A proposal for analyzing the inflammatory and remodeling processes of mucosa in chronic rhinosinusitis with nasal polyposis through MRI.

OBJECTIVES: Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) is a disease characterized by chronic inflammation and tissue remodeling process. The remodeling process in nasal polyps has mainly been studied by histology analysis. However, it is limited to a polyp fragment and requires tissue removal. The present study aims to evaluate the ability of Magnetic Resonance Imaging (MRI) to depict and characterize the remodeling process in patients with CRSwNP. METHODS: 30 patients that met clinical diagnostic criteria for CRSwNP, without previous history of rhinosinusitis surgery were submitted to MRI scan (conventional, diffusion-weighted and DCE MRI) and compared with polyp tissue histological findings, IL-6 concentrations in the tissue and eosinophil count in the blood. The examinations were evaluated, independently, by two radiologists blinded to other radiological and histological data. The pathologist, blinded to MRI results, also compared the tissue sample from the most central and the most peripheral portion of the polypoid tissue adjacent to the floor of the nasal fossa. RESULTS: This study demonstrated a characteristic pattern of nasal polyps, whose peripheral portions of nasal polypoid tissue are edematous, whereas the central portions in the middle meatus and in the middle and upper ethmoid are predominantly fibrotic. ADC values found in the most anterior portion of the polyps may be a marker for radiological phenotyping the remodeling process. This non-invasive analysis presented a high degree of agreement in the fibrosis and edema rating by two radiologists and the histological analysis was concordant with the MRI findings. The polyps were characterized as eosinophilic, and no relationship was found between the severity of the eosinophilic inflammatory process or concentration of IL-6 and the remodeling process. CONCLUSION: MRI by using T2-weighted imaging sequence and ADCs values allows tissue characterization and is an effective tool for the differentiation of edematous and fibrotic components in CRSwNP.

Inflammatory Profile of Chronic Rhinosinusitis With Nasal Polyp Patients in Brazil: Multicenter Study.

OBJECTIVES: To determine the inflammatory profile of CRSwNP in Brazil and characterize the subgroups of CRSwNP patients in this population through cluster analysis. STUDY DESIGN: Multicenter cross-sectional study involving 15 centers representing different regions of Brazil. SUBJECTS AND METHODS: Clinical data of 166 patients and 80 controls, aged 18 to 70 years old, number of surgeries for CRS, history of asthma and aspirin sensitivity, and Lund-Mackay scores on CT scans. During nasal endoscopy, we obtained the Lund-Kennedy scores and collected 2 samples of nasal polyps: one for eosinophil and neutrophil tissue counts and one to quantify different cytokines. RESULTS: 79.6% of our patients had 10 or more eosinophils/HPF. CRSwNP groups exhibited significantly lower concentrations of TNF-alpha and significantly higher concentrations of IFN-gamma, CCL11/Eotaxin, CCL24/Eotaxin-2/MPIF-2, and CCL26/Eotaxin-3 versus the control group (Kruskal-Wallis test). Comparison between CRSwNP groups (≥10 vs <10 eosinophils/HPF) showed no difference in cytokine concentration (Mann-Whitney test). Hierarchical clustering and PCA according to cytokine concentrations revealed 2 main Clusters, with a significantly higher concentration of all cytokines in Cluster 1 (n = 35) than in Cluster 2 (n = 121), except IL-6 and IL-33 (Mann-Whitney test). According to ROC curve analysis the best cut-off to differentiate the 2 clusters was 43 eosinophils/HPF. The group with ≥43 presented a higher prevalence of men and a higher Lund-Mackay score (Mann-Whitney test). CONCLUSIONS: CRSwNP patients in Brazil present mixed inflammation, with 2 distinct groups (high and low inflammatory pattern) that can be distinguished by tissue eosinophilia of ≥43 eosinophils/HPF cut-off in nasal polyps.

Simulating federated learning for steatosis detection using ultrasound images.

