scholarly journals 2167 Beyond diagnosis: Using ultrasound to affect tumor vasculature for hepatocellular carcinoma (HCC) therapy

2018 ◽  
Vol 2 (S1) ◽  
pp. 5-6
Author(s):  
Julia D’Souza ◽  
Laith Sultan ◽  
Sean Carlin ◽  
Terence Gade ◽  
Stephen Hunt ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dose Group ◽  
Low Dose ◽  
Tissue Injury ◽  
Power Doppler ◽  
Tumor Vasculature ◽  
High Dose ◽  
Differential Effects ◽  
Low Intensity ◽  
High Doses

OBJECTIVES/SPECIFIC AIMS: Preliminary animal studies showed that low-intensity ultrasound (US) coincident with intravascularly administered microbubbles locally disrupts tumor vasculature. This study translates the novel therapy of antivascular ultrasound (AVUS) into an autochthonous model of hepatocellular carcinoma (HCC). The differential effects produced by AVUS at low and high doses are evaluated. METHODS/STUDY POPULATION: HCC was induced in 12 Wistar rats by ingestion of 0.01% diethylnitrosamine in drinking water for 12 weeks. Rats received AVUS treatment at low and high doses. Low dose group (n=6) received 1 W/cm2 US for 1 minute with 0.2 mL microbubbles injected IV. High dose group (n=6) received 2 W/cm2 for 2 minute with 0.7 mL microbubbles IV. Perfusion was measured before and after AVUS with contrast-enhanced ultrasound (CE-US) and power Doppler (PD-US). Peak enhancement (PE) and perfusion index (PI) were measured from each US mode. Histology after sacrifice or natural death was compared to pre/post US. Analysis of H&E and trichrome sections was evaluated for percent area of hemorrhage and findings of tissue injury and repair including inflammation, necrosis, and fibrosis. RESULTS/ANTICIPATED RESULTS: After high dose AVUS, PE, and PI of CE-US decreased from baseline by an average of 33.3% and 29.7%, respectively. Histology showed extensive tissue injury (hemorrhage, necrosis, fibrosis) in 58% of tumor cross-sectional area. Conversely, low dose AVUS increased PE and PI of CE-US by an average of 39.3% and 67.8%, respectively. Histology showed smaller areas of microhemorrhage Versus large pools of hemorrhage (only 17% area). PD-US changes were similar to CE-US. DISCUSSION/SIGNIFICANCE OF IMPACT: In summary, the opposing effects of AVUS observed at 2 doses allows for multiple roles in tumor therapy. Enhanced perfusion at a low dose may improve drug delivery or radiation therapy. Whereas, vascular disruption at high doses of AVUS may allow noninvasive ischemic therapy. Furthermore, AVUS is ripe for translation given the use its component parts clinically: low-intensity long-tone burst for physiotherapy and microbubbles as an US contrast agent. Thus, AVUS should be evaluated for translation of its differential effects into noninvasive therapies for HCC and other tumors.

scholarly journals Evaluation of the BDNF, NGF, NT3 and NT4 Genes Expressions in the Brains of Neonatal Mice with Hypothyroidism

2017 ◽  
Vol 7 (1) ◽  
pp. 171
Author(s):  
Hamid Reza Adeli Bhroz ◽  
Kazem Parivar ◽  
Iraj Amiri ◽  
Nasim Hayati Roodbari
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Pure Water ◽  
Intervention Group ◽  
Control Group ◽  
High Dose ◽  
Endocrine Glands ◽  
Blood Samples ◽  
High Doses ◽  
The Brain

Background and Aim: Thyroid is one of the endocrine glands, (T3 and T4) play a significant role in the development of prenatal brain and the following stages. The study aimed to evaluate the effect of hypothyroidism on the amount of expression of NT4, NT3, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in brain of one-day rat neonates with hypothyroidism.Materials and Methods: In total, 25 mature mice of Albino NMRI race were selected after mating, divided into three group, control, as well as low-dose and high-dose intervention groups. Samples of the control group received pure water during pregnancy, whereas subjects of the intervention group with low and high doses of the medication were administered with 20 mg and 100 mg methimazole powder (dissolved in 100 cc water), respectively. After child delivery, blood samples were obtained from mother mice to determine the level of T3 and T4 in blood serum. Following that, the brain of one-day mice were removed by surgery and assessed to determine the amount of expression of NT4, NT3, NGF and BDNF using the complete kit of RT-PCR.Results: Levels of T4 and T3 in the control group were 28 ug/dl and 1.59 ug/dl, respectively. In the low-dose intervention group, the amounts of the mentioned hormones were 8 ug/dl and 0.85 ug/dl, significantly, indicating a significant reduction in the expression of NT4, NT3, NGF and BDNF genes, compared to the control group. Moreover, T4 and T3 were 6 ug/dl and 0.79 ug/dl in the high-dose group, respectively, conveying a significant decrease in the expression of NT4, NT3, NGF and BDNF genes, compared to the control group (P<0.05).

