Single Large Dose Research Articles

Effects of Intravenous Glucose on Blood Potassium in Cattle

Abstract The aim of this study was to confirm whether a rapid intravenous glucose administration can lead to a significant drop in blood potassium levels in cattle. For this study, seven cattle were used according to internationally recognized guidelines for animal welfare. Glucose at a dose of 1 g.kg−1 body weight was administrated intravenously and then blood samples were taken before and 0.5, 1, 2, 4, and 6 hours after administration of glucose for measurement of potassium and glucose blood concentrations. For statistical analysis of glucose effects on both glucose and potassium levels one-way analysis of variance (ANOVA) for repeated measures was used. ANOVA showed a strong significant effect of the glucose administration on plasma glucose levels (P < 0.001). The glucose administration resulted in a mean plasma increase from 4.2 mmol.l−1 to 21.2 mmol.l−1 within the first minutes after the administration followed by a steady decrease back to the initial values. In contrast, ANOVA showed no significant effect of the glucose administration on plasma potassium levels. In conclusion, the glucose does not have a potassium-lowering effect when administered in a single large intravenous dose.

Enhancement of Radiation Therapy through Blockade of the Immune Checkpoint, V-domain Ig Suppressor of T Cell Activation (VISTA), in Melanoma and Adenocarcinoma Murine Models.

Radiation therapy (RT) has recently demonstrated promise at stimulating an enhanced immune response. The recent success of immunotherapies, such as checkpoint inhibitors, CART cells, and other immune modulators, affords new opportunities for combination with radiation. The aim of this study is to evaluate whether and to what extent blockade of VISTA, an immune checkpoint, can potentiate the tumor control ability of radiation therapy. Our study is novel in that it is the first comparison of two VISTA-blocking methods (antibody inhibition and genetic knockout) in combination with RT. VISTA was blocked either through genetic knockout (KO) or an inhibitory antibody and combined with RT in two syngeneic murine flank tumor models (B16 and MC38). Selected mRNA, immune cell infiltration, and tumor growth delay were used to assess the biological effects. When combined with a single 15Gy radiation dose, VISTA blockade via genetic knockout in the B16 model and via anti-VISTA antibodies in the MC38 model significantly improved survival compared to RT alone by an average of 5.5 days and 6.3 days, respectively (p < 0.05). The gene expression data suggest that the mechanism behind the enhanced tumor control is primarily a result of increased apoptosis and immune-mediated cytotoxicity. VISTA blockade significantly enhances the anti-tumor effect of a single dose of 15Gy radiation through increased expression and stimulation of cell-mediated apoptosis pathways. These results suggest that VISTA is a biologically relevant immune promoter that has the potential to enhance the efficacy of a large single radiation dose in a synergic manner.

Mechanistic approaching study in COVID-19 patients treated with high doses of vitamin D

Aim: To evaluate angiotensin II (Ang II) and Ang-(1-7) levels and the cytokine profile in patients hospitalized with mild coronavirus disease 2019 (COVID-19) and contrast them with patients with identical clinical conditions but treated with high doses of vitamin D (vitD). Methods: From the 218 patients recruited (ClinicalTrials.gov NCT04411446), 16 participated in this sub-study and were randomized to a single oral dose of 500,000 IU vitD (n = 10) or placebo (n = 6). Plasmatic Ang II and Ang-(1-7) levels were determined by radioimmunoassay and interleukins (ILs) 1, 6, 8, and 10 and tumor necrosis factor alpha (TNF-α) by enzyme-linked immunosorbent assay before and after treatment. Parallel, serum 25-hydroxyvitamin D3 (25-OH vitD) concentrations as vitD status was measured by a chemiluminescence immunoassay. Results: A trend towards an increase in Ang-(1-7) and a decrease in Ang II levels were observed in placebo- and vitD-treated COVID-19 patients compared to baseline values. There was no difference in Ang II and Ang-(1-7) levels between placebo- and vitD-treated COVID-19 patients. Similar results were obtained with ILs profile. COVID-19 patients showed an increase in the protective component of the RAS which was not improved by vitD treatment. Conclusions: VitD did not improve RAS disbalance in COVID-19. Notwithstanding, the authors visualize that acute treatment with high doses of vitD may show a trend to a decline in inflammatory ILs and an increase in protective markers. Finally, the authors would like to highlight the limitations of this preliminary study, namely the small number of patients and the use of a large single bolus dose of vitD rather than lower daily doses for extended periods with prolonged follow-up times. All these factors need special consideration in the designs of new vitD supplementation trials. All these factors need special consideration in the designs of new vitD supplementation trials (ClinicalTrials.gov identifier: NCT04411446).

