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Abstract Background The conventional clinical trial design in Alzheimer’s disease (AD) and AD-related disorders (ADRDs) is the parallel-group randomized controlled trial. However, in heterogeneous disorders like AD/ADRDs, this design requires large sample sizes to detect meaningful effects in an “average” patient. They are very costly and, despite many attempts, have not yielded new treatments for many years. An alternative, the multi-crossover, randomized control trial (MCRCT) is a design in which each patient serves as their own control across successive, randomized blocks of active treatment and placebo. This design overcomes many limitations of parallel-group trials, yielding an unbiased assessment of treatment effect at the individual level (“N-of-1”) regardless of unique patient characteristics. The goal of the present study is to pilot a MCRCT of a potential symptomatic treatment, methylphenidate, for mild-stage AD/ADRDs, testing feasibility and compliance of participants in this design and efficacy of the drug using both standard and novel outcome measures suited for this design. Methods Ten participants with mild cognitive impairment or mild-stage dementia due to AD/ADRDs will undergo a 4-week lead-in period followed by three, month-long treatment blocks (2 weeks of treatment with methylphenidate, 2 weeks placebo in random order). This trial will be conducted entirely virtually with an optional in-person screening visit. The primary outcome of interest is feasibility as measured by compliance and retention, with secondary and exploratory outcomes including cognition as measured by neuropsychological assessment at the end of each treatment period and daily brain games played throughout the study, actigraphy, and neuropsychiatric and functional assessments. Discussion This pilot study will gauge the feasibility of conducting a virtual MCRCT for symptomatic treatment in early AD/ADRD. It will also compare home-based daily brain games with standard neuropsychological measures within a clinical trial for AD/ADRD. Particular attention will be paid to compliance, tolerability of drug and participation, learning effects, trends and stability of daily measures across blocks, medication carryover effects, and correlations between standard and brief daily assessments. These data will provide guidance for more efficient trial design and the use of potentially more robust, ecological outcome measures in AD/ADRD research. Trial registration ClinicalTrials.gov, NCT03811847 . Registered on 21 January 2019.

Cell division and tissue growth must be coordinated with development. Defects in these processes are the basis for a number of diseases, including developmental malformations and cancer. We have conducted an unbiased RNAi screen for genes that are required for growth in the Drosophila wing, using GAL4-inducible short hairpin RNA (shRNA) fly strains made by the Drosophila RNAi Screening Center. shRNA expression down the center of the larval wing disc using dpp-GAL4, and the central region of the adult wing was then scored for tissue growth and wing hair morphology. Out of 4,753 shRNA crosses that survived to adulthood, 18 had impaired wing growth. FlyBase and the new Alliance of Genome Resources knowledgebases were used to determine the known or predicted functions of these genes and the association of their human orthologs with disease. The function of eight of the genes identified has not been previously defined in Drosophila. The genes identified included those with known or predicted functions in cell cycle, chromosome segregation, morphogenesis, metabolism, steroid processing, transcription, and translation. All but one of the genes are similar to those in humans, and many are associated with disease. Knockdown of lin-52, a subunit of the Myb-MuvB transcription factor, or βNACtes6, a gene involved in protein folding and trafficking, resulted in a switch from cell proliferation to an endoreplication growth program through which wing tissue grew by an increase in cell size (hypertrophy). It is anticipated that further analysis of the genes that we have identified will reveal new mechanisms that regulate tissue growth during development.