We aimed to implement four data partitioning strategies evaluated with four federated learning (FL) algorithms and investigate the impact of data distribution on FL model performance in detecting steatosis using B-mode US images. A private dataset (153 patients; 1530 images) and a public dataset (55 patient; 550 images) were included in this retrospective study. The datasets contained patients with metabolic dysfunction-associated fatty liver disease (MAFLD) with biopsy-proven steatosis grades and control individuals without steatosis. We employed four data partitioning strategies to simulate FL scenarios and we assessed four FL algorithms. We investigated the impact of class imbalance and the mismatch between the global and local data distributions on the learning outcome. Classification performance was assessed with area under the receiver operating characteristic curve (AUC) on a separate test set. AUCs were 0.93 (95% CI 0.92, 0.94) for source-based partitioning scenario with FedAvg, 0.90 (95% CI 0.89, 0.91) for a centralized model, and 0.83 (95% CI 0.81, 0.85) for a model trained in a single-center scenario. When data was perfectly balanced on the global level and each site had an identical data distribution, the model yielded an AUC of 0.90 (95% CI 0.88, 0.92). When each site contained data exclusively from one single class, irrespective of the global data distribution, the AUC fell in the range of 0.34-0.70. FL applied to B-mode US images provide performance comparable to a centralized model and higher than single-center scenario. Global data imbalance and local data heterogeneity influenced the learning outcome.

Comparison of Radiologists and Deep Learning for US Grading of Hepatic Steatosis.

Background Screening for nonalcoholic fatty liver disease (NAFLD) is suboptimal due to the subjective interpretation of US images. Purpose To evaluate the agreement and diagnostic performance of radiologists and a deep learning model in grading hepatic steatosis in NAFLD at US, with biopsy as the reference standard. Materials and Methods This retrospective study included patients with NAFLD and control patients without hepatic steatosis who underwent abdominal US and contemporaneous liver biopsy from September 2010 to October 2019. Six readers visually graded steatosis on US images twice, 2 weeks apart. Reader agreement was assessed with use of κ statistics. Three deep learning techniques applied to B-mode US images were used to classify dichotomized steatosis grades. Classification performance of human radiologists and the deep learning model for dichotomized steatosis grades (S0, S1, S2, and S3) was assessed with area under the receiver operating characteristic curve (AUC) on a separate test set. Results The study included 199 patients (mean age, 53 years ± 13 [SD]; 101 men). On the test set (n = 52), radiologists had fair interreader agreement (0.34 [95% CI: 0.31, 0.37]) for classifying steatosis grades S0 versus S1 or higher, while AUCs were between 0.49 and 0.84 for radiologists and 0.85 (95% CI: 0.83, 0.87) for the deep learning model. For S0 or S1 versus S2 or S3, radiologists had fair interreader agreement (0.30 [95% CI: 0.27, 0.33]), while AUCs were between 0.57 and 0.76 for radiologists and 0.73 (95% CI: 0.71, 0.75) for the deep learning model. For S2 or lower versus S3, radiologists had fair interreader agreement (0.37 [95% CI: 0.33, 0.40]), while AUCs were between 0.52 and 0.81 for radiologists and 0.67 (95% CI: 0.64, 0.69) for the deep learning model. Conclusion Deep learning approaches applied to B-mode US images provided comparable performance with human readers for detection and grading of hepatic steatosis. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Tuthill in this issue.

Assessment of macrobenthos diversity and a zoning proposal for Seixas coral reefs (northeastern Brazil).

Coral reefs worldwide are under severe threat due to their inherent fragility and urgent need for conservation. The escalating tourism in coral reefs significantly impacts the marine ecosystem's biodiversity and conservation. This study analyzed the diversity and conservation status of macrobenthos in the Seixas coral reef, located in northeastern Brazil, and proposed a zoning plan. We employed monitoring protocols adapted from the Reef Check Program, the Rapid Assessment Protocol for Atlantic and Gulf Reefs, and the Protocol for Monitoring Coastal Benthic Habitats. Species identification was carried out by analyzing 25 transects, each divided into 1 m2 grids, with photos recorded for each grid, totaling 625 photos. Margalef, Shannon-Weaver, Simpson, and Pielou indices were used to analyze species distribution and diversity. The results indicated Dictyotaceae, Sargassaceae, and Corallinaceae as prevalent families. This research offers decision-makers a snapshot of species distribution in the Seixas coral reefs, providing a non-destructive, efficient methodology for assessing environmental impacts on coastal coral reefs.