Abstract 6716: Preclinical evaluation of nano-liposomal irinotecan in pediatric solid tumor patient-derived xenografts

Abstract Background: Pediatric solid tumors are rare and the use of well characterized preclinical models can be a helpful tool to prioritize novel drug combinations and formulations which are challenging to test in a limited patient population. Irinotecan (IRN) has shown efficacy in diverse pediatric cancers where children are often treated on an extended low-dose schedule rather than a single large dose commonly used in adults. The use of nano-liposomal irinotecan (nal-IRI) is a promising strategy as 95% of the drug remains encapsulated during systemic exposure while maintaining prolonged exposure in the tumor. Adult clinical trials have shown reduced side effects without compromising efficacy but nal-IRI has had limited use thus far in pediatric cancers. Methods: Orthotopic xenograft models of Ewing sarcoma (EWS, 4 models) and rhabdomyosarcoma (RMS, 2 models) were generated by injecting luciferase labeled cells into the femur and hind-leg muscle of nude mice respectively. Pharmacokinetic (PK) studies on normal and tumor-bearing mice were performed for both nal-IRI and standard IRN to determine matched human AUC-guided dosing and schedule of chemotherapy agents. Mice were randomized to single agent and relevant combinations of nal-IRI with PARP inhibitors and temozolomide (EWS) and with vincristine and temozolomide (RMS) and compared to the same regimens using standard IRN. Therapy was given on a clinically relevant schedule with each course consisting of 21 days and tumor response was measured weekly using bioluminescence. Results: PK studies showed that plasma levels of the active metabolite of IRN (SN-38) drop quickly for both standard IRN and nal-IRI single dosed mice while the levels of SN-38 were maintained in the tumor for several days using the nal-IRI formulation. In all 6 models tested, nal-IRI combinations were as or more effective when compared to regimens using standard IRN. No significant toxicity was seen in mice treated with nal-IRI combinations. Conclusions: The substitution of nal-IRI for standard IRN remains a promising strategy in pediatrics with the potential to reduce side effects as well as hospital visits due to the dosing schedule with nal-IRI given once per cycle where standard IRN is often given for 5 or 10 days in children. Our preclinical PK data confirmed the liposomal formulation resulted in sustained SN-38 levels in the tumor and efficacy was maintained or improved in pediatric cancer models. The combination of nal-IRI with temozolomide and talazoparib is now being tested in a multi-center randomized phase I/II trial for children with relapsed solid tumors and this data supports consideration for use in other pediatric cancer trials both in the upfront and relapse setting. Citation Format: Elizabeth Stewart, Kaley Blankenship, Burgess Freeman, Sara Federico, Michael Dyer. Preclinical evaluation of nano-liposomal irinotecan in pediatric solid tumor patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6716.

Multidose Hyaluronidase Administration as an Optimal Procedure to Degrade Resilient Hyaluronic Acid Soft Tissue Fillers.

Minimally invasive hyaluronan (HA) tissue fillers are routinely employed to provide tissue projection and correct age-related skin depressions. HA fillers can advantageously be degraded by hyaluronidase (HAase) administration in case of adverse events. However, clear guidelines regarding the optimal dosage and mode of administration of HAase are missing, leaving a scientific gap for practitioners in their daily practice. In this study, we implemented a novel rheological procedure to rationally evaluate soft tissue filler degradability and optimize their degradation kinetics. TEOSYAL RHA® filler degradation kinetics in contact with HAase was monitored in real-time by rheological time sweeps. Gels were shown to degrade as a function of enzymatic activity, HA concentration, and BDDE content, with a concomitant loss of their viscoelastic properties. We further demonstrated that repeated administration of small HAase doses improved HA degradation kinetics over large single doses. Mathematical analyses were developed to evaluate the degradation potential of an enzyme. Finally, we tuned the optimal time between injections and number of enzymatic units, maximizing degradation kinetics. In this study, we have established a scientific rationale for the degradation of HA fillers by multidose HAase administration that could serve as a basis for future clinical management of adverse events.

Long-term effect of a large dose of iodinated contrast in patients with mild thyroid dysfunction: a prospective cohort study.