Endoreplication is a cell cycle variant that entails cell growth and periodic genome duplication without cell division, and results in large, polyploid cells. Cells switch from mitotic cycles to endoreplication cycles during development, and also in response to conditional stimuli during wound healing, regeneration, aging, and cancer. In this study, we use integrated approaches in Drosophila to determine how mitotic cycles are remodeled into endoreplication cycles, and how similar this remodeling is between induced and developmental endoreplicating cells (iECs and devECs). Our evidence suggests that Cyclin A / CDK directly activates the Myb-MuvB (MMB) complex to induce transcription of a battery of genes required for mitosis, and that repression of CDK activity dampens this MMB mitotic transcriptome to promote endoreplication in both iECs and devECs. iECs and devECs differed, however, in that devECs had reduced expression of E2F1-dependent genes that function in S phase, whereas repression of the MMB transcriptome in iECs was sufficient to induce endoreplication without a reduction in S phase gene expression. Among the MMB regulated genes, knockdown of AurB protein and other subunits of the chromosomal passenger complex (CPC) induced endoreplication, as did knockdown of CPC-regulated cytokinetic, but not kinetochore, proteins. Together, our results indicate that the status of a CycA-Myb-MuvB-AurB network determines the decision to commit to mitosis or switch to endoreplication in both iECs and devECs, and suggest that regulation of different steps of this network may explain the known diversity of polyploid cycle types in development and disease.

Background: Epidermolysis bullosa is a rare, often severe, genetic disorder characterized by fragility of the skin and mucous membranes. Despite the important role of parents during wound care, an essential factor in adapting to this disease, studies focusing on the parent-child relationship during wound care are scarce. The current study is aimed at addressing this gap., Methods: A quantitative study among 31 children (n = 21 ≤ 17 years; n = 10 17-25 years) and 34 parents (including 27 parent-child dyads) was conducted to examine the relationship between pain, itch, anxiety, positive and negative feelings, and coping strategies assessed with the newly developed Epidermolysis Bullosa Wound Care List. The majority of the analyses were descriptive and the results were interpreted qualitatively because of the small sample size., Results: Children and parents both showed significantly more positive (i.e. 'protected', 'proud', 'calm', 'connected to each other' and 'courageous') than negative feelings (i.e. 'helpless', 'angry', 'insecure', 'guilty', 'gloomy' and 'sad') during wound care, with parents reporting both feelings more than children. The more children experienced pain, the more they were anxious, had negative feelings, were inclined to use distraction, to postpone wound care and to cry. The more parents experienced feelings (either positive or negative), the more likely they sought distraction. With regard to child-parent dyads the results showed that the more children expressed anxiety, the more parents experienced negative feelings. Furthermore, those who reported more negative feelings were more likely to hide their feelings, while those who reported more positive feelings were more inclined to show their feelings. Pain, itch and anxiety in the child were associated with more distraction or postponement of wound care by the parent., Conclusion: This study underlines the importance of paying attention to the relationship between feelings and coping strategies in child-parent dyads in the management of pain and anxiety during wound care. Further research could provide more insight how these feelings and coping strategies are related to the psychological well-being of both the child and the parent in the short term as well as in the long term., (© 2022. The Author(s).)

Background: Epidermolysis bullosa (EB) is a group of rare genetic skin disorders that primarily manifest as blisters and erosions following mild mechanical trauma. Despite the crucial role of the parents of children with EB in managing the disease, studies focusing on the parent-child relationship remain a gap in the literature. To address this gap, the current quantitative study, involving 55 children with all types of EB and 48 parents, assessed the relationship between their quality of life and coping strategies. Quality of life was measured with the Pediatric Quality of Life Inventory and TNO-AZL Questionnaire for Adult's Health- related Quality of Life, and coping strategies were assessed with the Coping with a Disease Questionnaire. The majority of the analyses were descriptive and the results were interpreted qualitatively because of the small sample size., Results: Overall, the quality of life of children with EB and that of their parents was somewhat lower compared with the quality of life of healthy children and adults. Children with EB who more frequently used emotional reactions and cognitive-palliative strategies to cope with the disease demonstrated lower levels of emotional and social functioning, while children who showed more acceptance and distancing showed higher levels of functioning on all domains. Parents who frequently demonstrated emotional reactions reported lower levels of social functioning and experienced more depressive emotions and anger. Parents who used more avoidance showed higher levels of positive emotions. Within parent-child dyads, acceptance, cognitive-palliative strategies and distancing were positively related. Children's emotional and social functioning were negatively associated with their parents' depressive emotions. Parents' acceptance was linked to higher physical functioning in children, whereas children's avoidance was linked to a lower level of anger in parents., Conclusion: Children who are able to accept the disease or distance themselves from it appear to be better off in contrast to those who tend to engage in the cognitive-palliative strategies and expressing emotional reactions. Parents seem to be better off when they are able to use avoidance in contrast to those who tend to show emotional reactions. Further research is needed to substantiate these findings.