scholarly journals CD8+ T Cells Mediate Recovery andImmunopathology in West Nile VirusEncephalitis

2003 ◽  
Vol 77 (24) ◽  
pp. 13323-13334 ◽  
Author(s):  
Yang Wang ◽  
Mario Lobigs ◽  
Eva Lee ◽  
Arno Müllbacher
Keyword(s):  
T Cells ◽  
Dose Group ◽  
Low Dose ◽  
Neuronal Degeneration ◽  
High Dose ◽  
West Nile ◽  
Activation Markers ◽  
High Doses ◽  
The Brain ◽  
Deficient Mice

ABSTRACT C57BL/6J mice infected intravenously with the Sarafend strain of West Nile virus (WNV) develop a characteristic central nervous system (CNS) disease, including an acute inflammatory reaction. Dose response studies indicate two distinct kinetics of mortality. At high doses of infection (108 PFU), direct infection of the brain occurred within 24 h, resulting in 100% mortality with a 6-day mean survival time (MST), and there was minimal destruction of neural tissue. A low dose (103 PFU) of infection resulted in 27% mortality (MST, 11 days), and virus could be detected in the CNS 7 days postinfection (p.i.). Virus was present in the hypogastric lymph nodes and spleens at days 4 to 7 p.i. Histology of the brains revealed neuronal degeneration and inflammation within leptomeninges and brain parenchyma. Inflammatory cell infiltration was detectable in brains from day 4 p.i. onward in the high-dose group and from day 7 p.i. in the low-dose group, with the severity of infiltration increasing over time. The cellular infiltrates in brain consisted predominantly of CD8+, but not CD4+, T cells. CD8+ T cells in the brain and the spleen expressed the activation markers CD69 early and expressed CD25 at later time points. CD8+ T-cell-deficient mice infected with 103 PFU of WNV showed increased mortalities but prolonged MST and early infection of the CNS compared to wild-type mice. Using high doses of virus in CD8-deficient mice leads to increased survival. These results provide evidence that CD8+ T cells are involved in both recovery and immunopathology in WNV infection.

Effects of long-term continuous GnRH administration on the pituitary–gonadal axis in Eld's deer stags (Cervus eldi thamin)

1995 ◽  
Vol 73 (9) ◽  
pp. 1609-1619 ◽  
Author(s):  
S. L. Monfort ◽  
J. L. Brown ◽  
T. C. Wood ◽  
M. Bush ◽  
L. R. Williamson ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Fertile Period ◽  
Nonbreeding Season ◽  
Testosterone Secretion ◽  
High Doses ◽  
Seasonal Decline ◽  
Seasonally Breeding

Eld's deer stags (Cervus eldi thamin) (in groups of three) were continuously administered gonadotropin-releasing hormone (GnRH) in control, low, medium, or high doses (0, 20.1 ± 0.7, 83.3 ± 2.6, and 292.9 ± 4.9 ng∙kg−1∙d−1, respectively) via osmotic minipumps for ~80 d to investigate the potential for precociously reactivating the pituitary–testicular axis during the nonbreeding season. Secretory patterns of LH, FSH, and testosterone concentrations were qualitatively similar among treatments. However, in the low-dose group, basal LH and FSH concentrations were both increased (p < 0.05) and pituitary responsiveness to a superimposed GnRH challenge was augmented (p < 0.05) after 12 weeks of treatment compared with all other groups. Despite these endocrine changes, continuous low-dose GnRH administration was not effective for precociously inducing testicular activity in this seasonally breeding species. High-dose GnRH administration initially induced a transient increase in LH, FSH, and testosterone secretion and delayed, but did not prevent, the seasonal decline in spermatogenesis. After 6–12 weeks of high-dose GnRH administration, however, attenuated pituitary responsiveness appeared to delay the normal seasonal reactivation of the pituitary–gonadal axis. In conclusion, prolonged, continuous low-dose GnRH administration did not effectively translate into a precocious onset of testicular activity; therefore, this specific approach is unlikely to be useful for prolonging the fertile period in this seasonally breeding species.

