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Flow Cytometry of DNMT1 as a Biomarker of Hypomethylating Therapies
Get PDFThe 5-azacytidine (AZA) and decitabine (DEC) are noncytotoxic, differentiation-inducing therapies approved for treatment of myelodysplastic syndrome, acute myeloid leukemias (AML), and under evaluation as maintenance therapy for AML postallogeneic hematopoietic stem cell transplant and to treat hemoglobinapathies. Malignant cell cytoreduction is thought to occur by S-phase specific depletion of the key epigenetic regulator, DNA methyltransferase 1 (DNMT1) that, in the case of cancers, thereby releases terminal-differentiation programs. DNMT1-targeting can also elevate expression of immune function genes (HLA-DR, MICA, MICB) to stimulate graft versus leukemia effects. In vivo, there is a large inter-individual variability in DEC and 5-AZA activity because of pharmacogenetic factors, and an assay to quantify the molecular pharmacodynamic effect of DNMT1-depletion is a logical step toward individualized or personalized therapy. We developed and analytically validated a flow cytometric assay for DNMT1 epitope levels in blood and bone marrow cell subpopulations defined by immunophenotype and cell cycle state. Wild type (WT) and DNMT1 knock out (DKO) HC116 cells were used to select and optimize a highly specific DNMT1 monoclonal antibody. Methodologic validation of the assay consisted of cytometry and matching immunoblots of HC116-WT and -DKO cells and peripheral blood mononuclear cells; flow cytometry of H116-WT treated with DEC, and patient samples before and after treatment with 5-AZA. Analysis of patient samples demonstrated assay reproducibility, variation in patient DNMT1 levels prior to treatment, and DNMT1 depletion posttherapy. A flow-cytometry assay has been developed that in the research setting of clinical trials can inform studies of DEC or 5-AZA treatment to achieve targeted molecular pharmacodynamic effects and better understand treatment-resistance/failure
Multispecies Comparative Prostate Anatomy by Imaging: Implications for Experimental Models of Prostatic Disease
Get PDFBackground: There is an increasing interest in using preclinical models for development and assessment of medical devices and imaging techniques for prostatic disease care. Still, a comprehensive assessment of the prostate\u27s radiological anatomy in primary preclinical models such as dogs, rabbits, and mice utilizing human anatomy as a reference point remains necessary with no optimal model for each purpose being clearly defined in the literature. Therefore, this study compares the anatomical characteristics of different animal models to the human prostatic gland from the imaging perspective. Methods: We imaged five Beagle laboratory dogs, five New Zealand White rabbits, and five mice, all sexually mature males, under Institutional Animal Care and Use Committee (IACUC) approval. Ultrasonography (US) was performed using the Vevo® F2 for mice (57 MHz probe). Rabbits and dogs were imaged using the Siemens® Acuson S3000 (17 MHz probe) and endocavitary (8 MHz) probes, respectively. Magnetic resonance imaging (MRI) was also conducted with a 7T scanner in mice and 3T scanner in rabbits and dogs. Results: Canine transrectal US emerged as the optimal method for US imaging, depicting a morphologically similar gland to humans but lacking echoic zonal differentiation. MRI findings in canines indicated a homogeneously structured gland similar to the human peripheral zone on T2-weighted images (T2W) and apparent diffusion coefficient (ADC). In rabbits, US imaging faced challenges due to the pubic symphysis, whereas MRI effectively visualized all structures with the prostate presenting a similar aspect to the human peripheral gland on T2W and ADC maps. Murine prostate assessment revealed poor visualization of the prostate glands in ultrasound due to its small size, while 7T MRI delineated the distinct prostates and its lobes, with the lateral and dorsal prostate resembling the peripheral zone and the anterior prostate the central zone of the human gland. Conclusion: Dogs stand out as superior models for advanced preclinical studies in prostatic disease research. However, mice present as a good model for early stage studies and rabbits are a cost-effective alternative and serve as valuable tools in specific research domains when canine research is not feasible
Nurse Practitioners in Critical Care Transport
