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"Paraplegics."
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Cycle of the werewolf
Terror began in January, by the light of the full moon. The first scream came from the snowbound railwayman who felt the werewolf's fangs ripping at his throat. The next month there was a scream of agony from the woman attacked in her cozy bedroom. Now scenes of unbelievable horror unfold each time the full moon shines on the isolated Maine town of Tarker's Mills. Only one thing is sure-- when the full moon rises, a paralyzing fear sweeps through Tarker's Mills. For snarls that sound like human words can be heard whining through the wind. And all around are the footprints of a monster whose hunger cannot be sated.
Book
ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling
Stimulator of interferon genes (STING) is an intracellular sensor of cyclic di-nucleotides involved in the innate immune response against pathogen- or self-derived DNA. STING trafficking is tightly linked to its function, and its dysregulation can lead to disease. Here, we systematically characterize genes regulating STING trafficking and examine their impact on STING-mediated responses. Using proximity-ligation proteomics and genetic screens, we demonstrate that an endosomal sorting complex required for transport (ESCRT) complex containing HGS, VPS37A and UBAP1 promotes STING degradation, thereby terminating STING-mediated signaling. Mechanistically, STING oligomerization increases its ubiquitination by UBE2N, forming a platform for ESCRT recruitment at the endosome that terminates STING signaling via sorting in the lysosome. Finally, we show that expression of a UBAP1 mutant identified in patients with hereditary spastic paraplegia and associated with disrupted ESCRT function, increases steady-state STING-dependent type I IFN responses in healthy primary monocyte-derived dendritic cells and fibroblasts. Based on these findings, we propose that STING is subject to a tonic degradative flux and that the ESCRT complex acts as a homeostatic regulator of STING signaling.
STING is an intracellular sensor of pathogen- or host-derived DNA. In this study, the authors identify an ESCRT complex that regulates STING degradation, thus acting as a homeostatic regulator of STING signalling and type-I interferon responses.
Journal Article
How to walk away
\"Margaret Jacobsen is just about to step into the bright future she's worked for so hard and so long: a new dream job, a fiancé she adores, and the promise of a picture-perfect life just around the corner. Then, suddenly, on what should have been one of the happiest days of her life, everything she worked for is taken away in a brief, tumultuous moment. In the hospital and forced to face the possibility that nothing will ever be the same again, Maggie must confront the unthinkable. First there is her fiancé, Chip, who wallows in self-pity while simultaneously expecting to be forgiven. Then, there's her sister Kit, who shows up after pulling a three-year vanishing act. Finally, there's Ian, her physical therapist, the one the nurses said was too tough for her. Ian, who won't let her give in to her pity, and who sees her like no one has seen her before. Sometimes the last thing you want is the one thing you need. Sometimes we all need someone to catch us when we fall. And sometimes love can find us in the least likely place we would ever expect\"-- Provided by publisher.
Book
Sex differences in susceptibility, severity, and outcomes of coronavirus disease 2019: Cross-sectional analysis from a diverse US metropolitan area
Sex is increasingly recognized as an important factor in the epidemiology and outcome of many diseases. This also appears to hold for coronavirus disease 2019 (COVID-19). Evidence from China and Europe has suggested that mortality from COVID-19 infection is higher in men than women, but evidence from US populations is lacking. Utilizing data from a large healthcare provider, we determined if males, as compared to females have a higher likelihood of SARS-CoV-2 susceptibility, and if among the hospitalized COVID-19 patients, male sex is independently associated with COVID-19 severity and poor in-hospital outcomes.
Using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, we conducted a cross-sectional analysis of data from a COVID-19 Surveillance and Outcomes Registry (CURATOR). Data were extracted from Electronic Medical Records (EMR). A total of 96,473 individuals tested for SARS-CoV-2 RNA in nasopharyngeal swab specimens via Polymerized Chain Reaction (PCR) tests were included. For hospital-based analyses, all patients admitted during the same time-period were included. Of the 96,473 patients tested, 14,992 (15.6%) tested positive, of whom 4,785 (31.9%) were hospitalized and 452 (9.5%) died. Among all patients tested, men were significantly older. The overall SARS-CoV-2 positivity among all tested individuals was 15.5%, and was higher in males as compared to females 17.0% vs. 14.6% [OR 1.20]. This sex difference held after adjusting for age, race, ethnicity, marital status, insurance type, median income, BMI, smoking and 17 comorbidities included in Charlson Comorbidity Index (CCI) [aOR 1.39]. A higher proportion of males (vs. females) experienced pulmonary (ARDS, hypoxic respiratory failure) and extra-pulmonary (acute renal injury) complications during their hospital course. After adjustment, length of stay (LOS), need for mechanical ventilation, and in-hospital mortality were significantly higher in males as compared to females.
In this analysis of a large US cohort, males were more likely to test positive for COVID-19. In hospitalized patients, males were more likely to have complications, require ICU admission and mechanical ventilation, and had higher mortality than females, independent of age. Sex disparities in COVID-19 vulnerability are present, and emphasize the importance of examining sex-disaggregated data to improve our understanding of the biological processes involved to potentially tailor treatment and risk stratify patients.
Journal Article
Rick Hansen's man in motion world tour : 30 years later : a celebration of courage, strength, and the power of community
A look back on and celebration of Rick Hansen's Man In Motion World Tour, which began in 1985 and covered 40,000 kilometres through 34 countries on four continents before ending in Canada in 1987, and raised $26 million for spinal cord injury research and initiatives to improve the quality of life and accessibility for those with disabilities.
Book
Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors
KIF1A is a kinesin family motor involved in the axonal transport of synaptic vesicle precursors (SVPs) along microtubules (MTs). In humans, more than 10 point mutations in KIF1A are associated with the motor neuron disease hereditary spastic paraplegia (SPG). However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus a cogent molecular explanation for how KIF1A mutations lead to neuropathy is not available. In this study, we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility. Introduction of the corresponding mutations into the Caenorhabditis elegans KIF1A homolog unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs. Our data reveal that hyperactivation of kinesin motor activity, rather than its loss of function, is a cause of motor neuron disease in humans.
Journal Article
Research and evaluation of functional clothing for patients with paraplegia of both lower limbs
Because of the particularity of the body, the clothes of ordinary people are not suitable for paraplegia patients. In this paper, by means of questionnaire survey and incision experiment, a functional garment is developed for patients with paraplegia of both lower extremities, which integrates the structural fitness and convenience of wearing and taking off. Moreover, the functional clothing was evaluated by referring to the convenience evaluation system and combining with the subjective evaluation method. The results showed that the structural fitness of the functional garments was improved, especially the tension of the elbows and knees was significantly reduced. In addition, the convenience of wearing functional pants was also significantly improved: participants' participation in the three ADLs was significantly increased when wearing functional pants, all of which were 100%. The time taken to complete three ADLs in functional pants was also reduced, among which the replacement of diapers was the most efficient, reducing the time by 70.39%.
Journal Article
AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient
There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the
AP4M1
gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and
Clostridioides difficile
gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration:
NCT06069687
.
In a phase 1 trial in a single patient with hereditary spastic paraplegia type 50, a personalized AAV9-based gene therapy was developed within 3 years from diagnosis and was well tolerated, showing preliminary evidence of disease stabilization.
Journal Article