Evaluating Complete Response Rates and Predictors in Total Neoadjuvant Therapy for Rectal Cancer.

INTRODUCTION: In the management of locally advanced rectal cancer (LARC), there is a paradigm shift from conventional neoadjuvant treatment to total neoadjuvant therapy (TNT). Despite its growing acceptance, there are limited studies have examined its effects on disease presentation. It is also important to determine the factors that play a role in complete response (CR). Our previous data with 119 patients revealed that the CR rate was 37%, and low rectal tumors and the absence of extramural vascular invasion (EMVI) were predictors of CR. Unfortunately, there continues to be a lack of data, and reliable markers are still needed to consistently identify the best respondents. Therefore, we aimed to determine factors associated with CR. We hypothesized that due to the growing patient population, both predictive factors and CR ratio might evolve over time. METHODS: A retrospective analysis of patients who completed TNT for LARC at our tertiary care center between 2015 and 2022 was performed. Our primary outcome was to determine predictors of CR. As a secondary outcome, we evaluated the 2-year disease-free and overall survival rates. CR consists of patients who sustained clinical CR (cCR) for at least 12 months under WW or had pathological CR (pCR) after surgery. RESULTS: Out of 339 patients with LARC, 208 (61.3%) successfully completed TNT. Among them, 57 (27.4%) patients achieved cCR, and 80% sustained without tumor regrowth after a year. The remaining 151 (72.6%) patients underwent surgery, and 42 had pCR. The final CR rate was 42.3%. The median age of the patients was 56 (49-66), and 63.5% of the participants were male (n=132), while 36.5% were female (n=76). The median tumor size was 4.95cm (3.6-6.43), with most tumors in the low rectum (119, 57.2%). The MRF involvement rate was 25% (n=52), and EMVI was observed in 20.7% of patients (n=43). based on MRI findings. Low rectal tumors, the absence of MRF involvement, and the absence of EMVI were predicted CR. With a median follow-up of 24.7 months, 2-year disease-free survival and overall survival were significantly higher among patients with CR (91.3% vs 71%, p<0.01 and 98.8% vs 90.2% p=0.03, respectively). CONCLUSION: In our updated dataset, we observed an increasing CR rate compared to our previous study. In addition to previously identified predictors, low tumor location and the absence of EMVI, we also found the absence of MRF involvement as a predictor of CR. These findings offer valuable insights for clinical practice, helping clinicians set clear expectations when counseling patients.

Constant surface area-to-volume ratio during cell growth as a design principle in mammalian cells.

All cells are subject to geometric constraints, such as surface area-to-volume (SA/V) ratio, that impact cell functions and force biological adaptations. Like the SA/V ratio of a sphere, it is generally assumed that the SA/V ratio of cells decreases as cell size increases. Here, we investigate this in near-spherical mammalian cells using single-cell measurements of cell mass and surface proteins, as well as imaging of plasma membrane morphology. We find that the SA/V ratio remains surprisingly constant as cells grow larger. This observation is largely independent of the cell cycle and the amount of cell growth. Consequently, cell growth results in increased plasma membrane folding, which simplifies cellular design by ensuring sufficient membrane area for cell division, nutrient uptake and deformation at all cell sizes.

Drug-Induced dermatomyositis following COVID-19 vaccination.

Dermatomyositis (DM) is a multi-organ idiopathic inflammatory myopathy that presents with proximal symmetric muscle weakness accompanied by characteristic cutaneous findings. Most individuals present with skin manifestations prior to muscle involvement and its course can involve the blood vessels, joints, esophagus, and lungs and can be paraneoplastic, making a malignancy assessment imperative. Although its etiology is unknown, type I interferon appears to be a component in evoking the characteristic inflammatory response and patients with DM often have an increase in type I inducible genes. Suspected triggers for DM are environmental factors, drugs, viral infections, and vaccines. The association of DM with vaccination poses a new conundrum within the medical community as people continue to get vaccinated and boosted with SARS-CoV2 vaccines, though it is worth noting that the most common challenges arose as type I hypersensitivity reactions and new onset autoimmune disorders are rare. Presented here is a 53-year-old man who was diagnosed with DM after receiving the second dose of the Pfizer vaccine. His case highlights the importance of the potential onset of autoimmune diseases following the COVID-19 vaccine, a phenomenon that clinicians should be aware of as the discourse concerning the pandemic continues.