Analysis of marine diversity and anthropogenic pressures on Seixas coral reef ecosystem (northeastern Brazil).

Coral reefs, vital and ecologically significant ecosystems, are among the most jeopardized marine environments in the Atlantic Ocean, particularly along the northeastern coast of Brazil. The persistent lack of effective management and conservation has led to fragmented information on reef use and pressures, hindering the understanding of these ecosystems' health. Major difficulties and challenges include inadequate data, diverse anthropogenic pressures, and the complex interaction between marine species. This study sought to bridge this knowledge gap by conducting a comprehensive analysis of marine diversity and anthropogenic pressures, specifically focusing on Seixas coral reef near João Pessoa city, an area notably impacted by tourism. Utilizing 25 monitoring transects, subdivided into 1 m2 quadrants, the marine diversity was meticulously evaluated through innovative procedures including (a) sedimentological and geochemical field surveys, (b) application of Shannon-Weaver diversity and Simpson dominance indices, (c) cluster analysis, (d) species identification of macroalgae, coral, and fish, and (e) an examination of anthropogenic interactions and pressures on the coral reef. The assessment encompassed three distinct zones: Back Reef, Reef Top, and Fore Reef, and identified a total of 25 species across 15 genera and 10 fish families. The findings revealed the prevalence of brown macroalgae, fish, and coral, with heightened abundance of red macroalgae in the Fore Reef, which also exhibited the greatest diversity (2.816) and dominance (0.894). Original achievements include the identification of specific spatial variations, recognition of the anthropogenic factors leading to ecological changes, and the formulation of evidence-based recommendations. The study concludes that escalating urbanization and burgeoning daily tourist visits to the reef have exacerbated negative impacts on Seixas coral reef's marine ecosystem. These insights underscore the urgent need for strategic planning and resource management to safeguard the reef's biodiversity and ecological integrity.

Multi-proxy assessment of coral reef formation and biotic-abiotic diversity in an urban coastal reef ecosystem in northeastern Brazil.

Coral reefs are habitats with high animal and mineral diversity and are subject to both climate change and anthropogenic impacts. This article presents novel and relevant data on the Seixas coral reef environment's geological, sedimentological, mineralogical, and biotic aspects in Paraíba State, northeastern Brazil. The aim of this study is to evaluate the processes of reef formation and the diversity of coral reef species in urban coastal environments in northeastern Brazil using a multi-proxy approach. Materials and methods employed to analyze the formation and diversity of biotic and abiotic species include (a) bathymetric survey, (b) collection of sedimentological, mineralogical, and granulometric data, (c) geological and stratigraphic determination, and (d) identification of biotic and abiotic species. Mineralogical slide results reveal that the Seixas Reef is a recent biogenic coral-algal carbonate formation associated with coastline evolution, high coastal sedimentation, and changes that occurred alongside sea-level rise (Holocene-Quaternary period). The diversity results indicate that benthic organism settlement occurred on a consolidated arenite base, with the fauna undergoing continuous succession processes. It can be concluded that this coral reef is highly vulnerable due to the material of its formation and comprises subsectors with high diversity (fore reef) and others with low diversity (reef top), which are affected by both anthropogenic and natural factors. Studies of this nature can contribute to understanding the evolution of coastal reefs, as their proximity to the continent makes them more vulnerable, and they experience direct physical impacts from fishing and tourist activities.

Potential Biomarkers of impulsivity in mild traumatic brain injury: A pilot study.

