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1.
Antimicrob Agents Chemother ; 66(12): e0213021, 2022 12 20.
Article in English | MEDLINE | ID: mdl-36374023

ABSTRACT

Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 µg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 µg/mL (tested with a fixed vaborbactam concentration of 8 µg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.


Subject(s)
Anti-Bacterial Agents , Urinary Tract Infections , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , beta-Lactamase Inhibitors/pharmacology , Urinary Tract Infections/drug therapy , Klebsiella pneumoniae , Administration, Intravenous , Pseudomonas aeruginosa , Microbial Sensitivity Tests
2.
Antimicrob Agents Chemother ; 65(9): e0260620, 2021 08 17.
Article in English | MEDLINE | ID: mdl-34097490

ABSTRACT

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated urinary tract infections and in Europe for other serious bacterial infections, including hospital-acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time course of meropenem and vaborbactam using pooled data from two phase 1 and two phase 3 studies. Multicompartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data, and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end-stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different between phase 1 noninfected subjects and phase 3 infected patients. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.


Subject(s)
Anti-Bacterial Agents , Boronic Acids , Anti-Bacterial Agents/therapeutic use , Drug Combinations , Heterocyclic Compounds, 1-Ring , Humans , Meropenem
3.
Pulm Pharmacol Ther ; 22(4): 279-85, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19328861

ABSTRACT

Pirfenidone is a small, synthetic molecule under investigation for treatment of idiopathic pulmonary fibrosis. In an open-label, single-dose crossover study, the pharmacokinetics (PK) of pirfenidone were investigated with or without food and antacids in healthy adult volunteers. Concentrations of pirfenidone and its metabolites in plasma and urine were determined by liquid chromatography with tandem mass spectrometry, and candidate pharmacokinetic models were fit to plasma data using weighted, non-linear regression. The effect of food and antacids on pirfenidone exposure was evaluated by determining 'equivalence' using FDA guidelines. Adverse events were recorded by site personnel and classified by investigators on the basis of severity and relationship to study drug. Sixteen subjects yielded 64 pharmacokinetic profiles. The best fit was achieved using a five-compartment, linear model with an allowance for direct conversion to the primary metabolite (5-carboxy-pirfenidone). Coadministration with food decreased the rate and, to a lesser degree, the extent of pirfenidone absorption of absorption. Analysis of adverse events revealed a correlation between pirfenidone C(max) and the risk of gastrointestinal (GI) adverse events, suggesting that food may reduce the risk of certain adverse events associated with pirfenidone. Administration of pirfenidone with food has a modest effect on overall exposure but results in lower peak concentrations, which may improve tolerability.


Subject(s)
Antacids/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Pyridones/pharmacokinetics , Aged , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Area Under Curve , Biotransformation , Double-Blind Method , Drug Interactions , Female , Food-Drug Interactions , Humans , Intestinal Absorption , Linear Models , Male , Middle Aged , Pyridones/adverse effects , Therapeutic Equivalency
4.
N Engl J Med ; 352(22): 2271-84, 2005 Jun 02.
Article in English | MEDLINE | ID: mdl-15930418

ABSTRACT

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.


Subject(s)
Chickenpox Vaccine , Herpes Zoster/prevention & control , Herpesvirus 3, Human , Neuralgia/prevention & control , Aged , Chickenpox Vaccine/adverse effects , Chickenpox Vaccine/immunology , Cost of Illness , Double-Blind Method , Female , Follow-Up Studies , Herpes Zoster/complications , Herpes Zoster/epidemiology , Herpesvirus 3, Human/immunology , Humans , Immunologic Memory , Incidence , Male , Middle Aged , Neuralgia/virology , Vaccines, Attenuated/adverse effects , Vaccines, Attenuated/immunology , Virus Activation
7.
Hosp Pract (1995) ; 33(12): 37-8, 41-4, 49, 1998 Dec 15.
Article in English | MEDLINE | ID: mdl-9866646

ABSTRACT

Children with young cats, HIV-infected patients with low CD4 counts, and lice-infested homeless people are among those with an increased risk. Clinical presentation varies with the infecting Bartonella species and the host. Treatment for cat-scratch disease is supportive; macrolide therapy is an appropriate choice for other Bartonella infections.