The Year in Aortic Surgery: Selected Highlights From 2023.

This article reviews the recent and relevant literature to the field of aortic surgery. Specific areas highlighted include outcomes of Stanford type A dissection, management of acute aortic syndromes, management of aortic aneurysms, and traumatic aortic injury. Although the focus was on articles from 2023, literature from prior years also was included, given that this article is the first of a series. Notably, the pertinent sections from the 2022 American College of Cardiology/American Heart Association Guidelines for the Diagnosis and Management Aortic Disease are discussed.

Measuring the Direct Medical Costs of Hospital-Onset Infections Using an Analogy Costing Framework.

BACKGROUND: The majority of recent estimates on the direct medical cost attributable to hospital-onset infections (HOIs) has focused on device- or procedure-associated HOIs. The attributable costs of HOIs that are not associated with device use or procedures have not been extensively studied. OBJECTIVE: We developed simulation models of attributable cost for 16 HOIs and estimated the total direct medical cost, including nondevice-related HOIs in the USA for 2011 and 2015. DATA AND METHODS: We used total discharge costs associated with HOI-related hospitalization from the National Inpatient Sample and applied an analogy costing methodology to develop simulation models of the costs attributable to HOIs. The mean attributable cost estimate from the simulation analysis was then multiplied by previously published estimates of the number of HOIs for 2011 and 2015 to generate national estimates of direct medical costs. RESULTS: After adjusting all estimates to 2017 US dollars, attributable cost estimates for select nondevice-related infections attributable cost estimates ranged from $7661 for ear, eye, nose, throat, and mouth (EENTM) infections to $27,709 for cardiovascular system infections in 2011; and from $8394 for EENTM to $26,445 for central nervous system infections in 2016 (based on 2015 incidence data). The national direct medical costs for all HOIs were $14.6 billion in 2011 and $12.1 billion in 2016. Nondevice- and nonprocedure-associated HOIs comprise approximately 26-28% of total HOI costs. CONCLUSION: Results suggest that nondevice- and nonprocedure-related HOIs result in considerable costs to the healthcare system.

Crohn's disease-related versus sporadic colorectal cancer: A stage-matched case-control study based on four decades of experience.

BACKGROUND AND OBJECTIVES: This study compares surgical and oncological outcomes in patients with Crohn's disease (CD)-related colorectal cancer (CRC) to those with sporadic CRC. METHODS: Patients treated between 1983 and 2013 were matched by stage, age, gender, American Society of Anesthesiologists (ASA), cancer site, and adjuvant chemotherapy. RESULTS: For stages I and II, 107 patients were matched (58.9% male, mean age 59 years, 59.8% with ASA score 3). Tumor sites included the right (17.7%), transverse (4.7%), left colon (15.9%), and rectum (61.7%). CD patients exhibited longer operative times, higher pT stages, and 2.60 times the odds of postoperative complications (p = 0.03). Overall and disease-free survival were similar. For stage III, 54 patients were matched (57.4% male, mean age 54 years, 46.3% with ASA score 3). The cancer site distribution was right (29.7%), transverse (3.7%), left colon (18.5%), and rectum (48.1%). CD patients had longer operative times, increased blood loss, more involved lymph nodes, higher pT- and pN-stages. The rates of postoperative complications were not different (p = 0.19). CD-related CRC patients had similar overall (p = 0.06), and local recurrence-free survival (p = 0.07). CONCLUSIONS: Despite facing worse perioperative and pathological characteristics, survival differences in stages I-III CD-related CRC compared with sporadic CRC patients were not significantly different.

Endothelial-adipocyte Cx43 mediated gap junctions can regulate adiposity.