Get PDFThe inclusion of nurse practitioners (NPs) in critical care transport teams has the potential to enhance patient care and improve team operations. NPs can manage complex clinical situations during transport and excel in various roles such as leadership, education, mentoring, research, quality improvement, and clinical expertise. As we navigate the evolving landscape of critical care transport, it is crucial to explore the potential benefits offered by NPs. Their distinct skills and experiences effectively position them to improve patient outcomes, enhance team performance, and contribute to health care\u27s financial sustainability. This article discusses the role of NPs in critical care transport, providing insight into their current uses, and recommendations for optimal use
Seeking Sufficient and Appropriate Care During the First Year After Spinal Cord Injury: A Qualitative Study
Get PDFStudy design: Longitudinal qualitative study, based on a constructivist grounded theory and transformative approach. Objectives: This study investigated experiences of individuals with spinal cord injury (SCI) while navigating rehabilitation, resources for recovery, and community reintegration during the first year after injury. Setting: An acute inpatient rehabilitation facility in the Midwest United States. Methods: In-depth, semi-structured interviews were conducted with 20 individuals with newly-acquired SCI. Interviews were conducted approximately every other month for one year, beginning at acute inpatient rehabilitation. Data were analyzed and interpreted using a constructivist grounded theory approach and transformative paradigm, which examines power and social structures within and across institutions and gives voice to people at risk for marginalization. Results: Participants experienced variable post-injury trajectories, with an average of four transitions within and across healthcare institutions in the first three months. Half of the cohort was discharged to a skilled nursing facility (SNF). Emergent themes included discharge (un)readiness; length of stay uncertainty and insurance impacts; challenges choosing a SNF including time-sensitive decisions; and early cessation of therapy in the SNF. Participants experienced resource navigation challenges such as communication/information access barriers and contending with many concerns at once. Conclusions: The experiences of this cohort reveal significant challenges to attaining sufficient and appropriate rehabilitation. Acute inpatient rehabilitation is a critical aspect of recovery, but does not ensure sufficient intervention for maximization of functional skills and community reintegration. Innovative rehabilitation models need to be developed for positive impacts on successful transition to independent living in the community
Spinal Movement Disorders in NMOSD, MOGAD, and Idiopathic Transverse Myelitis: A Prospective Observational Study
Get PDFBackground: Retrospective studies suggest that spinal movement disorders, especially tonic spasms, are prevalent in NMOSD. However, there have been no prospective studies evaluating spinal movement disorders in NMOSD, MOGAD, and idiopathic transverse myelitis (ITM). Methods: Patients referred to a tertiary neuroimmunology clinic for spinal cord demyelination (excluding MS) were evaluated. All patients answered a movement disorders survey and underwent a movement disorder-focused exam. Movement disorders were compared among patients with NMOSD with and without AQP4-IgG, MOGAD, and ITM. Patients with and without involuntary movements were also compared to identify predictors of spinal movement disorders. Results: Sixty-three patients were evaluated from 2017 to 2021 (71% females, median age 49 years, range 18–72 years, median disease duration 12 months, range 1–408). Of the total, 49% had ITM, 21% had NMOSD without AQP4-IgG, 19% had NMOSD with AQP4-IgG, and 11% had MOGAD. Movement disorders were present in 73% of the total patients and were most frequent in NMOSD with AQP4-IgG (92%) and least frequent in MOGAD (57%). The most frequent spinal movement disorders were tonic spasms (57%), focal dystonia (25%), spinal tremor (16%), spontaneous clonus (9.5%), secondary restless limb syndrome (9.5%), and spinal myoclonus (8%). Multivariate analysis showed that longitudinally extensive myelitis and AQP4-IgG are independent risk factors for the development of spinal movement disorders, while MOG-IgG and African American race were associated with a lower risk of developing these movement disorders. Conclusions: Spinal movement disorders are highly prevalent in non-MS demyelinating disorders of the spinal cord. Prevalence rates exceed those reported in MS and retrospective NMOSD studies
The Utility of Sentinel Lymph Node Biopsy in Elderly Patients with Melanoma