Very few studies have investigated cognition and impulsivity following mild traumatic brain injury (mTBI) in the general population. Furthermore, the neurobiological mechanisms underlying post-TBI neurobehavioral syndromes are complex and remain to be fully clarified. Herein, we took advantage of machine learning based-modeling to investigate potential biomarkers of mTBI-associated impulsivity. Twenty-one mTBI patients were assessed within one-month post-TBI and their data were compared to 19 healthy controls on measures of impulsivity (Barratt Impulsiveness Scale - BIS), executive functioning, episodic memory, self-report cognitive failures and blood biomarkers of inflammation, vascular and neuronal damage. mTBI patients were significantly more impulsive than controls in BIS total and subscales. Serum levels of sCD40L, Cathepsin D, IL-4, Neuropilin-1, IFN-α2, and Copeptin were associated with impulsivity in mTBI patients. Besides showing that mTBI are associated with impulsivity in non-military people, we unveiled different pathophysiological pathways potentially implicated in mTBI-related impulsivity.

Transnasal endoscopy-guided percutaneous access to the sphenopalatine ganglion for neurostimulation in the treatment of primary headache: operative technique and feasibility

Abstract Objectives: Cluster headache is considered a trigeminal autonomic cephalalgia and may present with characteristic symptoms of sympathetic/parasympathetic activation on the affected side of the face, such as nasal discharge, tearing, and conjunctival injection. Invasive therapies targeting the sphenopalatine ganglion have been performed in these headache syndromes and can have a medication-sparing effect, especially in refractory, difficult-to-manage cases. The gate control theory of pain suggests that electric pulses delivered to nerve tissues can modulate neuronal activity, thus aiding in management of nociceptive or neuropathic pain, and studies have demonstrated the efficacy and safety of sphenopalatine ganglion neurostimulation. Within this context, we sought to assess the feasibility of a new surgical technique for neurostimulation of the sphenopalatine ganglion in a cadaver dissection model. Methods: The technique was developed through dissection of two cadaver heads. We divided the procedure into two stages: an endonasal endoscopic approach to expose the sphenopalatine ganglion and confirm electrode placement, and a cervicofacial approach to introduce the electrode array and position the internal pulse-generator unit. Computed tomography was performed to confirm implant placement at the end of the procedure. Results: The pulse-generator unit was successfully placed through a retroauricular incision, as is already standard for cochlear implant placement. This should reduce the incidence of perioperative sequelae, especially pain and swelling in the oral region, which are a common complication of previous approaches used for this purpose. Control imaging confirmed proper electrode placement. The device used in this study allows the patient to modulate the intensity of the stimulus, reducing or even obviating the need for drug therapy. Conclusion: The novel technique described herein, based on percutaneous access guided by transmaxillary endoscopy, can provide great precision in electrode array positioning and decreased perioperative morbidity, combining the advantages of endoscopic approaches with those of the retroauricular route. Level of evidence: 3.

Transnasal endoscopy-guided percutaneous access to the sphenopalatine ganglion for neurostimulation in the treatment of primary headache: operative technique and feasibility.

OBJECTIVES: Cluster headache is considered a trigeminal autonomic cephalalgia and may present with characteristic symptoms of sympathetic/parasympathetic activation on the affected side of the face, such as nasal discharge, tearing, and conjunctival injection. Invasive therapies targeting the sphenopalatine ganglion have been performed in these headache syndromes and can have a medication-sparing effect, especially in refractory, difficult-to-manage cases. The gate control theory of pain suggests that electric pulses delivered to nerve tissues can modulate neuronal activity, thus aiding in management of nociceptive or neuropathic pain, and studies have demonstrated the efficacy and safety of sphenopalatine ganglion neurostimulation. Within this context, we sought to assess the feasibility of a new surgical technique for neurostimulation of the sphenopalatine ganglion in a cadaver dissection model. METHODS: The technique was developed through dissection of two cadaver heads. We divided the procedure into two stages: an endonasal endoscopic approach to expose the sphenopalatine ganglion and confirm electrode placement, and a cervicofacial approach to introduce the electrode array and position the internal pulse-generator unit. Computed tomography was performed to confirm implant placement at the end of the procedure. RESULTS: The pulse-generator unit was successfully placed through a retroauricular incision, as is already standard for cochlear implant placement. This should reduce the incidence of perioperative sequelae, especially pain and swelling in the oral region, which are a common complication of previous approaches used for this purpose. Control imaging confirmed proper electrode placement. The device used in this study allows the patient to modulate the intensity of the stimulus, reducing or even obviating the need for drug therapy. CONCLUSION: The novel technique described herein, based on percutaneous access guided by transmaxillary endoscopy, can provide great precision in electrode array positioning and decreased perioperative morbidity, combining the advantages of endoscopic approaches with those of the retroauricular route.