Obesity is a multifactorial metabolic disorder associated with endothelial dysfunction and increased risk of cardiovascular disease. Adipose capillary adipose endothelial cells (CaECs), plays a crucial role in lipid transport and storage. Here, we investigated the mechanisms underlying CaEC-adipocyte interaction and its impact on metabolic function. Single-cell RNA sequencing revealed an enrichment of fatty acid handling machinery in CaECs from high fat diet (HFD) mice, suggesting their specialized role in lipid metabolism. Transmission Electron microscopy (TEM) confirmed direct heterocellular contact between CaECs and adipocytes. To model this, we created an in vitro co-culture transwell system to model the heterocellular contact observed with TEM. Contact between ECs and adipocytes in vitro led to upregulation of fatty acid binding protein 4 in response to lipid stimulation, hinting intercellular signaling may be important between ECs and adipocytes. We mined our and others scRNAseq data sets to examine which connexins may be present in adipose capillaries and adipocytes and consistently identified Connexin 43 (Cx43) in mouse and humans. Genetic deletion of endothelial Cx43 resulted in increased epididymal fat pad (eWAT) adiposity and dyslipidemia in HFD mice. Consistent with this observation, phosphorylation of Cx43 at serine 368, which closes gap junctions, was increased in HFD mice and lipid treated ECs. Mice resistant to this post-translational modification, Cx43S368A, were placed on a HFD and were found to have reduced eWAT adiposity and improved lipid profiles. These findings suggest Cx43-mediated heterocellular communication as a possible regulatory mechanism of adipose tissue function.

MicroRNA Signatures Associated with Basal Cell Carcinoma Subtypes.

Basal cell carcinoma (BCC) is classified histologically into subtypes that determine treatment decisions. MicroRNAs (miRs) are short noncoding RNAs that may serve as diagnostic biomarkers. We investigated if particular miRs could distinguish BCC subtypes. We sequenced miRs from 55 archival BCC and 9 control skin specimens and then validated these miRs by qRT-PCR assay on a second BCC cohort (18 superficial, 16 nodular, 15 infiltrative) and control skin (n = 12). Expression values for individual miRs were normalized to miR-16-5p, which was the least variant among the control skin and BCC samples. We found that (i) miR-383-5p and miR-145-5p are downregulated in all BCC subtypes compared with control skin, (ii) miR-181c-5p is downregulated in superficial compared with invasive (nodular/infiltrative) BCC, and (iii) miR-22-5p and miR-708-5p are upregulated in infiltrative compared with superficial/nodular BCC and miR-30c-5p is downregulated in infiltrative compared with nodular BCC. Receiver operating characteristic analysis demonstrated excellent capacity of these miRs to discriminate between BCC and control skin (area under the curve, 0.94-0.98), whereas the capacity to discriminate between superficial and invasive subtypes was less robust (area under the curve, 0.7-0.8). Future prospective studies may determine the utility of these miRs as diagnostic biomarkers to guide biopsy and treatment of BCC.

Transcriptome and metabolome analyses reveal regulatory networks associated with nutrition synthesis in sorghum seeds.

Cereal seeds are vital for food, feed, and agricultural sustainability because they store and provide essential nutrients to human and animal food and feed systems. Unraveling molecular processes in seed development is crucial for enhancing cereal grain yield and quality. We analyze spatiotemporal transcriptome and metabolome profiles during sorghum seed development in the inbred line 'BTx623'. Morphological and molecular analyses identify the key stages of seed maturation, specifying starch biosynthesis onset at 5 days post-anthesis (dpa) and protein at 10 dpa. Transcriptome profiling from 1 to 25 dpa reveal dynamic gene expression pathways, shifting from cellular growth and embryo development (1-5 dpa) to cell division, fatty acid biosynthesis (5-25 dpa), and seed storage compounds synthesis in the endosperm (5-25 dpa). Network analysis identifies 361 and 207 hub genes linked to starch and protein synthesis in the endosperm, respectively, which will help breeders enhance sorghum grain quality. The availability of this data in the sorghum reference genome line establishes a baseline for future studies as new pangenomes emerge, which will consider copy number and presence-absence variation in functional food traits.

Cell size, density, and nutrient dependency of unicellular algal gravitational sinking velocities.

Eukaryotic phytoplankton, also known as algae, form the basis of marine food webs and drive marine carbon sequestration. Algae must regulate their motility and gravitational sinking to balance access to light at the surface and nutrients in deeper layers. However, the regulation of gravitational sinking remains largely unknown, especially in motile species. Here, we quantify gravitational sinking velocities according to Stokes' law in diverse clades of unicellular marine microalgae to reveal the cell size, density, and nutrient dependency of sinking velocities. We identify a motile algal species, Tetraselmis sp., that sinks faster when starved due to a photosynthesis-driven accumulation of carbohydrates and a loss of intracellular water, both of which increase cell density. Moreover, the regulation of cell sinking velocities is connected to proliferation and can respond to multiple nutrients. Overall, our work elucidates how cell size and density respond to environmental conditions to drive the vertical migration of motile algae.

