domains at each evaluation. Modeling cognitive change in an epidemiologic sample may serve as a useful benchmark for evaluating cognitive change in future intervention studies.