BackgroundThe progressive neurodegenerative disorder Alzheimer’s disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (Aβ42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The Aβ42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for Aβ42 mediated neurodegeneration is yet to be fully understood.Methodology/Principal FindingsWe have utilized Gal4/UAS system to develop a transgenic fruit fly model for Aβ42 mediated neurodegeneration. Targeted misexpression of human Aβ42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer’s like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of Aβ42 mediated neurodegeneration. Targeted misexpression of CBP along with Aβ42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues Aβ42 mediated neurodegeneration by blocking cell death. Misexpression of Aβ42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with Aβ42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.Conclusions/SignificanceWe have identified CBP as a genetic modifier of Aβ42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.

Alzheimer's disease (AD, OMIM: 104300), a progressive neurodegenerative disorder with no cure to date, is caused by the generation of amyloid-beta-42 (Aβ42) aggregates that trigger neuronal cell death by unknown mechanism(s). We have developed a transgenic Drosophila eye model where misexpression of human Aβ42 results in AD-like neuropathology in the neural retina. We have identified an apical-basal polarity gene crumbs (crb) as a genetic modifier of Aβ42-mediated-neuropathology. Misexpression of Aβ42 caused upregulation of Crb expression, whereas downregulation of Crb either by RNAi or null allele approach rescued the Aβ42-mediated-neurodegeneration. Co-expression of full length Crb with Aβ42 increased severity of Aβ42-mediated-neurodegeneration, due to three fold induction of cell death in comparison to the wild type. Higher Crb levels affect axonal targeting from the retina to the brain. The structure function analysis identified intracellular domain of Crb to be required for Aβ42-mediated-neurodegeneration. We demonstrate a novel neuroprotective role of Crb in Aβ42-mediated-neurodegeneration.

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Background: Anterior cruciate ligament (ACL) injuries are relatively common among younger athletes, with significant physical, psychological, and financial consequences. Research has largely focused on female athletes by identifying specific risk factors for an ACL injury, including variation in pubertal growth timing. There is less known about risk factors in males, and little is known about the effects of pubertal development on ACL injury risk in men. Purpose/Hypothesis: The purpose of this study was to analyze the relationship between an indicator of pubertal growth timing (age at adult height) and biomechanical risk for ACL injuries in men. We hypothesized that earlier age at adult height is correlated with riskier landing biomechanics during a drop vertical jump (DVJ) in men. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 21 recreationally active male students (age range, 20-33 years) were included. Participants completed a questionnaire on age at adult height and limb dominance, and anthropometric measurements were taken. There were 6 DVJ tests performed, with participants landing on a force plate while digital cameras recorded kinematic data from retroreflective markers placed according to the Helen Hayes marker system. Primary outcomes were sagittal and frontal plane knee kinematics and kinetics during contact. Data were analyzed using Pearson product-moment correlation. Results: In both limbs, age at achieving adult height was significantly negatively correlated with knee flexion/extension angle at toe-off (dominant: r = –0.79, P < .01; nondominant: r = –0.74, P < .01) and with peak flexion (dominant: r = –0.63, P < .01; nondominant: r = –0.70, P < .01) and extension (dominant: r = –0.66, P < .01; nondominant: r = –0.56, P = .01) angles during contact. In the nondominant limb, age at adult height was significantly negatively correlated with varus/valgus angle at initial contact ( r = –0.43; P = .05) and toe-off ( r = –0.44; P = .04) and was positively correlated with peak varus moment during contact ( r = 0.42; P = .06). Age at adult height was also positively correlated with peak vertical ground-reaction force ( r = 0.58; P < .01). Conclusion: Later age at adult height was correlated with riskier landing profiles in this study. This suggests that males with later or longer pubertal growth may have increased mechanical risk for ACL injuries. A better understanding of the effects of pubertal growth on landing biomechanics can improve the early identification of male athletes at greater risk for injuries.

The goal of this study was to compare information available on the Internet about the treatment of distal radius fractures with the guidelines established by the American Academy of Orthopaedic Surgeons (AAOS) in a qualitative observational study. A scoring system was used to compare the top 20 websites, excluding advertisements, from Google, Bing, and Yahoo with the AAOS guidelines. In addition, the results of the advertising content and the social media content were discussed. Of the 32 unique websites included in the study, 22 (68.75%) suggested operative fixation for fractures with unacceptable postreduction alignment (radial shortening >3 mm, dorsal tilt >10°, or intra-articular displacement or step-off >2 mm) as opposed to cast fixation. Of the 32 sites, 26 (81.25%) were unable to recommend for or against any 1 specific operative method for fixation of distal radius fractures. Only 2 of 32 (6.25%) sites mentioned age-specific recommendations, and 6 of 32 (18.75%) mentioned accurate activity protocols. Because the AAOS cannot recommend for or against immobilization of the elbow in patients treated with cast immobilization, it is reasonable that 7 of 32 (21.88%) sites discussed these options. The websites common to all 3 search engines also scored very well, with 84.89% of their recommendations being consistent with the AAOS recommendations. Most websites contain appropriate recommendations for the treatment of distal radius fractures. However, there is a significant amount of misinformation as well. The available information may be difficult for patients to interpret and may affect their expectations about care. [ Orthopedics . 2020;43(2):e79–e86.]