Cutaneous hypersensitivity to chlorhexidine following facial fat grafting: a delayed intradermal response.

Chlorhexidine (CHD) is commonly included in surgical antiseptics and can be associated with adverse reactions ranging from contact dermatitis to anaphylaxis. A 32-year-old female presented to the OR for facial fat grafting. Surgical sites were prepped with CHD gluconate or topical iodine. Donor and recipient sites were infiltrated with local anesthetic injection prior to fat harvest and facial injection. Eleven days later, she presented with new painful, pruritic rash over donor sites where CHD had been applied prior to local anesthetic infiltration. Treatment with topical clobetasol and prednisone taper resulted in complete symptom resolution. This patient's response most likely represented a delayed type IV, T-cell mediated hypersensitivity. CHD is a known trigger of allergic reactions. Infiltration of local anesthetic may introduce skin prep into the subcutaneous tissue akin to intradermal testing. For those with delayed cutaneous reactions, steroids may provide symptomatic relief.

Trends and Distribution of IPAAs in the United States: Becoming Harder to Find in Colon and Rectal Surgery Residency Training?

BACKGROUND: There has been concern among colon and rectal surgery residency programs in the United States that IPAA procedures have been decreasing, but evidence is limited. OBJECTIVE: The study aimed to evaluate the number of IPAAs performed by colon and rectal surgery residents in the United States and analyze the distribution of these cases on a national level. DESIGN: Retrospective. SETTINGS: The Accreditation Council for Graduate Medical Education Case Log National Data Reports were used to evaluate the number of IPAAs performed by residents from 2005 to 2021. The Nationwide Inpatient Sample database was used to identify all patients undergoing these procedures from 2005 to 2019. PATIENTS: All IPAA procedures regardless of indication. MAIN OUTCOME MEASURES: The primary outcome was the number of IPAAs performed by residents yearly. The secondary outcome was the national distribution of these procedures. RESULTS: Among colon and rectal surgery residents, case log data revealed an increase in mean and total number of IPAAs from 2005 to 2013, followed by a decline in both metrics after 2013. Despite the decrease, the mean number of cases per resident remained fewer than 6 between 2011 and 2021. A weighted national estimate of 48,532 IPAA patients were identified in the Nationwide Inpatient Sample database. A significant decrease was noted in the number of IPAAs after 2015 that persisted through 2019. There was a significant decrease in rural and urban nonteaching hospitals (from 2.1% to 1.6% and 25.6% to 4.3%, respectively; p < 0.001) and an increase in urbanteaching hospitals (from 72.4% to 94.1%; p < 0.001). LIMITATIONS: Nonrandomized retrospective study design. CONCLUSIONS: Despite the recent increase in the percentage of IPAAs performed at urban academic centers, there has been a decrease in cases performed by colon and rectal surgery residents. This can have significant implications for residents who graduate without adequate experience in performing this complex procedure independently, as well as training programs that may face challenges with maintaining accreditation. See Video Abstract. TENDENCIAS Y DISTRIBUCIN DE LA ANASTOMOSIS ANAL CON BOLSA ILEAL EN LOS ESTADOS UNIDOS SE EST VOLVIENDO MS DIFCIL DE ENCONTRAR EN LA CAPACITACIN DE RESIDENCIA EN CIRUGA DE COLON Y RECTO: ANTECEDENTES:Ha habido preocupación entre los programas de capacitación de residencia en cirugía de colon y recto en los Estados Unidos porque los procedimientos de anastomosis anal con bolsa ileal han estado disminuyendo; sin embargo, la evidencia es limitada.OBJETIVO:Evaluar el número de anastomosis anales con bolsa ileal realizadas por residentes de cirugía de colon y recto en los Estados Unidos y examinar la distribución de estos casos a nivel nacional.DISEÑO:Retrospectivo.AJUSTES:Se utilizaron los informes de datos nacionales del registro de casos de educación médica de posgrado del Consejo de Acreditación para examinar el número de anastomosis anales con bolsa ileal realizadas por residentes de 2005 a 2021. Se utilizó la base de datos de muestra nacional de pacientes hospitalizados para identificar a todos los pacientes sometidos a estos procedimientos de 2005 a 2019.PACIENTES:Todos los procedimientos de anastomosis anal con bolsa ileal independientemente de la indicación.MEDIDA DE RESULTADO PRINCIPAL:El resultado primario es el número de anastomosis anales con bolsa ileal realizadas por los residentes anualmente. El resultado secundario es la distribución nacional de estos procedimientos.RESULTADOS:Entre los residentes de cirugía de colon y recto, los datos de los registros de casos revelaron un aumento en el número medio y total de anastomosis anal con bolsa ileal de 2005 a 2013, seguido de una disminución en ambas métricas después de 2013. A pesar de la disminución, el número medio de casos por El residente permaneció >6 entre 2011 y 2021. Se identificó una estimación nacional ponderada de 48 532 pacientes con anastomosis anal con bolsa ileal en la base de datos de la Muestra Nacional de Pacientes Hospitalizados. Se observó una disminución significativa en el número de anastomosis anales con bolsa ileal después de 2015 que persistió hasta 2019. Hubo una disminución significativa en los hospitales no docentes rurales y urbanos (del 2,1% al 1,6% y del 25,6% al 4,3% respectivamente, p < 0,001) y un aumento en los hospitales universitarios urbanos (del 72,4% al 94,1%, p < 0,001).LIMITACIONES:Estudio retrospectivo no aleatorizado.CONCLUSIÓN:A pesar del reciente aumento en el porcentaje de anastomosis anal con bolsa ileal realizadas en centros académicos urbanos, ha habido una disminución en los casos realizados por residentes de cirugía de colon y recto. Esto puede tener implicaciones significativas para los residentes que se gradúan sin la experiencia adecuada en la realización de este complejo procedimiento de forma independiente, así como para los programas de capacitación que pueden enfrentar desafíos para mantener la acreditación. (Traduccion-AI-generated).

