The nature of eye movements in Cerebral Palsy: A case study on the effects of posture on oculomotor control and visual function

A case study was performed on a child with cerebral palsy to evaluate the effects of providing postural support on visual performance, including oculomotor control, visual acuity, and reading comprehension. The hypothesis was that providing postural support for specific visual tasks would help the subject perform at a level of maximal efficiency for learning. We tested the subject with and without postural support, and measured the effects on visual acuity, oculomotor accuracy and reading comprehension. Oculomotor skills were measured by using a modified NSUCO Oculomotor Test and Visagraph II. The Visagraph II was also used to test reading comprehension. Postural support was provided in the form of a cervical collar. Results suggest that postural support does not improve visual acuity or oculomotor control. Instead, postural support seemed to impede those precise visual tasks by restraining the child\u27s head movement. We have found that in this case study, this subject had learned to use head movement for reading and precise visual tasks. Postural head support seemed to restrict the head movement, thereby restricting the child\u27s visual function

The DNA relaxation activity and covalent complex accumulation of Mycobacterium tuberculosis topoisomerase I can be assayed in Escherichia coli: application for identification of potential FRET-dye labeling sites

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium tuberculosis </it>topoisomerase I (MtTOP1) and <it>Escherichia coli </it>topoisomerase I have highly homologous transesterification domains, but the two enzymes have distinctly different C-terminal domains. To investigate the structure-function of MtTOP1 and to target its activity for development of new TB therapy, it is desirable to have a rapid genetic assay for its catalytic activity, and potential bactericidal consequence from accumulation of its covalent complex.</p> <p>Results</p> <p>We show that plasmid-encoded recombinant MtTOP1 can complement the temperature sensitive <it>topA </it>function of <it>E. coli </it>strain AS17. Moreover, expression of MtTOP1-G116 S enzyme with the TOPRIM mutation that inhibits DNA religation results in SOS induction and loss of viability in <it>E. coli</it>. The absence of cysteine residues in the MtTOP1 enzyme makes it an attractive system for introduction of potentially informative chemical or spectroscopic probes at specific positions via cysteine mutagenesis. Such probes could be useful for development of high throughput screening (HTS) assays. We employed the AS17 complementation system to screen for sites in MtTOP1 that can tolerate cysteine substitution without loss of complementation function. These cysteine substitution mutants were confirmed to have retained the relaxation activity. One such mutant of MtTOP1 was utilized for fluorescence probe incorporation and fluorescence resonance energy transfer measurement with fluorophore-labeled oligonucleotide substrate.</p> <p>Conclusions</p> <p>The DNA relaxation and cleavage complex accumulation of <it>M. tuberculosis </it>topoisomerase I can be measured with genetic assays in <it>E. coli</it>, facilitating rapid analysis of its activities, and discovery of new TB therapy targeting this essential enzyme.</p

Trend of Outcome Metrics in Recent Out-of-Hospital-Cardiac-Arrest Research: A Narrative Review of Clinical Trials

Cardiopulmonary resuscitation (CPR) research traditionally focuses on survival. In 2018, the International Liaison Committee on Resuscitation (ILCOR) proposed more patient-centered outcomes. Our narrative review assessed clinical trials after 2018 to identify the trends of outcome metrics in the field OHCA research. We performed a search of the PubMed database from 1 January 2019 to 22 September 2023. Prospective clinical trials involving adult humans were eligible. Studies that did not report any patient-related outcomes or were not available in full-text or English language were excluded. The articles were assessed for demographic information and primary and secondary outcomes. We included 89 studies for analysis. For the primary outcome, 31 (35%) studies assessed neurocognitive functions, and 27 (30%) used survival. For secondary outcomes, neurocognitive function was present in 20 (22%) studies, and survival was present in 10 (11%) studies. Twenty-six (29%) studies used both survival and neurocognitive function. Since the publication of the COSCA guidelines in 2018, there has been an increased focus on neurologic outcomes. Although survival outcomes are used frequently, we observed a trend toward fewer studies with ROSC as a primary outcome. There were no quality-of-life assessments, suggesting a need for more studies with patient-centered outcomes that can inform the guidelines for cardiac-arrest management

Contemporary Analysis of Malignancies in Women of Child-Bearing Age: An NSQIP Analysis

Background: Recent evidence suggests that cancer incidence among pregnant women is increasing. The pattern of malignancies in pregnant women and how these compare to their nonpregnant counterparts has not been explored. Here we describe the differences in the proportion of resected malignancies in this population. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify women aged 18-49 who underwent an operation for malignancy from 2007-2012. Age-adjusted distribution of specific surgical interventions for malignancy based on ICD-9 codes were compared among pregnant and non-pregnant women using logistic regression analysis. Results: 42,732 subjects with malignancies surgically treated during child-bearing age were identified. 0.33% (n=143) were pregnant. The most common tumors requiring resection were breast (51%), thyroid (17%), and colorectal (9%). The distribution for most cancers was similar between groups. The age-adjusted proportion was significantly increased in breast, major salivary gland and oropharyngeal malignancies (p\u3c0.05). The proportion of resected colorectal cancers was significantly lower in pregnant women (p\u3c0.05; Table 1). Conclusion: This study serves as the first comprehensive and contemporary overview of malignancies resected in women of childbearing age. This study demonstrates that the proportion of resections among pregnant women was significantly greater in breast, major salivary gland and oropharyngeal cancers and lower for colorectal cancers. While these data might represent true differences in cancer incidence, further work is necessary to demonstrate if these are true differences in incidence versus differences in detection and treatment of the pregnant patient