Subject(s)
Bartonella Infections/diagnosis , Bartonella Infections/drug therapy , AIDS-Related Opportunistic Infections/diagnosis , AIDS-Related Opportunistic Infections/drug therapy , Adult , Angiomatosis, Bacillary/diagnosis , Angiomatosis, Bacillary/drug therapy , Animals , Bacteremia/microbiology , Bartonella Infections/etiology , Bartonella henselae , Cat-Scratch Disease/diagnosis , Cat-Scratch Disease/drug therapy , Cats , Child , Endocarditis/microbiology , Female , Humans , Male , Risk Factors
8.
South Med J ; 90(6): 640-3, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9191743

ABSTRACT

Lemierre's syndrome is an acute medical condition characterized by anaerobic oropharyngeal infection leading to septic thrombophlebitis of the internal jugular vein. The illness is often complicated by septic pulmonary emboli and distant metastatic infections. Treatment consists of surgical drainage of purulent collections and long-term intravenous antibiotic therapy. Although Lemierre's syndrome is rare, it is potentially fatal and remains an important entity for clinicians to recognize and treat appropriately.


Subject(s)
Gram-Negative Anaerobic Bacteria , Gram-Negative Bacterial Infections , Jugular Veins/microbiology , Thrombosis/microbiology , Tonsillitis/microbiology , Abscess/drug therapy , Abscess/microbiology , Abscess/surgery , Adult , Anti-Bacterial Agents , Cause of Death , Drainage , Drug Therapy, Combination/administration & dosage , Drug Therapy, Combination/therapeutic use , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/surgery , Humans , Injections, Intravenous , Male , Pulmonary Embolism/drug therapy , Pulmonary Embolism/microbiology , Pulmonary Embolism/surgery , Sepsis/drug therapy , Sepsis/surgery , Syndrome , Thrombosis/drug therapy , Thrombosis/surgery , Tonsillitis/drug therapy , Tonsillitis/surgery
10.
J Cardiovasc Surg (Torino) ; 37(6): 631-3, 1996 Dec.
Article in English | MEDLINE | ID: mdl-9016982

ABSTRACT

Prosthetic valve endocarditis is a potential complication of valve replacement surgery and warrants prompt diagnosis and appropriate treatment. Thus, the blood culture in addition to providing an etiological organism is important in establishing appropriate antibiotic therapy. A case of prosthetic valve endocarditis (PVE) is presented with repeatedly negative blood cultures at a community hospital and refractory to prolonged therapy with standard antibiotic regimens. Appropriate workup eventually identified the causative organism as Legionella pneumophila, and antimicrobial therapy directed against Legionella combined with a repeat valve replacement effectively treated this case. Aspects of culture-negative PVE including the microbiology and etiology are discussed. Legionella endocarditis represents an important cause of culture negative PVE and should be considered in the differential diagnosis of culture negative PVE refractory to standard antimicrobial therapy.


Subject(s)
Endocarditis, Bacterial/microbiology , Heart Valve Prosthesis/adverse effects , Legionella pneumophila , Legionnaires' Disease/microbiology , Prosthesis-Related Infections/microbiology , Adult , Aortic Valve/surgery , Diagnosis, Differential , Endocarditis, Bacterial/surgery , False Negative Reactions , Humans , Legionella pneumophila/isolation & purification , Legionnaires' Disease/surgery , Male , Prosthesis-Related Infections/surgery , Reoperation
11.
Infect Immun ; 63(11): 4553-6, 1995 Nov.
Article in English | MEDLINE | ID: mdl-7591104

ABSTRACT

Bartonella henselae expresses pili phenotypically similar to type 4 pili. B. henselae pilus expression undergoes phase variation with multiple passages. Low-passage-number, piliated B. henselae adhered to and invaded HEp-2 cells to a greater extent than did multiply passaged B. henselae with reduced pilus expression. Pili may be a pathogenic determinant for Bartonella species.