Inflammasome activation and assembly in Huntington's disease.

Huntington's disease (HD) is a rare neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Inflammasomes are multiprotein complexes capable of sensing pathogen-associated and damage-associated molecular patterns, triggering innate immune pathways. Activation of inflammasomes results in a pro-inflammatory cascade involving, among other molecules, caspases and interleukins. NLRP3 (nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3) is the most studied inflammasome complex, and its activation results in caspase-1 mediated cleavage of the pro-interleukins IL-1ß and IL-18 into their mature forms, also inducing a gasdermin D mediated form of pro-inflammatory cell death, i.e. pyroptosis. Accumulating evidence has implicated NLRP3 inflammasome complex in neurodegenerative diseases. The evidence in HD is still scant and mostly derived from pre-clinical studies. This review aims to present the available evidence on NLRP3 inflammasome activation in HD and to discuss whether targeting this innate immune system complex might be a promising therapeutic strategy to alleviate its symptoms.

Mature Naive B Cells Regulate the Outcome of Murine Acute Graft-versus-Host Disease in an IL-10-Independent Manner.

Graft-versus-host disease (GVHD) is the main complication of bone marrow transplantation (BMT). CD4+ T lymphocytes are the main effector cells for disease development, but other cell types can determine disease outcome through cytokine production and antigen presentation. B cells are abundant in BMT products and are involved in chronic GVHD immunopathogenesis. However, their role in acute GVHD is still unclear. Here we studied the role of donor resting B cells in a model of acute GVHD. Animals receiving transplants depleted of B cells developed more severe disease, indicating a protective role for B cells. Mice undergoing transplantation with IL-10 knockout B cells developed GVHD as severe as those receiving wild-type B cells. Moreover, mice that received MHC II-deficient B cells, and thus were unable to present antigen to CD4+ T cells, developed as severe GVHD as animals receiving transplants without B cells. This result suggests that the protection provided by mature naive B cells depends on antigen presentation and not on IL-10 production by B cells. Mice who underwent transplantation in the absence of donor B cells exhibited disorganized lymphoid splenic tissue. In addition, donor B cell depletion diminished the follicular T (Tfh)/effector T (Teff) cell ratio, suggesting that protection was correlated with a shift to Tfh differentiation, reducing the number of Teff cells. Importantly, the Tfh/Teff shift impacts disease outcome, with observed proinflammatory cytokine levels and tissue damage in target organs consistent with disease protection. The role of transplanted B cells in the outcome of BMT and the development of acute GVHD merits careful study, given that these cells are abundant in BMT products and are potent modulator and effector cells in the allogeneic response.

Chronic nutritional restriction of omega-3 fatty acids induces a pro-inflammatory profile during the development of the rat visual system.

Modern western diets have been associated with a reduced proportion of dietary omega-3 fatty acids leading to decreased levels of DHA (docosahexaenoic acid) in the brain. Low DHA content has been associated with altered development of visual acuity in infants and also with an altered time course of synapse elimination and plasticity in subcortical visual nuclei in rodents. Microglia has an active role in normal developmental processes such as circuitry refinement and plasticity, and its activation status can be modulated by omega-3 (ω3) and omega-6 (ω6) essential fatty acids. In the present study, we investigated the impact of dietary restriction of DHA (ω3-), through the chronic administration of a coconut-based diet as the only fat source. This dietary protocol resulted in a reduction in DHA content in the retina and superior colliculus (SC) and in a neuroinflammatory outcome during the development of the rodent visual system. The ω3- group showed changes in microglial morphology in the retina and SC and a corresponding altered pattern of pro-inflammatory cytokine expression. Early and late fish oil protocols supplementation were able to restore DHA levels. The early supplementation also decreased neuroinflammatory markers in the visual system. The present study indicates that a chronic dietary restriction of omega-3 fatty acids and the resulting deficits in DHA content, commonly observed in Western diets, interferes with the microglial profile leading to an inflamed microenvironment which may underlie a disruption of synapse elimination, altered topographical organization, abnormal plasticity, and duration of critical periods during brain development.