Get PDFBackground: Sentinel lymph node biopsy (SLNB) is performed less often for older patients with melanoma. We investigated the association of SLNB and melanoma-specific survival (MSS) in the elderly. Methods: We retrospectively reviewed the Surveillance, Epidemiology, and End Results (SEER: 2010–2019) for patients ≥ 70 years with cT2-4N0M0 melanoma. We used multivariable Cox proportional hazard models to evaluate the impact of SLNB performance and SLN status on MSS at increasing age cutoffs. In addition, we evaluated the association of different factors with SLNB performance using multivariable logistic regression. Results: We identified 11,548 patients. Sentinel lymph node biopsy occurred in 6754 (58.5%) patients, 1050 (15.5%) of whom had a positive SLN. On adjusted SEER analysis, a negative SLN was independently associated with improved MSS (overall hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.63–0.67) for patients up to 87 years old. Positive SLNB was independently associated with inferior MSS (HR 1.71, 95% CI 1.93–1.98). Increasing age groups were significantly associated with decreased SLNB performance. Conclusions: Sentinel lymph node biopsy is associated with cancer-specific survival and adds prognostic information for elderly patients with melanoma. Sentinel lymph node biopsy performance should not be eliminated in elderly patients based on age alone, unless justified by poor performance status, patient preference, or other surgical contraindications. Decreased SLNB performance with increasing age in our cohort may indicate a missed therapeutic opportunity in the care of elderly patients with melanoma
Viral Meningitis and Encephalitis Update
Get PDFPurpose of Review: This review describes advances in the diagnosis, treatment, and prevention of non-bacterial meningitis and encephalitis, with a focus on emerging viral causes of central nervous system (CNS) infection. Recent Findings: The Infectious Diseases Society of America recently published new guidelines for the management of encephalitis. Multiple articles have been published detailing emerging etiologies in human CNS infections, including analyses of neurological complications in the ongoing COVID-19 pandemic. Finally, several novel viral detection methods have been described, which may improve the detection of the specific etiologies of CNS infections (Hongyan et al. Front Neurol 14, [1]). Summary: Meningitis and encephalitis remain important causes of morbidity and mortality. They are as a whole uncommon, yet timely diagnosis, treatment, and disposition are still critical to improve patient outcomes. In clinical practice the exact cause of encephalitis is frequently unidentified, making supportive care often the only available treatment. Emergency physicians, neurologists, infectious disease doctors, and intensive care unit specialists will benefit from reviewing this discussion on emerging pathogens, as well as from reviewing advances in virology, immunology, and the imaging of inflammatory CNS conditions
Leczenie uzależnień materiały na zamówienie [Addiction Treatment: Requested Materials]
No full textKsiążka będąca poradnikiem i przewodnikiem po świecie uzależnień jest zbiorem wcześniej opublikowanych artykułów autora, który ma bardzo bogate doświadczenie teoretyczne i praktyczne w tym zakresie. Autor pokazuje swoje spojrzenie na uzależnienia chemiczne i behawioralne, na rolę stresu i traumy w leczeniu uzależnień. Niejako przy okazji dzieli się szeroką i ugruntowaną wiedzą o najnowszych metodach leczenia w USA i wyjaśnia wiele kwestii związanych poruszanymi zagadnieniami, jednocześnie wskazując na wiele wątpliwości i pytań, na które trudno udzielić jednoznacznej odpowiedzi. Tym samym dowodzi, że problematyka uzależnień i ich leczenia jest wielowymiarowa i skomplikowana, co utrudnia stosowanie metod i praktyk.
Głównym walorem tej książki jest prezentacja bogatych doświadczeń autora w zakresie leczenia uzależnień specyficznych grup i jednostek niepotrafiących poradzić sobie z emocjami, trudnymi przeżyciami, smutną historią życia. Wieloaspektowe spojrzenie autora na poruszane zagadnienia czyni tę książkę ważnym podręcznikiem dla szerokiego grona osób zajmujących się pracą socjalną, terapia, wspieraniem osób uzależnionych i zagubionych we współczesnym świecie.
dr hab. Anna Michalska, UAM
This book, a guide to the world of addiction, is a collection of previously published articles by the author, a professional and educator with extensive practical and theoretical experience in this field. The author presents his perspective on chemical and behavioral addictions and the role of stress and trauma in addiction treatment. He also shares knowledge of the latest treatment methods in the United States and clarifies many related issues, highlighting uncertainties and questions that are not easy to answer definitively. The issue of addiction and its treatment is multidimensional and complex, making it difficult to apply specific methods and practices.
