scholarly journals High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in Pex1-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 40
Author(s):  
Tanguy Demaret ◽  
Jonathan Evraerts ◽  
Joachim Ravau ◽  
Martin Roumain ◽  
Giulio G. Muccioli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Low Dose ◽  
Genetic Alterations ◽  
Hepatocyte Transplantation ◽  
High Dose ◽  
Nmri Mouse ◽  
History Of ◽  
Spectrum Disorders ◽  
Zellweger Spectrum Disorders

Genetic alterations in PEX genes lead to peroxisome biogenesis disorder. In humans, they are associated with Zellweger spectrum disorders (ZSD). No validated treatment has been shown to modify the dismal natural history of ZSD. Liver transplantation (LT) improved clinical and biochemical outcomes in mild ZSD patients. Hepatocyte transplantation (HT), developed to overcome LT limitations, was performed in a mild ZSD 4-year-old child with encouraging short-term results. Here, we evaluated low dose (12.5 million hepatocytes/kg) and high dose (50 million hepatocytes/kg) syngeneic male HT via intrasplenic infusion in the Pex1-G844D NMRI mouse model which recapitulates a mild ZSD phenotype. HT was feasible and safe in growth retarded ZSD mice. Clinical (weight and food intake) and biochemical parameters (very long-chain fatty acids, abnormal bile acids, etc.) were in accordance with ZSD phenotype but they were not robustly modified by HT. As expected, one third of the infused cells were detected in the liver 24 h post-HT. No liver nor spleen microchimerism was detected after 7, 14 and 30 days. Future optimizations are required to improve hepatocyte engraftment in Pex1-G844D NMRI mouse liver. The mouse model exhibited the robustness required for ZSD liver-targeted therapies evaluation.

scholarly journals Differences in Therapeutic Efficacy in Pancreatic Cancer Between Interstitial and Superficial Light Delivery Strategies in Targeted Photo Therapy

2018 ◽  
Author(s):  
Nzola De Magalhães ◽  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Low Dose ◽  
Near Infrared ◽  
High Dose ◽  
Signal Recovery ◽  
Light Delivery ◽  
Fixed Power ◽  
Delivery Strategies

AbstractThe purpose of this study was to determine if therapeutic efficacy of a Cetuximab based near-infrared (NIR) targeted photo therapy (TPT) was dependent on light delivery strategies. We examined the cytotoxic effects of TPT in a pancreatic cancer mouse model, when administered to tumors interstitially and superficially.A subcutaneous mouse model of pancreatic cancer using BXPC-3 -GFP cells was established in male athymic (nu/nu) mice. The mice received intravenous (IV) injection of Cetuximab-IR700DX, 24 hours prior to near-infrared light irradiation. Interstitial illumination was administered at a 400mW/cm fixed power output, at a light dose of 100 J/cm to half the mice and at 300 J/cm to the remaining mice. Superficial illumination was administered at a 150mw/cm2 fixed power density at a dose of 50 J/cm2 to half the mice, and at 250 J/cm2 to the other half. Cellular damage and decrease in cell viability was determined by the decrease in GFP fluorescence intensity levels in whole animal images and in relative intensity measurements.Interstitially administered TPT resulted in greater long-term permanent damage (72 hours post treatment) to tumor cells (0% recovery at low dose, and 11% recovery at high dose) compared to superficially administered TPT (1% recovery at low dose, and 44% recovery at high dose). While these results demonstrated that near-infrared targeted photo therapy efficacy was dependent on the type of light delivery strategy, overall, both superficial and interstitial Cet-IR700DX based near-infrared targeted photo therapy can effect significant long-term damage (less signal recovery) to pancreatic cancer cells in vivo at lower doses regimens, compared to higher dose regimens (higher signal recovery).

Long Term Infectious Complications Following Reduced Intensity Conditioning (RIC) Allogeneic HLA-Identical Sibling Transplantation (allo-SCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2850-2850
Author(s):  
Anne Etienne ◽  
Mohamad Mohty ◽  
Catherine Faucher ◽  
Sabine Furst ◽  
Jean El-Cheikh ◽  
...  
Keyword(s):  
Low Dose ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Prior History ◽  
High Dose ◽  
Infectious Episode ◽  
Donor Bone Marrow ◽  
Increased Risk ◽  
History Of