More than 75 million procedures with intravascular iodine-based contrast media (ICM) are performed worldwide every year, and some patients undergoing these procedures do not have normal thyroid function. The long-term effects of ICM in patients with mild thyroid dysfunction (TD) are unclear. This prospective cohort study was conducted in China. Patients with stable angina pectoris with total triiodothyronine (TT3) reduction, normal thyroid-stimulating hormone, and reverse triiodothyronine (rT3) were enrolled and divided into high-dose (≥100 mL ICM) and low-dose groups (<100 mL ICM). We dynamically investigated the trends in thyroid function, rT3, and thyroid antibodies 1 year after ICM exposure. A total of 154 patients completed 6 months of follow-up and 149 completed 1 year of follow-up. Thyroglobulin antibody (TGAB) levels were elevated in 41 (26.6%) patients before ICM exposure, 11 (7.1%) of whom also had elevated thyroid peroxidase antibody levels. Transient subclinical TD occurred 6 months after ICM exposure; 75.5% of post-operative TD occurred in the high-dose group. One patient developed severe hypothyroidism with myxedema, requiring drug intervention 1 year after ICM exposure. The level of rT3 showed no statistically significant changes during post-operative follow-up (P = 0.848). The TGAB level decreased at 6th month (P < 0.001), but increased at 1 year after ICM exposure (P = 0.002). Patients with T3 reduction are at risk of transient subclinical TD and hypothyroidism after a single large dose of ICM. Follow-up of this population at 9-12 months after ICM exposure is warranted.

Characteristics of ivermectin toxicity in patients taking veterinary and human formulations for the prevention and treatment of COVID-19

Background US poison control centers reported increased cases of ivermectin toxicity during the COVID-19 pandemic. Previous descriptions of ivermectin toxicity have evaluated heterogeneous groups with a variety of ivermectin sources and dosage patterns. We sought to compare the clinical effects of ivermectin toxicity in patients taking human- vs. veterinary-formulations and acute- vs. chronic-ingestion patterns. Methods We performed a retrospective analysis of cases from the Oregon Poison Center of ivermectin exposures for the prevention or treatment of COVID-19 that resulted in a healthcare visit over a 24-week period (14 August 2021 − 31 January 2022). Results We identified 37 cases of ivermectin toxicity. The median age of patients was 64 years, and most patients were male. The majority of patients were hospitalized (21) or treated in an emergency department (13). A minority were treated in an outpatient setting (3) and one patient died. Seventeen ingested veterinary formulations and fifteen ingested prescription tablets. Patients reported taking ivermectin for treatment (23) and prevention (14) of COVID-19. Clinical effects included neurotoxicity (30), gastrointestinal symptoms (14), and musculoskeletal complaints (7). Patients taking veterinary products took higher doses of ivermectin and had higher rates of altered mental status than those taking prescription tablets. Patients taking ivermectin chronically took smaller doses (daily dose of 13.5 mg) over a prolonged period (median 3.8 weeks) and developed toxicity that was milder than those with acute ingestions. Conclusion Ivermectin toxicity developed in predominantly male patients >60 years old who ingested higher than recommended doses and developed neurologic symptoms. Patients who took a veterinary formulation of ivermectin ingested large single doses or large daily doses for several days and developed rapid onset of neurotoxicity. Patients with chronic toxicity developed milder symptoms and tended to take typical therapeutic doses, but continued therapy for weeks rather than days.

PSAT364 High-Dose Levothyroxine to Exclude Malabsorption as a Cause of Refractory Hypothyroidism in Hospitalized Patients: Two Cases