Molecular remission using low-dose immunotherapy for relapsed refractory Philadelphia chromosome-positive precursor B-cell acute lymphoblastic leukemia post-allogeneic stem cell transplant.

Adults with relapsed/refractory acute lymphoblastic leukemia have a poor prognosis. While current immunotherapies are promising, they are toxic, with graft-versus-host disease a major complication of allogeneic therapy. Here, we report a patient with high-risk relapsed/refractory Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (ALL) following chemotherapy induction, matched related donor allogeneic hematopoietic stem cell transplantation (allo-HCT), donor lymphocyte infusion and two tyrosine kinase inhibitors. The patient achieved a complete molecular and cytogenetic remission with minimal adverse events or evidence of GVHD following recombinant human IL-2 (rIL-2), in combination with a tyrosine kinase inhibitor (TKI). There was a ninefold increase in natural killer (NK) cell activity and natural killer T cells (NKT) cells (CD2+CD26+). Personalized low dose recombinant human IL-2-mediated NK cell stimulation represents an effective, nontoxic immunotherapy administered in the outpatient setting for relapsed acute lymphoblastic leukemia and warrants further investigation.

Effects of a Single Dose of Parecoxib on Inflammatory Response and Ischemic Tubular Injury Caused by Hemorrhagic Shock in Rats.

Parecoxib, a selective COX-2 inhibitor, is used to improve analgesia in postoperative procedures. Here we evaluated whether pretreatment with a single dose of parecoxib affects the function, cell injury, and inflammatory response of the kidney of rats subjected to acute hemorrhage. Inflammatory response was determined according to serum and renal tissue cytokine levels (IL-1α, IL-1ß, IL-6, IL-10, and TNF-α). Forty-four adult Wistar rats anesthetized with sevoflurane were randomized into four groups: placebo/no hemorrhage (Plc/NH); parecoxib/no hemorrhage (Pcx/NH); placebo/hemorrhage (Plc/H); and parecoxib/hemorrhage (Pcx/H). Pcx groups received a single dose of intravenous parecoxib while Plc groups received a single dose of placebo (isotonic saline). Animals in hemorrhage groups underwent bleeding of 30% of blood volume. Renal function and renal histology were then evaluated. Plc/H showed the highest serum levels of cytokines, suggesting that pretreatment with parecoxib reduced the inflammatory response in rats subjected to hemorrhage. No difference in tissue cytokine levels between groups was observed. Plc/H showed higher percentage of tubular dilation and degeneration, indicating that parecoxib inhibited tubular injury resulting from renal hypoperfusion. Our findings indicate that pretreatment with a single dose of parecoxib reduced the inflammatory response and tubular renal injury without altering renal function in rats undergoing acute hemorrhage.

Probiotic treatment during neonatal age provides optimal protection against experimental asthma through the modulation of microbiota and T cells.