Abstract In the setting of RIC for allo-SCT, long term outcomes are still poorly defined. Of note, the epidemiology of long term transplant-related infections is still sparse. This prospective report describes infectious complications occurring beyond 6 months after allo-SCT, in 159 consecutive patients who received a RIC allo-SCT from an HLA-identical sibling. Patients characteristics are as follow: median age was 50 (range, 18–68) years. 68 patients (43%) had a myeloid malignancy, whereas 66 patients (41%) had a lymphoid malignancy. The remaining 25 patients (16%) were treated for metastatic non-hematological malignancies. The majority of patients (n=126, 79%) had an advanced disease with high risk features precluding the use of myeloablative allo-SCT. 24 patients (15%) received donor bone marrow (BM), while the remaining 135 patients (85%) received PBSCs. In addition to fludarabine and busulfan, the RIC regimen included high dose ATG in 20 patients (13%) and low dose ATG in 95 (60%). 24 patients (15%) received fludarabine, busulfan and TLI, while the remaining 24 patients (15%) received fludarabine and low dose TBI. With a median follow-up of 19 (range, 6–90) months, 120 patients (75%) experienced at least one infectious episode (total number of episodes, 366) beyond the first six months after allo-SCT developing at a median of 8 (range, 6–34) months. In all, 212 infectious episodes (58%) required hospitalization (7% in the intensive care unit) for a median duration of 10 (1–91) days. 144 episodes (39%) could be documented (bacterial, n=48; viral, n=78; fungal, n=18). Microbiologically documented infections were distributed as follow: gram negative bacteria (18%), other bacteria (15%), CMV positive antigenemia (17%), HSV (19%), VZV (15%), other viruses (3%), aspergillus (6%), candida species (6%), other (1%). 76% of patients with an infection were under systemic immunosuppressive therapy for chronic GVHD at time of infection. Moreover, 85 patients (71%) experienced more than one infectious episode (median, 2; range, 1–12). In multivariate analysis, active or prior history of extensive chronic GVHD and the use of a BM graft were the strongest factors significantly associated with an increased risk of long term infections (P=0.0003; RR=2.04; 95%CI, 1.4–3.0; and P=0.005; RR=2; 95%CI, 1.2–3.2 respectively), highlighting the raising concern about the deleterious impact of severe chronic GVHD occurring after RIC allo-SCT, but also the protective effect of donor origin immunity based on graft origin and content. In this series of patients surviving at least 6 months after RIC allo-SCT, the overall long term transplant-related mortality was 11% (n=18), of whom 12 deaths were attributed to chronic GVHD and its complications including infections, and 5 deaths solely attributed to infections. In all, these results suggest that, despite reduction in early toxicity associated with the use of RIC regimens, long term debilitating chronic GVHD and its corollary of continuous immunosuppression and subsequent infections are still a matter of concern. Prospective efforts to develop optimal antimicrobial preventive strategies are needed to further improve the safety of the procedure and the overall benefits of RIC preparative regimens before allo-SCT.

scholarly journals The Effect of Long-Term Low-Dose Atropine on Refractive Progression in Myopic Australian School Children

2021 ◽  
Vol 10 (7) ◽  
pp. 1444
Author(s):  
William Myles ◽  
Catherine Dunlop ◽  
Sally A. McFadden
Keyword(s):  
Low Dose ◽  
High Dose ◽  
Eye Drops ◽  
Myopia Progression ◽  
At Risk Children ◽  
Slow Group ◽  
Blue Eyes ◽  
Global Population ◽  
Axial Growth

Myopia will affect half the global population by 2050 and is a leading cause of vision impairment. High-dose atropine slows myopia progression but with undesirable side-effects. Low-dose atropine is an alternative. We report the effects of 0.01% or 0.005% atropine eye drops on myopia progression in 13 Australian children aged between 2 and 18 years and observed for 2 years without and up to 5 years (mean 2.8 years) with treatment. Prior to treatment, myopia progression was either ‘slow’ (more positive than −0.5D/year; mean −0.19D/year) or ‘fast’ (more negative than −0.5D/year; mean −1.01D/year). Atropine reduced myopic progression rates (slow: −0.07D/year, fast: −0.25D/year, combined: before: −0.74, during: −0.18D/year, p = 0.03). Rebound occurred in 3/4 eyes that ceased atropine. Atropine halved axial growth in the ‘Slow’ group relative to an age-matched model of untreated myopes (0.098 vs. 0.196mm/year, p < 0.001) but was double that in emmetropes (0.051mm/year, p < 0.01). Atropine did not slow axial growth in ‘fast’ progressors compared to the age-matched untreated myope model (0.265 vs. 0.245mm/year, p = 0.754, Power = 0.8). Adverse effects (69% of patients) included dilated pupils (6/13) more common in children with blue eyes (5/7, p = 0.04). Low-dose atropine could not remove initial myopia offsets suggesting treatment should commence in at-risk children as young as possible.

Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers

1987 ◽  
Vol 17 (4) ◽  
pp. 869-873 ◽  
Author(s):  
C. Schmauss ◽  
J.-C. Krieg
Keyword(s):  
Low Dose ◽  
Matched Control ◽  
Control Group ◽  
High Dose ◽  
Withdrawal Therapy ◽  
The Mean ◽  
Dose Dependent ◽  
Dose Dependent Effect ◽  
Age And Sex

SynopsisIn 17 benzodiazepine (BDZ) dependent in-patients a CT scan was performed before initiation of withdrawal therapy. The evaluation of the ventricular to brain ratio (VBR) by standardized and computerized measurements revealed significantly higher mean VBRs for both high-and low-dose BDZ-dependent patients compared to the mean VBR of an age- and sex-matched control group. In addition, the mean VBR of high-dose BDZ-dependent patients (N = 8) was significantly higher than the mean VBR of low-dose BDZ-dependent patients (N = 9). This difference could not be accounted for by the age of the patients or duration of BDZ-dependency and, therefore, suggests a dose-dependent effect of BDZs on the enlargement of internal CSF-spaces. On the other hand, higher values for the width of external CSF-spaces were found to be related to increasing age of the patients and duration of BDZ-dependency.

scholarly journals Advantages of Repeated Low Dose against Single High Dose of Kainate in C57BL/6J Mouse Model of Status Epilepticus: Behavioral and Electroencephalographic Studies

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e96622 ◽  
Author(s):  
Karen Tse ◽  
Sreekanth Puttachary ◽  
Edward Beamer ◽  
Graeme J. Sills ◽  
Thimmasettappa Thippeswamy
Keyword(s):  
Status Epilepticus ◽  
Mouse Model ◽  
Low Dose ◽  
High Dose ◽  
Single High Dose

scholarly journals Laporan Kasus: Manifestasi Oral Penderita Hipertensi berupa Ginggival Enlargement

2020 ◽  
Vol 17 (2) ◽  
pp. 54
Author(s):  
Anindita L. ◽  
Aris Aji K. ◽  
Arcadia Sulistijo J.
Keyword(s):  
Case Reports ◽  
Gingival Tissue ◽  
High Dose ◽  
Gingival Inflammation ◽  
Gingival Enlargement ◽  
History Of ◽  
Root Planning ◽  
Pro Inflammatory Cytokines

Hypertension presents an increase in blood pressure following the oral manifestations, such as gingival enlargement. A 42-year-old woman came to the General Sudirman University Dental and Oral Hospital complaining of enlarged front gums seven years ago. The patient had a history of hypertension and regularly consumed drugs, amlodipine 5 mg. Extraoral examination revealed no lymphadenopathy and no swelling of the head and neck area. Intraoral examination revealed a gingival enlargement involving the papilla to the gingival margin present on the entire upper and lower labial gingival surface. The patient's diagnosis was gingival enlargement caused by gingival enlargement due to the use of amlodipine. Gingival enlargement has been noted with long-term or high-dose amlodipine use. The mechanism of amlodipine in causing gingival enlargement is through the role of fibroblasts with abnormal susceptibility to the drug, resulting in increased levels of protein synthesis, especially collagen. The role of pro-inflammatory cytokines occurs through an increase in interleukin-1β (IL-1β) and IL-6 in the inflamed gingival tissue due to the gingival fibrogenic response to drugs. Therapies were DHE and scaling and root planning as phase I in periodontal treatment. Plaque elimination is vital to reduce gingival inflammation that may occur. Substitution of the drug amlodipine may be needed if there is no improvement. Based on case reports, hypertension patients who took amlodipine could have gingival enlargement. The therapy given was plaque elimination in the form of DHE and Scaling and regular check-ups with the dentist.