Extravasation Injury Associated with Low-Dose Dopamine

1998 ◽  
Vol 32 (5) ◽  
pp. 545-548 ◽  
Author(s):  
Julie L Chen ◽  
Marianne O'Shea
Keyword(s):  
Low Dose ◽  
Tissue Injury ◽  
Case Reports ◽  
Blood Perfusion ◽  
High Dose ◽  
Dopamine Infusion ◽  
Tissue Ischemia ◽  
Large Vein ◽  
High Concentrations ◽  
High Doses

OBJECTIVE: To describe the occurrence of extravasation in two patients receiving low-dose dopamine infusions. CASE SUMMARY: Intravenous dopamine was infused peripherally (in the antecubital fossa) to two patients in the cardiac intensive care unit in an attempt to enhance renal blood perfusion and urine output. Dopamine extravasation occurred in both patients while the low dose (<3 μg/kg/min) was infused. Significant local tissue injury was observed in both patients. DISCUSSION: Dopamine infusion can cause tissue ischemia or necrosis secondary to vasospasm and extravasation. Most of the case reports in the literature have occurred when relatively high doses of dopamine were infused. Only one reported extravasation-induced injury with low-dose dopamine. Although low-dose dopamine has a vasodilatory effect in selected tissues, high concentrations achieved locally as a result of extravasation can still cause severe vasoconstriction and ischemic tissue injury. CONCLUSIONS: Low-dose dopamine therapy should be administered with similar precautions as high-dose dopamine. A central intravenous access should be placed for dopamine infusion whenever possible. If this approach is not feasible, dopamine should be infused only peripherally through a long intravenous catheter into a large vein. A 5-cm angiocatheter that is 20 gauge or larger is recommended for peripheral dopamine infusion in our institution. The infusion site should be inspected frequently for early detection of extravasation, and changed to a central or a peripherally inserted central catheter as soon as possible, especially in patients at high risk for extravasation.

Preliminary results of sintilimab plus different dose of IBI305 (anti-VEGF monoclonal antibody) in patients with advanced hepatocellular carcinoma: A phase Ib study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3079-3079 ◽  
Author(s):  
Wen Zhang ◽  
Xinyu Bi ◽  
Yongkun Sun ◽  
Yue Yu ◽  
Jian-guo Zhou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dose Group ◽  
Low Dose ◽  
Objective Response ◽  
High Dose Group ◽  
High Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Dose Selection ◽  
Anti Vegf ◽  
Treatment Naïve

3079 Background: The study aimed to evaluate the safety and efficacy of sintilimab, a PD-1 blockade, plus IBI305, a biosimilar candidate of bevacizumab, in patients (pts) with advanced hepatocellular carcinoma (HCC). Methods: Adults with histocytologically confirmed advanced or metastatic HCC were enrolled in this two-part study. Part 1 was dose escalation trial, with initial dose of sintilimab 200 mg plus IBI305 7.5 mg/kg, q3w (low-dose group). If tolerable, IBI305 was escalated to 15 mg/kg (high-dose group). In part 2 for extension, at least 20 pts were enrolled to each tolerable dose group. Results: As data cutoff (Jan. 7, 2020), 50 pts were enrolled, 29 in low-dose group and 21 in high-dose group. 41 patients were systemic treatment naïve. The median treatment cycle was 4 (range: 1-19) in low-dose group and 11 (range: 1-16) in high-dose group. Most TRAEs were G1-2 with the most common being hypertension (28.0%) and pyrexia (26.0%). Totally, the grade 3 or more TRAEs were occurred in 6 (12.0%) pts, including hypertension occurred in 2 (4%) pts. The objective response rate (ORR) per RECIST v1.1 was 24.1% (95%CI: 10.3 - 43.5) in low-dose group, and 33.3% (95% CI:13.3 - 59.0) in high-dose group. As with the cutoff date, the median PFS has not been reached and the 6-month PFS rates were 60.5% (95%CI 36.1, 78.0) and 75.8% (95% CI: 47.3, 90.2), respectively. Conclusions: The combination of sintilimab and IBI305 showed promising efficacy and favourable safety profile in advanced HCC in both low-dose and high-dose groups. The preliminary result of this study warrant further exploration of dose selection for anti-VEGF/VEGFR agent when combined with PD-1/PD-L1 antibody. Clinical trial information: NCT04072679 . [Table: see text]

scholarly journals Effect of Acrylamide Supplementation on the CART-, VAChT-, and nNOS-Immunoreactive Nervous Structures in the Porcine Stomach