Posttranslational Modification of Vesicular Stomatitis Virus Glycoprotein, but Not JNK Inhibition, Is the Antiviral Mechanism of SP600125

Vesicular stomatitis virus (VSV), a negative-sense single-stranded-RNA rhabdovirus, is an extremely promising oncolytic agent for cancer treatment. Since oncolytic virotherapy is moving closer to clinical application, potentially synergistic combinations of oncolytic viruses and molecularly targeted antitumor agents are becoming a meaningful strategy for cancer treatment. Mitogenactivated protein kinase (MAPK) inhibitors have been shown to impair liver cell proliferation and tumor development, suggesting their potential use as therapeutic agents for hepatocellular carcinoma (HCC). In this work, we show that the impairment of MAPK in vitro did not interfere with the oncolytic properties of VSV in HCC cell lines. Moreover, the administration of MAPK inhibitors did not restore the responsiveness of HCC cells to alpha/beta interferon (IFN-α/β). In contrast to previous reports, we show that JNK inhibition by the inhibitor SP600125 is not responsible for VSV attenuation in HCC cells and that this compound acts by causing a posttranslational modification of the viral glycoprotein

Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation

The interleukin (IL)-1 family members IL-1α, -1β, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5−/− pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders

The role of community and culture in abortion perceptions, decisions, and experiences among Asian Americans

IntroductionCulture and community can play a role in views, stigma, and access related to abortion. No research to date has documented the influence of culture and community attitudes on Asian American (AA) experiences accessing abortion care in the United States (US). This paper aims to fill gaps in research and understand how cultural and community views influence medication abortion access and experiences among AAs.MethodsWe used a community-based participatory research approach, which included collaboration among experts in public health, advocates, practitioners, and community partners to understand abortion knowledge, attitudes, and experiences among AAs. Using a semi-structured interview guide, we interviewed twenty-nine eligible people of reproductive age over 18 that self-identified as Asian American or mixed race including Asian American, Native Hawaiian, and/or Pacific Islander (AANHPI), and had a medication abortion in the US between January 2016 and March 2021. Interviews were analyzed and coded in NVivo 12 using a modified grounded theory approach.ResultsParticipants described various influences of religion negatively impacting acceptability of abortion among their family and community. Lack of openness around sexual and reproductive health (SRH) topics contributed to stigma and influenced most participants' decision not to disclose their abortion to family members, which resulted in participants feeling isolated throughout their abortion experience. When seeking abortion care, participants preferred to seek care with providers of color, especially if they were AANHPI due to past experiences involving stigma and judgment from White providers. Based on their experiences, respondents recommended ways to improve the abortion experience for AAs in the US including, (1) more culturally aware abortion providers from one's community who better understand their needs; (2) clinics providing abortion services located in or near AA communities with signage in local languages; and (3) tailored mental health resources with culturally aware therapists.ConclusionThis study demonstrates ways in which culture and community opinions toward SRH can influence both the acceptability of abortion and experiences seeking abortion care among AAs. It is important to consider family and community dynamics among AAs to better tailor services and meet the needs of AAs seeking abortion care in the US

Cancer of the ampulla of Vater: analysis of the whole genome sequence exposes a potential therapeutic vulnerability

BACKGROUND: Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In rare tumors, where large-scale clinical trials are daunting, this targeted genomic approach offers a new perspective and hope for improved treatments. Cancers of the ampulla of Vater are rare tumors that comprise only about 0.2% of gastrointestinal cancers. Consequently, they are often treated as either distal common bile duct or pancreatic cancers. METHODS: We analyzed DNA from a resected cancer of the ampulla of Vater and whole blood DNA from a 63 year-old man who underwent a pancreaticoduodenectomy by whole genome sequencing, achieving 37× and 40× coverage, respectively. We determined somatic mutations and structural alterations. RESULTS: We identified relevant aberrations, including deleterious mutations of KRAS and SMAD4 as well as a homozygous focal deletion of the PTEN tumor suppressor gene. These findings suggest that these tumors have a distinct oncogenesis from either common bile duct cancer or pancreatic cancer. Furthermore, this combination of genomic aberrations suggests a therapeutic context for dual mTOR/PI3K inhibition. CONCLUSIONS: Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals

DNA Topoisomerases are essential to resolve topological problems during DNA metabolism in all species. However, the prevalence and function of RNA topoisomerases remain uncertain. Here, we show that RNA topoisomerase activity is prevalent in Type IA topoisomerases from bacteria, archaea, and eukarya. Moreover, this activity always requires the conserved Type IA core domains and the same catalytic residue used in DNA topoisomerase reaction; however, it does not absolutely require the non-conserved carboxyl-terminal domain (CTD), which is necessary for relaxation reactions of supercoiled DNA. The RNA topoisomerase activity of human Top3β differs from that of Escherichia coli topoisomerase I in that the former but not the latter requires the CTD, indicating that topoisomerases have developed distinct mechanisms during evolution to catalyze RNA topoisomerase reactions. Notably, Top3β proteins from several animals associate with polyribosomes, which are units of mRNA translation, whereas the Top3 homologs from E. coli and yeast lack the association. The Top3β-polyribosome association requires TDRD3, which directly interacts with Top3β and is present in animals but not bacteria or yeast. We propose that RNA topoisomerases arose in the early RNA world, and that they are retained through all domains of DNA-based life, where they mediate mRNA translation as part of polyribosomes in animals