Abstract Introduction Levothyroxine malabsorption is one of the causes of refractory hypothyroidism. Administration of a single large dose of levothyroxine can help distinguish this from refractory hypothyroidism due to other causes, but little is known about the utility of this test in patients hospitalized for severe hypothyroidism. Case 1 A 42-year-old woman with Hashimoto's thyroiditis presented with symptomatic hypothyroidism. She reported being compliant with 150 mcg of levothyroxine daily. However, in the past year, her free T4 remained &amp;lt; 0.10 ng/dL on several occasions with TSH &amp;gt; 80 uIU/mL. On admission, free T4 was 0.58 ng/dL, total T4 was 4.9 ug/dL, and TSH was 57.06 uIU/mL. We administered 1000 mcg levothyroxine and found an increase in total T4 at 4 hours (12.1 ug/dL from 4.9 ug/dL). Absorption was found to be 100% at 4 hours implying that she was not taking her levothyroxine appropriately. She was counseled to take levothyroxine at 150 mcg on an empty stomach. At outpatient follow up in 3 weeks, free T4 improved to 1.44 ng/dL and TSH decreased to 1.050 uIU/mL. Case 2 A 42-year-old woman with hypothyroidism, alcohol hepatitis, chronic pancreatitis and previous Roux-en-Y gastric bypass was admitted with progressive lower extremity edema and shortness of breath. She reported taking levothyroxine 175 mcg each morning with her other medications that included omeprazole and magnesium oxide, along with coffee and milk soon after. Her admission labs showed free T4 0.61 ng/dL, total T4 2.8 ug/dL and TSH 84.4 uIU/mL. After 1000 mcg of levothyroxine her total T4 increased from 2.6 ug/dL to 7.8 ug/dL in 4 hours, indicating 100% absorption. The reason for her inadequate outpatient response was probably the combined use of omeprazole, magnesium oxide and coffee with milk, being taken with levothyroxine. She was asked to continue levothyroxine 150 mcg on an empty stomach. Method: Patients were made NPO at midnight prior to the morning of the study. Baseline total T4 was obtained at 6: 00 AM and 1000 mcg of oral Levothyroxine was administered while the patient was monitored on telemetry. Total T4 was measured at 2 and 4 hours after administration. Percentage absorption (% absorbed) = [[Increment TT4 (mcg/dL)×10 (dL/L)]/[total administered LT4 (mcg)]]×Vd (L)X100; Increment TT4 = [Peak TT4] - [Baseline TT4]; Vd (volume of distribution) = 0.442×BMI1 Conclusion These cases indicate that a 1000 mcg T4 absorption study is safe and reasonable to perform in patients who are hospitalized for profound hypothyroidism when outpatient evaluation has been ineffective or challenging. 1 Gonzales KM, Stan MN, Morris JC 3rd, Bernet V, Castro MR. The Levothyroxine Absorption Test: A Four-Year Experience (2015-2018) at The Mayo Clinic. Thyroid. 2019 Dec;29(12): 1734-1742. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

The influence of hypoxia on LET and RBE relationships with implications for ultra-high dose rates and FLASH modelling

Objective. To investigate relationships between linear energy transfer (LET), fluence rates, changes in radiosensitivity and the oxygen enhancement ratio (OER) in different ion beams and extend these concepts to ultra-high dose rate (UHDR) or FLASH effects. Approach. LET values providing maximum relative biological effect (RBE), designated as LETU, are found for neon, carbon and helium beams. Proton experiments show reduced RBEs with depth in scattered (divergent) beams, but not with scanned beams, suggesting that instantaneous fluence rates (related to track separation distances) can modify RBE, all other RBE-determining factors being equal. Micro-volumetric energy transfer per μm3 (mVET) is defined by LET × fluence. High fluence rates will increase mVET rates, with proportional shifts of LETU to lower values due to more rapid energy transfer. From the relationship between LETU and OER at conventional dose rates, OER reductions in UHDR/FLASH exposures can be estimated and biological effective dose analysis of experimental lung and skin reactions becomes feasible. Main results. The Furusawa et al data show that hypoxic LETU values exceed their oxic counterparts. OER reduces from around 3–1.25 at LETU, although the relative radiosensitivities of the oxic and hypoxic α parameters (the OER(α)) exceed those of the standard OER values. Increased fluence rates are predicted to reduce LETU and OER. Large FLASH single doses will minimise RBE increments due to the β parameter reducing by a factor of 0.5–0.25 consistent with oxygen depletion, causing radioresistance. Similar results will occur for photons. Tissue α/β ratios increase by around 10 in FLASH conditions, agreeing with derived ion-beam dose rate equations. Significance. Increasing dose rates enhance local energy deposition rate per unit volume, probably causing oxygen depletion and radioresistance in pre-existing hypoxic sites during UHDR/FLASH exposures. The modelled equations provide testable hypotheses for further dose rate investigations in photon, proton and ion beams.

Role of Vitamin D Supplementation in Improving Cytokine Profile in Patients of Non-ST-Elevation Acute Coronary Syndrome.

Sub endothelial infarcts leads to non-ST-elevation acute coronary syndrome. Proinflammatory cytokines are raised in serum, the severity of which is a poor prognostic sign. Vitamin D deficiency is prevalent among patients of ACS. Vitamin D has immunomodulatory roles having effects on various aspects of inflammation. A total of 40 patients were divided into experimental (n=20) and control (n=20) groups. Experimental group was given single dose of vitamin D 200,000 IU. They were assessed for baseline C-reactive protein, interleukin-6, tumor necrosis factor-α levels by using sandwich ELISA technique. Four months after intervention resampling was done for the same parameters. Findings were expressed as mean±SD. Independent sample t-test was used to compare effect of vitamin D intervention between control group and intervention group. p-value of ≤0.05 was considered to be significant. The serum C-reactive protein showed significant reduction (p=0.028*) after intervention with vitamin D. Serum interleukin-6 (p=0.848), tumor necrosis factor-α (p=0.20) were decreased non-significantly in experimental as compared to the control group. It was concluded that a single large dose of vitamin D was able to reduce the C-reactive protein in non-ST-elevation acute coronary syndrome patients while non-significant reductions in interleukin-6 and tumor necrosis factor-α were observed.