Animals ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 555 ◽  
Author(s):  
Katarzyna Palus ◽  
Michał Bulc ◽  
Jarosław Całka
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Daily Intake ◽  
Food Products ◽  
Enteric Neurons ◽  
Control Group ◽  
High Dose ◽  
Double Immunofluorescence ◽  
High Temperature Processing ◽  
High Doses

Acrylamide is found in food products manufactured with high-temperature processing, and exposure to acrylamide contained in food products may cause a potential risk to human health. The aim of this investigation was to demonstrate the changes in the population of CART-, nNOS-, and VAChT-immunoreactive enteric neurons in the porcine stomach in response to supplementation of low and high acrylamide doses. The study was carried out with 15 Danish landrace gilts divided into three experimental groups: the control group—animals were administered empty gelatine capsules; the low-dose group—animals were administrated a tolerable daily intake (TDI) dose (0.5 µg/kg of body weight (b.w.)/day) of acrylamide capsules, and the high-dose group—animals were administrated high-dose (ten times higher than TDI: 5 µg/kg b.w./day) acrylamide capsules for 28 days. Using the double immunofluorescence staining method, it was established that supplementation with low and high doses of acrylamide resulted in alterations of the porcine stomach neuron phenotype, which was reflected in an increased number of CART-, VAChT-, and nNOS-immunoreactive neurons. These changes were accompanied by an increased density of CART-, VAChT-, and nNOS-positive fibres. The results suggest that the enteric nervous system plays an important role in protecting the gastrointestinal tract during acrylamide intoxication.

Impact of high doses of Statins on testosterone level in males with atherosclerotic coronary artery disease

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Walid Said Ibrahim ◽  
Mohamed Moustafa Farouk ◽  
Mazen Tawfik ◽  
Sherif Samir Elzahwy
Keyword(s):  
Testosterone Level ◽  
Dose Group ◽  
Low Dose ◽  
De Novo ◽  
Medical Center ◽  
Health Effect ◽  
High Dose Group ◽  
High Dose ◽  
High Doses ◽  
The Impact

Abstract Background Concern has always existed that statins might impair testosterone production either by reducing availability of its preferred substrate, that is, locally produced de novo cholesterol in the gonads and elsewhere, or by inhibiting steps in the steroidogenesis process, but this concern has been considered of little clinical significance. Objective To demonstrate the impact of high doses of statins on testosterone level in ischemic heart disease patients and to compare it with the impact of low doses of statins. Patients and Methods This study was approved by Ain Shams University. 90 candidates were randomly enrolled in the study divided into two groups, high dose group consisting of 45 patients and Low dose group including 45 patients. All patients were recruited from International Medical Center in Cairo, they were selected randomly from the outpatient clinic from the cardiology department. Results In our study there were a significant reduction in total cholesterol, LDL and TGs in both low dose and high dose groups, but the effect on testosterone was quite different between them, the reduction in testosterone was about 33% from the baseline in the high dose group while in the low dose there was no significant reduction in the testosterone level. Conclusion This study shows that statins reduce testosterone level. This finding does not demonstrate that androgens mediate any health effect of statins, but raises the question as to whether testosterone modulation plays a role in statins' effects on health, particularly among men where testosterone is an important hormone.

Intensive Initial Oral Anticoagulation and Shorter Heparin Treatment in Deep Vein Thrombosis

1984 ◽  
Vol 52 (03) ◽  
pp. 276-280 ◽  
Author(s):  
Sam Schulman ◽  
Dieter Lockner ◽  
Kurt Bergström ◽  
Margareta Blombäck
Keyword(s):  
Deep Vein Thrombosis ◽  
Oral Anticoagulation ◽  
Dose Group ◽  
Low Dose ◽  
Clinical Signs ◽  
Coagulation Factor ◽  
High Dose ◽  
Vein Thrombosis ◽  
Heparin Treatment ◽  
Deep Vein