Impaired contour object perception in psychosis.

Contour integration, the process of joining spatially separated elements into a single unified line, has consistently been found to be impaired in schizophrenia. Recent work suggests that this deficit could be associated with psychotic symptomatology, rather than a specific diagnosis such as schizophrenia. Examining a transdiagnostic sample of participants with psychotic psychopathology, we obtained quantitative indices of contour perception in a psychophysical behavioral task. We found impaired contour discrimination performance among people with psychotic psychopathology (PwPP, n = 62) compared to healthy controls (n = 34) and biological relatives of PwPP (n = 44). Participants with schizophrenia (n = 31) showed impaired task performance compared to participants with bipolar disorder (n = 18). We also measured responses during an analogous task using ultra-high field (7T) functional MRI and found higher responses in the lateral occipital cortex of PwPP compared to controls. Using task-based functional connectivity analyses, we observed abnormal connectivity between visual brain areas during contour perception among PwPP. These connectivity differences only emerged when participants had to distinguish the contour object from background distractors, suggesting that a failure to suppress noise elements relative to contour elements may underlie impaired contour processing in PwPP. Our results are consistent with impaired contour integration in psychotic psychopathology, and especially schizophrenia, that is related to cognitive dysfunction, and may be linked to impaired functional connectivity across visual regions.

EFFICACY OF INTRAVENOUS IMMUNOGLOBULIN ALONE ON CORONARY ARTERY LESION REDUCTION IN KAWASAKI DISEASE.