The incidence of allergic diseases, which increased to epidemic proportions in developed countries over the last few decades, has been correlated with altered gut microbiota colonization. Although probiotics may play a critical role in the restoration of gut homeostasis, their efficiency in the control of allergy is controversial. Here, we aimed to investigate the effects of probiotic treatment initiated at neonatal or adult ages on the suppression of experimental ovalbumin (OVA)-induced asthma. Neonatal or adult mice were orally treated with probiotic bacteria and subjected to OVA-induced allergy. Asthma-like symptoms, microbiota composition and frequencies of the total CD4+ T lymphocytes and CD4+Foxp3+ regulatory T (Treg) cells were evaluated in both groups. Probiotic administration to neonates, but not to adults, was necessary and sufficient for the absolute prevention of experimental allergen-induced sensitization. The neonatally acquired tolerance, transferrable to probiotic-untreated adult recipients by splenic cells from tolerant donors, was associated with modulation of gut bacterial composition, augmented levels of cecum butyrate and selective accumulation of Treg cells in the airways. Our findings reveal that a cross-talk between a healthy microbiota and qualitative features inherent to neonatal T cells, especially in the Treg cell subset, might support the beneficial effect of perinatal exposure to probiotic bacteria on the development of long-term tolerance to allergens.

Young donor white blood cell immunotherapy induces extensive tumor necrosis in advanced-stage solid tumors.

BACKGROUND: In the past decade, a variety of immunotherapy approaches focused predominantly on the adaptive immune system have shown unprecedented responses in patients with advanced-stage malignancies. However, studies in spontaneous regression/complete resistance (SR/CR) mice and humans have shown a novel innate cancer-killing activity mediated by granulocytes, which is completely transferable for prevention or therapy against established malignancies. METHODS: Three patients with advanced, relapsed or refractory solid tumors for which no standard therapy was available or was refused were enrolled into this ongoing combined phase I/II open label clinical trial testing the safety, dose tolerance, and possible antineoplastic efficacy of sequential infusions of HLA-mismatched non-irradiated allogeneic white cells (68-91% granulocytes) collected by leukapheresis from young, healthy donors (age 18-35) following mobilization with granulocyte colony stimulating factor (G-CSF) and dexamethasone. RESULTS: Besides fevers and flushing, no infusional toxicities were observed. All patients remained clinically stable following infusions with mild cytokine release syndrome and no evidence of transfusion-associated graft-versus-host disease, acute tumor lysis syndrome,or transfusion-associated acute lung injury. Pathological examination of all cases post-mortem revealed extensive tumor necrosis up to 80% in patients 1-2, 40-50% in patient 3, and leukocyte infiltration in all cases, which could not be attributed to disease progression. CONCLUSIONS: Allogeneic white cell immunotherapy (AWIT) from young, healthy donors is well tolerated with minimal side effects and shows antitumor activity against advanced-stage solid tumors. AWIT represents a novel, safe, and cost-effective immunotherapy that can be administered in an outpatient cancer clinic.

Cyclosporine A attenuates apoptosis and necrosis after ischemia-reperfusion-induced renal injury in transiently hyperglycemic rats.

PURPOSE:: To investigate the effects of cyclosporine A on renal ischemia-reperfusion injury during transient hyperglycemia in rats. METHODS:: In a model of ischemia-reperfusion-induced renal injury and transiently induced hyperglycemia by intraperitoneal injection of glucose, 2.5 g.kg-1, Wistar rats were anesthetized with either isoflurane or propofol and received intravenous cyclosporine A, 5 mg.kg-1, five minutes before reperfusion. Comparison groups were isoflurane and propofol sham groups and isoflurane and propofol ischemia-reperfusion-induced renal injury. Renal tubular cell viability was quantitatively assessed by flow cytometry after cell culture and classified as early apoptosis, necrotic cells, and intact cells. RESULTS:: Early apoptosis was significantly higher in isoflurane and propofol anesthetized animals subjected to renal ischemia-reperfusion injury when compared to both cyclosporine A treated and sham groups. Necrosis percentage was significantly higher in propofol-anesthetized animals subjected to renal ischemia-reperfusion injury. The percentage of intact cells was lower in both, isoflurane and propofol anesthetized animals subjected to renal ischemia-reperfusion injury. CONCLUSION:: In a model of ischemia-reperfusion-induced renal injury, cyclosporine A, 5 m.kg-1, administered five minutes before renal reperfusion in rats with acute-induced hyperglycemia under either isoflurano or propofol anesthesia, attenuated early apoptosis and preserved viability in renal tubular cells, regardless of the anesthetic used.