Improved cellular automata model shows that indirect apoptotic cell death due to vascular damage enhances the local control of tumors by single fraction high-dose irradiation

We investigated the effects of indirect apoptotic cell death due to vascular damage on tumor response to a single large dose with an improved two-dimensional cellular automata model. The tumor growth was simulated by considering the oxygen and nutrients supplied to the tumor through the blood vessels. The cell damage processes were modeled by taking account of the direct cell death and the indirect death due to the radiation-induced vascular damages. The radiation increased the permeation of oxygen and nutrients through the blood vessel or caused the breakdown of the vasculature. The amount of oxygen in cancer cells affected the response of cancer cells to radiation and the tumor growth rate after irradiation. The lack of oxygen led to the apoptotic death of cancer cells. We calculated the tumor control probability (TCP) at different radiation doses, the probability of apoptotic death, the threshold of the oxygen level for indirect apoptotic death, the average oxygen level in cancer cells and the vessel survival probability after radiation damage. Due to the vessel damage, indirect cell death led to a 4% increase in TCP for the dose ranging from 15 Gy to 20 Gy. TCP increased with increasing the probability of apoptotic death and the threshold of the oxygen level for indirect apoptotic death due to increased apoptotic death. The variation of TCP as a function of the average oxygen level exhibited the minimum at the average oxygen level of 2.7%. The apoptosis increased as the average oxygen level decreased, leading to an increasing TCP. On the other hand, the direct radiation damage increased, and the apoptosis decreased for higher average oxygen level, resulting in a higher TCP. We showed by modeling the radiation damage of blood vessels in a 2D CA simulation that the indirect apoptotic death of cancer cells, caused by the reduction of the oxygen level due to vascular damage after high dose irradiation, increased TCP.

Personalise vitamin D3 using physiologically based pharmacokinetic modelling.

Plasma concentration of vitamin D3 metabolite 25‐hydroxyvitamin D3 (25(OH)D3) is variable among individuals. The objective of this study is to establish an accurate model for 25(OH)D3 pharmacokinetics (PKs) to support selection of a suitable dose regimen for an individual. We collated vitamin D3 and 25(OH)D3 plasma PK data from reported clinical trials and developed a physiologically‐based pharmacokinetic (PBPK) model to appropriately recapitulate training data. Model predictions were then qualified with 25(OH)D3 plasma PKs under vitamin D3 and 25(OH)D3 dose regimens distinct from training data. From data exploration, we observed the increase in plasma 25(OH)D3 after repeated dosing was negatively correlated with 25(OH)D3 baseline levels. Our final model included a first‐order vitamin D3 absorption, a first‐order vitamin D3 metabolism, and a nonlinear 25(OH)D3 elimination function. This structure explained the apparent paradox. Remarkably, the model accurately predicted plasma 25(OH)D3 following repeated dosing up to 1250 μg/d in the test set. It also made sensible predictions for large single vitamin D3 doses up to 50,000 μg in the test set. Model predicts 10 μg/d regimen may be ineffective for achieving sufficiency (plasma 25(OH)D3 ≥ 75 nmol/L) for a severely deficient individual (baseline 25(OH)D3 = 10 nmol/L), and it might take the same person over 200 days to reach sufficiency at 20 μg/d dose. We propose to personalize vitamin D3 supplementation protocol with this PBPK model. It would require measuring 25(OH)D3 baseline levels, which is not routinely performed under the current UK public health advice.Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin D PK exhibits substantial inter‐individual variability. Different officially recommended daily doses are confusing.​ WHAT QUESTION DID THIS STUDY ADDRESS? Is the UK’s recommended 10 µg daily dose sufficient? Should everyone be given same dose?​ WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our model accurately predicts plasma 25(OH)D under daily oral administration of vitamin D3. The 10 µg daily vitamin D3 dose is insufficient for prophylaxis (plasma 25(OH)D at 75 nmol/L).​ HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? Combining blood test to measure 25(OH)D baseline with this PBPK model will help inform dosage selection and select follow‐up date to improve effectiveness of Hypovitaminosis D treatment.