Background: Though Aspirin and intravenous immunoglobulin (IVIG) remain the standard treatments for Kawasaki Disease (KD) to minimize coronary artery damage, the duration and dosage of aspirin are inconsistent across hospitals. However, the lack of multi-center randomized trials prevents definitive answers to the impact of high-dose aspirin. Methods: This clinical trial was structured as a prospective, evaluator-blinded, multi-center randomized controlled trial with two parallel arms, aiming to assess the effectiveness of IVIG as a standalone primary therapy of KD in comparison to the combination of IVIG with high-dose aspirin therapy. KD patients were enrolled between September, 2016 and August, 2019. A final cohort of 134 patients were randomly assigned to the standard and test groups with 69 and 65 patients, respectively. The Standard group received IVIG (2 g/kg) along with aspirin (80-100 mg/kg/day) until fever subsided for 48 hours. The test group received IVIG (2 g/kg) alone. Following the initial treatment, both groups received a daily aspirin dose (3-5 mg/kg) for six weeks. The primary outcome measure was the occurrence of coronary artery lesions (CAL) at the 6-8 weeks mark. The secondary outcome is IVIG resistance. Results: The overall rate of CAL in test group decreased from 10.8% at diagnosis to 1.5% and 3.1% at 6 weeks and 6 months, respectively. The CAL rate of standard group declined from 13.0% to 2.9% and 1.4%, with no statistically significant difference (P>0.1) in the frequency of CAL between the two groups. Furthermore, no statistically significant differences were found for treatment (P>0.1) and prevention (P>0.1) effect between the two groups. Conclusions: This marks the first prospective multi-center randomized controlled trial comparing the standard treatment of KD using IVIG plus high-dose aspirin against IVIG alone. Our analysis indicates that addition of high-dose aspirin during initial IVIG treatment is neither statistically significant nor clinically meaningful for CAL reduction. Registration: URL: http://www.clinicaltrials.gov ; identifier: NCT02951234. What is New?: This study represents the first multi-center randomized controlled trial investigating the efficacy of high-dose aspirin or intravenous immunoglobulin (IVIG) during the acute stage of KD. This study assessed the impact of discontinuing high-dose aspirin (80-100 mg/kg/day) on the occurrence of CAL during the acute phase treatment of Kawasaki Disease.No significant differences were observed between high-dose aspirin plus IVIG treatment and IVIG alone treatment in terms of the frequency of abnormal coronary artery abnormalities. Additionally, our analysis revealed no statistically significant differences in either the treatment effect (the number of cases successfully treated) or prevention effect (the prevention of new cases) between these two treatments. What Are the Clinical Implications?: Comparison analysis indicated the non-inferiority between two groups with or without high-dose aspirin.Administering the standard 2 g/kg/day IVIG without high-dose aspirin (80-100 mg/kg/day) during the acute phase therapy for KD does not increase the risk of coronary artery lesions, which are a primary cause of morbidity and mortality in KD patients.Addition of high-dose aspirin during initial IVIG treatment is not statistically significant or clinically meaningful.

Preserving isohydricity: vertical environmental variability explains Amazon forest water use strategies.

Increases in hydrological extremes, including drought, are expected for Amazon forests. A fundamental challenge for predicting forest responses lies in identifying ecological strategies which underlie such responses. Characterization of species-specific hydraulic strategies for regulating water use, thought to be arrayed along an 'isohydric-anisohydric' spectrum, is a widely used approach. However, recent studies have questioned the usefulness of this classification scheme, because its metrics are strongly influenced by environments, hence can lead to divergent classifications even within the same species. Here, we propose an alternative approach positing that individual hydraulic regulation strategies emerge from the interaction of environments with traits. Specifically, we hypothesize that the vertical forest profile represents a key gradient in drought-related environments (atmospheric vapor pressure deficit, soil water availability) that drives divergent tree water use strategies for coordinated regulation of stomatal conductance (gs) and leaf water potentials (ΨL) with tree rooting depth, a proxy for water availability. Testing this hypothesis in a seasonal eastern Amazon forest in Brazil, we found that hydraulic strategies indeed depend on height-associated environments. Upper canopy trees, experiencing high VPD, but stable soil water access through deep rooting, exhibited isohydric strategies, defined by little seasonal change in the diurnal pattern of gs and steady seasonal minimum ΨL. By contrast, understory trees, exposed to less variable VPD but highly variable soil water availability, exhibited anisohydric strategies, with fluctuations in diurnal gs that increased in the dry season along with increasing variation in ΨL. Our finding that canopy height structures the coordination between drought-related environmental stressors and hydraulic traits provides a basis for preserving the applicability of the isohydric-to-anisohydric spectrum, which we show here may consistently emerge from environmental context. Our work highlights the importance of understanding how environmental heterogeneity structures forest responses to climate change, providing a mechanistic basis for improving models of tropical ecosystems.

Accelerated Chest Pain Treatment With Artificial Intelligence-Informed, Risk-Driven Triage.

This quality improvement study evaluates the use of artificial intelligence to accelerate triage of patients presenting to the emergency department with chest pain.