Case Report: Rapid Response to Low-Dose Thalidomide in a Case of Severe Steroid Recalcitrant Erythema Nodosum Leprosum

2021 ◽  
Author(s):  
B. Savitha ◽  
Kabir Sardana ◽  
Ritu Kumari ◽  
Ananta Khurana ◽  
Surabhi Sinha ◽  
...  
Keyword(s):  
Low Dose ◽  
Erythema Nodosum ◽  
Lepromatous Leprosy ◽  
High Dose ◽  
Effective Treatment Option ◽  
Steroid Dependence ◽  
Erythema Nodosum Leprosum ◽  
Organ Specific ◽  
Inflammatory Drugs

Erythema nodosum leprosum (ENL), or type 2 lepra reaction, presents with crops of evanescent, tender erythematous nodules accompanied by fever, arthralgia, weight loss, malaise, and organ-specific manifestations, and is seen in borderline and lepromatous leprosy. The drugs approved for ENL include nonsteroidal anti-inflammatory drugs, systemic steroids, thalidomide, and clofazimine. The management of ENL is challenging because long-term steroid use leads to steroid dependence. Our patient had severe steroid recalcitrant ENL with vesicular and pustular lesions mimicking Sweet’s syndrome, and was treated effectively with a low-dose thalidomide regimen (100 mg/d) as opposed to the high dose (400 mg/d) recommended in the literature. We discuss the patho-mechanics and clinical utility of a low-dose thalidomide regimen as an effective treatment option for ENL.

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.

Knock-In of an Internal Tandem Duplication Mutation into Murine FLT3 Confers Myeloproliferative Disease in a Mouse Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 386-386
Author(s):  
Li Li ◽  
Obdulio Piloto ◽  
Ho Bao Nguyen ◽  
Kathleen Greenberg ◽  
Frederick Racke ◽  
...  
Keyword(s):  
Mouse Model ◽  
B Lymphocytes ◽  
Tandem Duplication ◽  
Genetic Alterations ◽  
Myeloproliferative Disease ◽  
Internal Tandem Duplication ◽  
Hematopoietic Stem ◽  
Complete Replacement

Abstract Activation of FLT3 by internal tandem duplication (ITD) mutations in the juxtamembrane domain is the most common molecular alteration known in AML and confers poor prognosis. Homozygous or hemizygous ITD mutations, with the loss of wild type FLT3, result in even worse prognosis. It has been previously reported that FLT3/ITD activates different signaling pathways as compared to wt FLT3. Several models designed to study the roles of FLT3/ITD in leukemogenesis have been reported, utilizing either retroviral infection of murine BM or transgenic expression off strong promoters. Those models have shown myeloproliferative disease (MPD) with FLT3/ITD expression alone and full transformation to leukemia when additional genetic alterations are added. However, these models utilize high level expression of FLT3/ITD, and potentially express the gene at inappropriate stages of development. In addition, retroviral integration sites could be playing an active role. To more closely simulate and study the in vivo biological impact of FLT3/ITD mutations in the development of leukemia, we generated a FLT3/ITD “knock-in” mouse model by inserting an ITD mutation into the juxtamembrane region of murine FLT3 genomic DNA. Young FLT3 wt/ITD mice showed signs of MPD which progressed to fatality at the age of 6–16 months. Older FLT3wt/ITD mice had significant splenomegaly with disruption of the normal splenic architecture. Increased WBC and reduced RBC counts were detected in the peripheral blood of these mice, with elevated monocyte and neutrophil counts. BM was hypercellular with an increased fraction of granulocytes/monocytes and their progenitors, dendritic cells (DCs), and a reduction in the fraction of B lymphocytes. No signs of leukemia were observed over the lifetime of these mice. Clonogenic assay demonstrated that BM from FLT3wt/ITD mice contained increased granulocytic/monocytic colony-forming cells. In addition, these cells were immortalized as they could undergo long-term serial culture in cytokine-supplemented liquid medium. BM from FLT3wt/ITD mice also generated more colonies in the in vivo spleen-CFU assay, and showed an enhanced ability to repopulate lethally irradiated recipients in the long-term competitive repopulation assay. FLT3ITD/ITD mice developed fatal MPD with a shorter latency. Leukocytosis and BM hypercellularity were more pronounced for these mice, with an even higher fraction of granulocytic/monocytic progenitors and a tremendous suppression of B lymphocytes in the BM. BM from these mice displayed reduced potential for reopulation in the long-term competitive repopulation assay. Some FLT3ITD/ITD mice spontaneously developed leukemia-like disease with a lag of 2–6 months. Histopathology revealed complete effacement of the normal spleen architecture, extensive infiltration of the liver and meninges, and complete replacement of the BM with immature myeloid cells. In summary, these data indicate that expression of a FLT3/ITD mutation alone is capable of partially transforming normal hematopoietic stem cells and progenitors to a phenotype of MPD. Additional cooperative events are likely required to progress to leukemia. These will serve as excellent models to study the pathways by which FLT3/ITD signaling contributes to leukemogenesis.

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