A 14-month-old, male American Bulldog presented to Texas A&M University Veterinary Medical Teaching Hospital in August of 2012 for anorexia, hydrophobia and gradually worsening neurologic signs. Grossly hemorrhage on the left side of the caudal cerebrum and cerebellum was observed and histologically corresponded with necrohemorrhagic and lymphoplasmacytic encephalitis associated with adult nematodes. Based on morphology and molecular analysis, these were identified as Ancylostoma sp., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this study, EPI pulse sequences with diffusion weighting for reduction of contributions from large vessels and inversion pulses in order to minimize the effects of CSF pulsations and CSF partial volume effects were developed for BOLD contrast investigations in functional MR imaging. One inversion recovery echo-planar imaging (IR-EPI) pulse sequence and one IR-EPI with additional diffusion weighting (DW-IR-EPI) were developed and compared to a standard gradient-echo EPI sequence in a cortical stimulation experiment in nine healthy volunteers. Stimulation of motor cortex was performed using a semi-complex finger-tapping paradigm in seven periods of alternating rest and stimulation. Comparison between the three pulse sequences was made by measuring the activated volume in each subject, as well as by calculating the relative signal increase during stimulation. Due to different baseline signal-to-noise levels in the images generated by the three pulse sequences, artificial noise was added so that the comparative investigation could be performed independently of the noise level. The activated volume was 128 +/- 73 pixels (mean +/- SD) using the standard EPI pulse sequence, 31 +/- 12 pixels using IR-EPI and 15 +/- 13 pixels when DW-IR-EPI was employed. The relative signal increase was 5.7 +/- 1.1% using standard EPI, 11.5 +/- 3.1% using IR-EPI and 9.9 +/- 2.4% using DW-IR-EPI. The activated volume obtained with the addition of extra noise, i.e. at equal S/N, was 70 +/- 50 pixels using the standard EPI, and when using IR-EPI, the activated volume was 28 +/- 13 pixels. At equal S/N, the signal increase was 7.3 +/- 1.4% using standard EPI and 12.0 +/- 3.6% using IR-EPI. In BOLD contrast imaging, a combination of diffusion weighting and inversion recovery appeared to reduce false activation caused by CSF pulsation and blood flow in large vessels., (Copyright 2002 John Wiley & Sons, Ltd.)

Regional cerebral blood flow (rCBF) was assessed using dynamic susceptibility-contrast MRI at 1.5 T. A simultaneous dual FLASH pulse sequence and Gd-DTPA-BMA (0.3 mmol/kg b.w.) were used for examination of 43 volunteers, measuring rCBF in frontal white matter (WM) and in gray matter in the thalamus (GM). Arterial input functions (AIFs) were registered 1) in the carotid artery and 2) in an artery within the GM/WM slice. The measured concentration-vs. -time curve was deconvolved with the AIF using both Fourier Transform (FT) and Singular Value Decomposition (SVD). Relative rCBF was given by the height of the deconvolved response curve. For each volunteer, eight different rCBF maps were calculated, representing different combinations of deconvolution techniques, AIFs, and filters. The average GM-WM rCBF ratios ranged from 2.0-2.2, depending on methodology. Absolute rCBF was 68 +/- 28 ml/(min 100 g) in GM and 35 +/- 13 ml/(min 100g) in WM (mean +/- SD, n = 39). GM-WM rCBF ratios obtained using SVD were 6-10% higher than corresponding ratios obtained using FT., (Copyright 2000 Wiley-Liss, Inc.)