Subject(s)
Bacterial Adhesion , Bartonella henselae/pathogenicity , Bartonella quintana/pathogenicity , Cells, Cultured , Epithelium/microbiology , Fimbriae, Bacterial/ultrastructure , Humans
12.
J Clin Microbiol ; 29(12): 2897-900, 1991 Dec.
Article in English | MEDLINE | ID: mdl-1684586

ABSTRACT

Conventional typing schemes for Pseudomonas aeruginosa may not discriminate strains. P. aeruginosa isolates from patients with cystic fibrosis were examined by restriction enzyme analysis and Southern hybridization. There was marked diversity of restriction enzyme analysis patterns among P. aeruginosa DNAs from cystic fibrosis isolates; however, sequential isolates obtained from individual patients showed very little variation over an 8-year period. DNA fragments from the alginate biosynthesis gene complex, the exotoxin A gene, and the elastase gene of P. aeruginosa were used in Southern hybridization analysis. The patterns of hybridization to the elastase and algD gene probes were highly conserved in all isolates, therefore, these DNA fragments are not useful in discriminating strains, in contrast to the exotoxin A gene probe.


Subject(s)
Blotting, Southern , Cystic Fibrosis/microbiology , Polymorphism, Restriction Fragment Length , Pseudomonas aeruginosa/genetics , Alginates , Humans , Pancreatic Elastase/genetics
13.
Rev Infect Dis ; 13(1): 155-9, 1991.
Article in English | MEDLINE | ID: mdl-2017616

ABSTRACT

Sparganosis is a rare infection caused by a tapeworm larva from the genus Spirometra. A 21-year-old Indian man presented with an 18-month history of episodic confusion followed by a grand mal seizure. Computed tomography and magnetic resonance imaging of the brain confirmed the presence of a lesion of the left occipital lobe. Subsequent stereotactic biopsy revealed a plerocercoid larva or sparganum. Surgical resection resulted in cure. This case prompted a review of the literature on central nervous system sparganosis. Altogether, 17 other cases of primary cerebral sparganosis have been reported previously. Seizures, headache, and focal neurologic signs are common at presentation. Neuroradiologic imaging is sensitive but not specific for the identification of lesions. Enzyme-linked immunosorbent assay of cerebrospinal fluid or serum may be diagnostically helpful. However, the diagnosis is generally made after surgical resection, which is usually curative.


Subject(s)
Brain Diseases/diagnosis , Brain/parasitology , Sparganosis/diagnosis , Sparganum/isolation & purification , Adult , Animals , Biopsy , Brain/surgery , Brain Diseases/surgery , Humans , Magnetic Resonance Imaging , Male , Sparganosis/surgery , Tomography, X-Ray Computed
14.
N Engl J Med ; 323(23): 1573-80, 1990 Dec 06.
Article in English | MEDLINE | ID: mdl-2233945

ABSTRACT

BACKGROUND: Bacillary angiomatosis is an infectious disease causing proliferation of small blood vessels in the skin and visceral organs of patients with human immunodeficiency virus infection and other immunocompromised hosts. The agent is often visualized in tissue sections of lesions with Warthin-Starry staining, but the bacillus has not been successfully cultured or identified. This bacillus may also cause cat scratch disease. METHODS: In attempting to identify this organism, we used the polymerase chain reaction. We used oligonucleotide primers complementary to the 16S ribosomal RNA genes of eubacteria to amplify 16S ribosomal gene fragments directly from tissue samples of bacillary angiomatosis. The DNA sequence of these fragments was determined and analyzed for phylogenetic relatedness to other known organisms. Normal tissues were studied in parallel. RESULTS: Tissue from three unrelated patients with bacillary angiomatosis yielded a unique 16S gene sequence. A sequence obtained from a fourth patient with bacillary angiomatosis differed from the sequence found in the other three patients at only 4 of 241 base positions. No related 16S gene fragment was detected in the normal tissues. These 16S sequences associated with bacillary angiomatosis belong to a previously uncharacterized microorganism, most closely related to Rochalimaea quintana. CONCLUSIONS: The cause of bacillary angiomatosis is a previously uncharacterized rickettsia-like organism, closely related to R. quintana. This method for the identification of an uncultured pathogen may be applicable to other infectious diseases of unknown cause.