The main value of this book is the presentation of the author\u27s work in treating addictions in specific groups and individuals who struggle to cope with emotions, difficult experiences, and traumatic life histories. The author\u27s broad perspective makes this book an important tool for a wide range of practitioners involved in social work, therapy, and the support of addicts and those struggling in the modern world.
Dr. hab. Anna Michalska, Adam Mickiewicz Universit
Dose-Dependent Effects of Gamma Radiation Sterilization on the Collagen Matrix of Human Cortical Bone Allograft and its Influence on Fatigue Crack Propagation Resistance
Get PDFFatigue crack propagation resistance and high-cycle S–N fatigue life of cortical bone allograft tissue are both negatively impacted in a radiation dose-dependent manner from 0 to 25 kGy. The standard radiation sterilization dose of 25–35 kGy has been shown to induce cleavage of collagen molecules into smaller peptides and accumulation of stable crosslinks within the collagen matrix, suggesting that these mechanisms may influence radiation-induced losses in cyclic fracture resistance. The objective of this study was to determine the radiation dose-dependency of collagen chain fragmentation and crosslink accumulation within the dose range of 0–25 kGy. Previously, cortical bone compact tension specimens from two donor femoral pairs were divided into four treatment groups (0 kGy, 10 kGy, 17.5 kGy, and 25 kGy) and underwent cyclic loading fatigue crack propagation testing. Following fatigue testing, collagen was isolated from one compact tension specimen in each treatment group from both donors. Radiation-induced collagen chain fragmentation was assessed using SDS-PAGE (n = 5), and accumulation of pentosidine, pyridinoline, and non-specific advanced glycation end products were assessed using a fluorometric assay (n = 4). Collagen chain fragmentation increased progressively in a dose-dependent manner (p \u3c 0.001). Crosslink accumulation at all radiation dose levels increased relative to the 0 kGy control but did not demonstrate dose-dependency (p \u3c 0.001). Taken together with our previous findings on fatigue crack propagation behavior, these data suggest that while collagen crosslink accumulation may contribute to reduced notched fatigue behavior with irradiation, dose-dependent losses in fatigue crack propagation resistance are mainly influenced by radiation-induced chain fragmentation
A Model of Time-Dependent Macromolecular and Elemental Composition of Phytoplankton
No full textPhytoplankton Chl:C:N:P ratios are important from both an ecological and a biogeochemical perspective. We show that these elemental ratios can be represented by a phytoplankton physiological model of low complexity that includes major cellular macromolecular pools. In particular, our model resolves time-dependent intracellular pools of chlorophyll, proteins, nucleic acids, carbohydrates/lipids, and N and P storage. Batch culture data for two diatom and two prasinophyte species are used to constrain parameters that represent specific allocation traits and strategies. A key novelty is the simultaneous estimation of physiological parameters for two phytoplankton groups of such different sizes. The number of free parameters is reduced by assuming (i) allometric scaling for maximum uptake rates, (ii) shared half-saturation constants for synthesis of functional macromolecules, (iii) shared exudation rates of functional macromolecules across the species. The rationale behind this assumption is that across the different species, the same or similar processes, enzymes, and metabolites play a role in key physiological processes. For the turnover numbers of macromolecular synthesis and storage exudation rates, differences between diatoms and prasinophytes need to be taken into account to obtain a good fit. Our model fits suggest that the parameters related to storage dynamics dominate the differences in the C:N:P ratios between the different phytoplankton groups. Since descriptions of storage dynamics are still incomplete and imprecise, predictions of C:N:P ratios by phytoplankton models likely have a large uncertainty
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