The role of the spatially fractionated radiation therapy in the management of advanced bulky tumors

Abstract Spatially fractionated radiation therapy (SFRT) refers to the delivery of a single large dose of radiation within the target volume in a heterogeneous pattern using either a custom GRID block, multileaf collimators, and virtual methods such as helical tomotherapy or synchrotron-based microbeams. The potential impact of this technique on the regression of bulky deep-seated tumors that do not respond well to conventional radiotherapy has been remarkable. To date, a large number of patients have been treated using the SFRT techniques. However, there are yet many technical and medical challenges that have limited their routine use to a handful of clinics, most commonly for palliative intent. There is also a poor understanding of the biological mechanisms underlying the clinical efficacy of this approach. In this article, the methods of SFRT delivery together with its potential biological mechanisms are presented. Furthermore, technical challenges and clinical achievements along with the radiobiological models used to evaluate the efficacy and safety of SFRT are highlighted.

Comparison of ferric carboxymaltose versus Iron Sucrose for treatment of iron deficiency anemia in pregnancy.

Objective: To compare the mean increase in hemoglobin level with ferric carboxymaltose injection and iron sucrose injection for the management of the pregnant females presenting with iron deficiency anemia. Study Design: Randomized Controlled Trial. Settings: Department of Obstetrics and Gynecology Madina Teaching Hospital affiliated with University medical and Dental College Faisalabad. Period: July 2019 to December 2019. Material &amp; Method: A total number of 100 patients presented in OPD satisfying the selection criteria were enrolled in the study after permission from ethical committee. On enrollment, a detailed clinical history which include previous iron treatment including and chronic medical disorders was taken. Clinical examination was done. Investigations for anemia include hemoglobin, reticulocyte count, peripheral film and red cell indices, serum ferritin level and Hb electrophoresis if indicated. The patients were randomly divided in two groups. In group A, females were given ferric carboxymaltose and in group B, females were given iron sucrose. After calculating the total iron deficit, patients in group A were given intravenous FCM. Patients in group B were given IS. Follow up of the patient was done after 3 weeks of intravenous iron treatment. The baseline Hb and values after 3 weeks of intravenous iron treatment were compared between the FCM and IS groups and increase in Hb level calculated as mean and SD. Both groups were analyzed for rise in Hb level by using independent sample t test. P value &lt; 0.05 was taken as significant. Results: A total 100 pregnant female were found eligible for study, and were randomized into two groups of 50 each. Mean increase in hemoglobin level with ferric carboxymaltose and iron sucrose was evaluated, it shows that baseline Hb was 8.84±0.68 in Group A and 8.78 ±0.76 in Group B, P value was 0.67, after treatment Hb was 12.02±0.89 in Group A and 10.92 ±0.99 in Group B. Mean increase was 3.18 ±0.60 in Group A and 2.14±0.81 in Group B. P value was 0.001. Conclusion: Ferric carboxymaltose significantly increase Hb level and restores the iron stores as compare to iron sucreose. FCM is safe and effective intravenous treatment for iron deficiency anemia in pregnancy. FCM has the advantages of single large dose administration and fewer hospital visit. FCM is most suitable drug for the treatment of patients with IDA who required quick replenishment of iron stores.

Predicting the effects of radiotherapy based on diffusion kurtosis imaging in a xenograft mouse model of esophageal carcinoma.

The aim of the present study was to assess the predictive value of diffusion kurtosis imaging (DKI) on the effects of radiotherapy in a xenograft model of esophageal cancer. A total of 40 tumor-bearing mice, established by injection of Eca-109 cells in nude mice, were used. The experimental group (n=24) received a single dose of 15 Gy (6 MV by X-ray), and the control group (n=16) did not receive any treatment. Tumor volume, apparent diffusion coefficient (ADC), mean kurtosis (MK) and mean diffusivity (MD) of the two groups were compared, and the expression of aquaporin (AQP) 3 and necrosis ratio at matched time points in xenografts were also observed. There was a significant difference between the two groups from the 7th day of radiotherapy onwards; the xenograft volume of the experimental group was significantly smaller compared with the control group (P<0.05). On the 3rd day, the ADC and MD of the experimental group was significantly higher compared with the control group, and MK was significantly lower compared with the control group (P<0.05). On the 3rd day, AQP3 expression in the experimental group was lower compared with the control group, and the proportion of necrotic cells was higher compared with the control group (P<0.05). Single large fraction dose radiotherapy inhibited the growth of a xenografted esophageal tumor. Changes in ADC, MK and MD were observed prior to morphological changes in the tumor. The change in AQP3 expression and necrosis ratio was in also agreement with the DKI parameters assessed. DKI may thus provide early predictive ability on the effect of radiotherapy in esophageal carcinoma.

Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice.

Recent data have shown that single-fraction irradiation delivered to the whole brain in less than tenths of a second using FLASH radiotherapy (FLASH-RT), does not elicit neurocognitive deficits in mice. This observation has important clinical implications for the management of invasive and treatment-resistant brain tumors that involves relatively large irradiation volumes with high cytotoxic doses. Therefore, we aimed at simultaneously investigating the antitumor efficacy and neuroprotective benefits of FLASH-RT 1-month after exposure, using a well-characterized murine orthotopic glioblastoma model. As fractionated regimens of radiotherapy are the standard of care for glioblastoma treatment, we incorporated dose fractionation to simultaneously validate the neuroprotective effects and optimized tumor treatments with FLASH-RT. The capability of FLASH-RT to minimize the induction of radiation-induced brain toxicities has been attributed to the reduction of reactive oxygen species, casting some concern that this might translate to a possible loss of antitumor efficacy. Our study shows that FLASH and CONV-RT are isoefficient in delaying glioblastoma growth for all tested regimens. Furthermore, only FLASH-RT was found to significantly spare radiation-induced cognitive deficits in learning and memory in tumor-bearing animals after the delivery of large neurotoxic single dose or hypofractionated regimens. The present results show that FLASH-RT delivered with hypofractionated regimens is able to spare the normal brain from radiation-induced toxicities without compromising tumor cure. This exciting capability provides an initial framework for future clinical applications of FLASH-RT.See related commentary by Huang and Mendonca, p. 662.

Suppression of IgE-mediated anaphylaxis and food allergy with monovalent anti-FcεRIα mAbs

Mast cell and basophil activation by antigen cross-linking of FcεRI-bound IgE is central to allergy pathogenesis. We previously demonstrated global suppression of this process by rapid desensitization with anti-FcεRIα mAbs. We sought to determine whether use of monovalent (mv) anti-FcεRIα mAbs increases desensitization safety without loss of efficacy. mv anti-human (hu) FcεRIα mAbs were produced with mouse-derived immunoglobulin variable regions and huIgG1 or huIgG4 C regions and were used to suppress murine IgE-mediated anaphylaxis and food allergy. mAbs were administered as a single dose or as serially increasing doses to mice that express hu instead of mouse FcεRIα; mice that additionally have an allergy-promoting IL-4Rα mutation; and hu cord blood-reconstituted immunodeficient, hu cytokine-secreting, mice that have large numbers of activated hu mast cells. Anaphylaxis susceptibility was sometimes increased by treatment with IL-4 or a β-adrenergic receptor antagonist. mv anti-hu FcεRIα mAbs are considerably less able than divalent mAbs are to induce anaphylaxis and deplete mast cell and basophil IgE, but mv mAbs still strongly suppress IgE-mediated disease. The mv mAbs can be safely administered as a single large dose to mice with typical susceptibility to anaphylaxis, while a rapid desensitization approach safely suppresses disease in mice with increased susceptibility. Our huIgG4 variant of mv anti-huFcεRIα mAb is safer than our huIgG1 variant is, apparently because reduced interactions with FcεRs decrease ability to indirectly cross-link FcεRI. mv anti-FcεRIα mAbs more safely suppress IgE-mediated anaphylaxis and food allergy than divalent variants of the same mAbs do. These mv mAbs may be useful for suppression of huIgE-mediated disease.

Radionecrosis and cellular changes in small volume stereotactic brain radiosurgery in a porcine model

Stereotactic radiosurgery (SRS) has proven an effective tool for the treatment of brain tumors, arteriovenous malformation, and functional conditions. However, radiation-induced therapeutic effect in viable cells in functional SRS is also suggested. Evaluation of the proposed modulatory effect of irradiation on neuronal activity without causing cellular death requires the knowledge of radiation dose tolerance at very small tissue volume. Therefore, we aimed to establish a porcine model to study the effects of ultra-high radiosurgical doses in small volumes of the brain. Five minipigs received focal stereotactic radiosurgery with single large doses of 40–100 Gy to 5–7.5 mm fields in the left primary motor cortex and the right subcortical white matter, and one animal remained as unirradiated control. The animals were followed-up with serial MRI,PET scans, and histology 6 months post-radiation. We observed a dose-dependent relation of the histological and MRI changes at 6 months post-radiation. The necrotic lesions were seen in the grey matter at 100 Gy and in white matter at 60 Gy. Furthermore, small volume radiosurgery at different dose levels induced vascular, as well as neuronal cell changes and glial cell remodeling.