SummaryIn order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation (“low-dose”) and heparin or a more intense oral anticoagulation (“high-dose”) with a shorter period of heparin treatment.In the first part of the study 129 patients were randomized. The “low-dose” group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the “high-dose” group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis.In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 (“low-dose”) and 3.7 (“high-dose”) days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred.Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.

scholarly journals Newly Developed Recombinant Antithrombin Protects the Endothelial Glycocalyx in an Endotoxin-Induced Rat Model of Sepsis

2020 ◽  
Vol 22 (1) ◽  
pp. 176
Author(s):  
Toshiaki Iba ◽  
Jerrold H. Levy ◽  
Koichiro Aihara ◽  
Katsuhiko Kadota ◽  
Hiroshi Tanaka ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Leukocyte Adhesion ◽  
Endothelial Glycocalyx ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Protective Effects ◽  
Circulating Levels

(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.

High-dose statin therapy and the risk of haemorrhagic stroke in Asian patients with stable coronary artery disease: insights from the REAL-CAD study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Takahashi ◽  
K Tsuchida ◽  
Y Sato ◽  
S Iimuro ◽  
K Kario ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Dose Group ◽  
Low Dose ◽  
Japanese Patients ◽  
Haemorrhagic Stroke ◽  
High Dose ◽  
The Real ◽  
Artery Disease ◽  
Stable Cad ◽  
Bleeding Score

Abstract Background/Introduction The REAL-CAD study identified that aggressive lipid lowering with high-dose statin reduced cardiovascular events also in Japanese patients with coronary artery disease (CAD). However, data from the SPARCL trial found that the benefits of high-dose atorvastatin treatment were partially offset by an increase in haemorrhagic stroke (HS). Although meta-analysis showed statin does not increase HS in Western countries, the evidence about the relation between statin and HS in Asian countries is still conflicting. In addition, the CREDO-Kyoto score is one of the prediction scorings for bleeding after coronary revascularization and might be a useful tool for the prediction of HS in this cohort. Recognizing the risk of HS and predicting of HS in the Asian cohort is clinically important. Purpose This study examined the factors associated with HS using the REAL-CAD cohort. Furthermore, we evaluated the performance of the CREDO-Kyoto bleeding risk score to predict HS in this cohort. We also performed the corresponding analysis of ischaemic stroke for reference purposes. Methods We sub-analysed the REAL-CAD study, prospective, multicentre, randomized, open-label, blinded endpoint study, in which 13,054 Japanese patients with stable CAD were randomized to high-dose (4 mg/day) or low-dose (1 mg/day) pitavastatin. Associations for stroke were determined using competing risk models: the Fine and Gray subdistribution hazards model accounting for the competing risk of death in models of haemorrhagic and ischaemic stroke in REAL-CAD trial. Patients were categorized to low (score 0), moderate (score 1–2), and high (score&gt;3) according to CREDO-Kyoto bleeding score for predicting of HS. Results The HS events in high-dose group tended to be higher than low-dose group (4mg vs. 1mg: 43 (0.7%) vs. 30 (0.5%)). The associated factors of HS on univariate analysis were non-prior myocardial (hazard ratio (HR): 0.62, 95% CI: 0.39–0.99) and non-prior cerebral (HR: 0.25, 95% CI: 0.09–0.70) infarction, atrial fibrillation (HR: 2.4, 95% CI: 1.2–4.7), prior HS (HR: 4.2, 95% CI: 1.5–11.8), anaemia (HR: 2.4, 95% CI: 1.4–4.1), and non-statins use before run-in period (HR: 0.52, 95% CI: 0.28–0.99). High-dose pitavastatin was not a correlate with HS. The multivariate analysis revealed anaemia might have a relation with HS (HR: 4.3, 95% CI: 0.90–20.6). The number of HS was the highest in the high CREDO-Kyoto bleeding score group (Figure 1, HR: 2.4, 95% CI: 1.3–4.6), whereas there was no significant difference in the number of HS between the moderate- and low-risk groups (HR: 1.4, 95% CI: 0.84–2.3). Conclusions High-dose pitavastatin was not associated with the incidence of HS in this large Japanese cohort with stable CAD. High CREDO-Kyoto bleeding score was associated with HS as compared with low or moderate scores, even each of the variables consisting of CREDO-Kyoto score was not associated with HS. Figure 1 Funding Acknowledgement Type of funding source: None

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