Selecting the Most Relevant Mouse Strains for Evaluating Radiation-Induced Multiple Tissue Injury after Leg-Shielded Partial-Body Gamma Irradiation.

Animal studies are needed that best simulate a large-scale, inhomogeneous body exposure after a radiological or nuclear incident and that provides a platform for future development of medical countermeasures. A partial-body irradiation (PBI) model using 137Cs gamma rays with hind limb (tibia) shielding was developed and assessed for the sequalae of radiation injuries to gastrointestinal tract, bone marrow (BM) and lung and among different genetic mouse strains (C57BL/6J, C57L/J, CBA/J and FVB/NJ). In this case, a marginal level of BM shielding (∼2%) provided adequate protection against lethality from infection and hemorrhage and enabled escalation of radiation doses with evaluation of both acute and delayed radiation syndromes. A steep radiation dose-dependent body weight loss was observed over the first 5 days attributed to enteritis with C57BL/6J mice appearing to be the most sensitive strain. Peripheral blood cell analysis revealed significant depression and recovery of leukocytes and platelets over the first month after PBI and were comparable among the four different mouse strains. Latent pulmonary injury was observed on micro-CT imaging at 4 months in C57L/J mice and confirmed histologically as severe pneumonitis that was lethal at 12 Gy. The lethality and radiological densitometry (HUs) dose responses were comparable to previous studies on C57L/J mice after total-body irradiation (TBI) and BM transplant rescue as well as after localized whole-thorax irradiation (WTI). Indeed, the lethal radiation doses and latency appeared similar for pneumonitis appearing in rhesus macaques after WTI or PBI as well as predicted for patients given systemic radiotherapy. In contrast, PBI treatment of C57BL/6 mice at a higher dose of 14 Gy had far longer survival times and developed extreme and debilitating pIeural effusions; an anomaly as similarly reported in previous thorax irradiation studies on this mouse strain. In summary, a radiation exposure model that delivers PBI to unanesthetized mice in a device that provides consistent shielding of the hind limb BM was developed for 137Cs gamma rays with physical characteristics and relevance to relatively high photon energies expected from the detonation of a nuclear device or accidental release of ionizing radiation. Standard strains such as C57BL/6J mice may be used reliably for early GI or hematological radiation syndromes while the C57L/J mouse strain stands out as the most appropriate for evaluating the delayed pulmonary effects of acute radiation exposure and recapitulating this disease in humans.

Reduced Expression of Oligodendrocyte Linage-Enriched Transcripts During the Endoplasmic Reticulum Stress/Integrated Stress Response.

Endoplasmic reticulum (ER) stress in oligodendrocyte (OL) linage cells contributes to several CNS pathologies including traumatic spinal cord injury (SCI) and multiple sclerosis. Therefore, primary rat OL precursor cell (OPC) transcriptomes were analyzed using RNASeq after treatments with two ER stress-inducing drugs, thapsigargin (TG) or tunicamycin (TM). Gene ontology term (GO) enrichment showed that both drugs upregulated mRNAs associated with the general stress response. The GOs related to ER stress were only enriched for TM-upregulated mRNAs, suggesting greater ER stress selectivity of TM. Both TG and TM downregulated cell cycle/cell proliferation-associated transcripts, indicating the anti-proliferative effects of ER stress. Interestingly, many OL lineage-enriched mRNAs were downregulated, including those for transcription factors that drive OL identity such as Olig2. Moreover, ER stress-associated decreases of OL-specific gene expression were found in mature OLs from mouse models of white matter pathologies including contusive SCI, toxin-induced demyelination, and Alzheimer's disease-like neurodegeneration. Taken together, the disrupted transcriptomic fingerprint of OL lineage cells may facilitate myelin degeneration and/or dysfunction when pathological ER stress persists in OL lineage cells.

The ER stress response compromises the transcriptomic identity of the OL lineage. Therefore, persistent, pathological ER stress may have a negative impact on structural and/or functional integrity of the white matter.

Modulation of Fe-Fe distance and spin in diiron complexes using tetradentate ligands with different flanking donors.

Here we report the synthesis and characterization of diiron complexes containing triaryl N4 and N2S2 ligands derived from o-phenylenediamine. The complexes display significant differences in Fe-Fe distances and magnetic properties that depend on the identity of the flanking NMe2 and SMe donor groups.