Inhibition of rat brain and human red cell acetylcholinesterase by thiocarbamate herbicides.

Thiocarbamates are a major class of herbicides that were used extensively in the agricultural industry. Toxicological evaluation showed molinate caused reproductive impairment in male rats, whilst others produced behavioural effects at high doses. Rats dosed with molinate either as a single large oral dose of 100mg/kg or as multiple doses of 50mg/kg for 7 days produced inhibition of brain acetylcholinesterase (AChE). Molinate and other thiocarbamate herbicides undergo metabolism to form sulphoxides that can carbamoylate thiol's such as glutathione and proteins. We have chemically synthesised the sulphoxide and sulphone metabolites of six thiocarbamate herbicides and examined their ability to inhibit rat brain and human red cell AChE in vitro. Parent thiocarbamates were inactive, whilst the sulphoxides produced inhibition with IC50's in the 1-10mM range, the sulphone metabolites were the most active with IC50's for molinate, pebulate, EPTC and vernolate in the μM range. Inhibition was both time- and dose-dependent with biomolecular rate constants for the inhibition of the human red cell enzyme of 0.3×102 and 2.0×102M-1min-1 for molinate sulphoxide and sulphone, respectively. No recovery of enzyme activity, with either enzyme, was seen following dilution of the inhibitor to a concentration that does not inhibit the enzyme for up to 24h at 25°C at pH7.4. The metabolites of these thiocarbamate herbicides are rather poor inhibitors of AChE when compared to the organophosphorus ester, paraoxon or the monomethylcarbamate, eserine. Unlike eserine the inhibition produced by the thiocarbamates is irreversible.

No Longterm Severe Thyroid Dysfunction Seen In Patients With Preexisting Reduced Serum Tt3 Concentrations After A Single Large Dose Of Iodinated Contrast

After an intravenous bolus injection of 100 mL of iodinated contrast agent (370 mgI/mL), the amount of iodine atoms entering the blood is tens of thousands of times the daily dose of iodine recommended by the World Health Organization. However, the effect of iodinated contrast in patients with nonthyroidal illness, manifested as reduced serum total triiodothyronine (TT3) concentrations, is unclear. We studied the effect of iodinated contrast on thyroid function and auto-antibodies in patients with reduced TT3 after diagnosis and treatment of coronary heart disease. This was a prospective cohort study. One hundred and fifty-four stable angina pectoris patients with reduced TT3 and normal thyroid-stimulating hormone (TSH), free thyroxine (FT4), and reverse triiodothyronine (rT3) were enrolled from January, 2017, to June, 2018. All subjects had no history of thyroid dysfunction and had no recent infections, tumors, trauma, or other critical illnesses. Fourty-one patients underwent coronary angiography and 113 patients underwent coronary intervention. There were 6 patients (3.9%) with hypothyroidism and 30 patients (19.5%) developed subclinical hypothyroidism (SCHypo) on the first day after surgery. There were 6 patients (3.9%) with hypothyroidism, 6 patients (3.9%) with SCHypo, and 18 patients (11.7%) with subclinical hyperthyroidism (SCHyper) at the first month postsurgery. There were 23 patients (14.9%) with SCHyper and 6 patients (3.9%) with SCHypo at the sixth month after surgery. No patient with longterm severe thyroid dysfunction occurred during follow-up. The levels of free triiodothyronine, FT4, TT3, total thyroxine, and TSH showed statistically significant changes at 1 day, and 1, 3, and 6 months postoperative (P<.005). The level of rT3 showed no statistically significant change at 1, 3, and 6 months postoperative (P>.05). The levels of thyroglobulin antibody and thyroid peroxidase antibody decreased at 6 months postoperative (P<.001). The risk of subclinical thyroid dysfunction and transient hypothyroidism occurred with a single large dose of iodinated contrast in the diagnosis and treatment of coronary heart disease, but no longterm severe thyroid dysfunction occurred. Patients with preoperative thyroid antibody elevation were more likely to have subclinical thyroid dysfunction after surgery. FT3 = free triiodothyronine; FT4 = free thyroxine; PCI = percutaneous coronary intervention; rT3 = reverse triiodothyronine; SCHyper = subclinical hyperthyroidism; SCHypo = subclinical hypothyroidism; TGAB = thyroglobulin antibody; TPOAB = thyroid peroxidase antibody; TT3 = total triiodothyronine; TT4 = total thyroxine; TSH = thyroid-stimulating hormone; WHO = World Health Organization.