Subject(s)
Angiomatosis/microbiology , Bacterial Infections/microbiology , HIV Infections/complications , Opportunistic Infections/complications , Acquired Immunodeficiency Syndrome/complications , Adult , Bacterial Infections/complications , Base Sequence , Cat-Scratch Disease/complications , Female , Gene Amplification , Humans , Immunosuppression Therapy/adverse effects , Male , Middle Aged , Molecular Sequence Data , Opportunistic Infections/microbiology , Polymerase Chain Reaction , RNA, Ribosomal, 16S/analysis , Rickettsiaceae/isolation & purification , Rickettsiaceae Infections/complications
15.
Article in English | MEDLINE | ID: mdl-3493993

ABSTRACT

Plutonium-239 was injected into 12-week-old female CBA/H mice in the range 1.85-18.5 kBq kg-1 either as a single injection or as 16 injections spaced at 3.5 day intervals over eight weeks. There was a highly significant increase in the yield of fully developed osteosarcomas with increased amounts of 239Pu for both modes of injection. Osteosarcomas too small to be diagnosed radiographically were also seen in many bones and small but significant yields of myeloid leukaemia were seen in animals given plutonium. Although more myeloid leukaemia was seen in the mice given plutonium in divided amounts than in those given the plutonium in a single injection it could not be shown that multiple injection significantly affected the yield of either late effect.


Subject(s)
Leukemia, Radiation-Induced/etiology , Neoplasms, Radiation-Induced/etiology , Plutonium , Sarcoma, Experimental/etiology , Animals , Dose-Response Relationship, Radiation , Female , Mice , Mice, Inbred CBA , Neoplasms, Radiation-Induced/pathology , Osteosarcoma/etiology , Osteosarcoma/pathology , Sarcoma, Experimental/pathology
16.
Article in English | MEDLINE | ID: mdl-3491802

ABSTRACT

Haematological information on steel (Sl) mice is limited largely to Sl/Sld mice of Bar Harbor stock (WC.B6 F1). Therefore, two Harwell alleles, SlgbH and Slcon, were investigated. In the steady state both heterozygotes were modestly anaemic, homozygous Slcon and compound Slcon/SlgbH more so. On perturbation by X-irradiation Slcon/SlgbH showed a decrease in median lethal dose (MLD)--6.5 Gy, Slcon/+ and Slcon/Slcon slightly less change (7.5 Gy) compared with +/+, 8 Gy. In recovery from sublethal doses single heterozygotes, double heterozygotes with Wv, and compounds showed no delay in restoration of the count of red blood corpuscles (RBC) such as that seen in typical W mice (e.g. Wv/+, W/Wv). Effects on Slcon/Slcon and Slcon/SlgbH differ from those reported for Sl/Sld in that they show normal growth of spleen colonies when used as lethally irradiated recipients of bone marrow, they support growth of implanted bone marrow to form radiation chimaeras. When Harwell steel mice are donors of bone marrow to lethally irradiated +/+ mice the chimaeras ultimately are not anaemic; when lethally irradiated Harwell steel mice are recipients of +/+ marrow they remain macrocytically anaemic. One deduces that, for normal development and production of normal RBC in the steady state, the erythron requires intrinsic factors determined by wild type alleles at the W locus and extrinsic factors determined by wild type alleles at the Sl locus. Mutant alleles at either locus may determine macrocytosis. Two mutant alleles at either locus are still more deleterious, often lethal. Whereas mutant W alleles may also influence the pluripotent haematopoietic stem cell (HSC) leading to reduced MLD on X-irradiation, a similarly reduced MLD for Sl mutants may represent an increased need for and consumption of products of the haematopoietic stem cells rather than truly increased radiosensitivity, since the Do for spleen colony-forming units is the same for Slcon/SlgbH as +/+ mice.


Subject(s)
Hematopoiesis/radiation effects , Animals , Blood Cell Count , Hematopoietic Stem Cells/radiation effects , Mice , Mice, Mutant Strains , Radiation Chimera , Radiation Dosage , Radiation Tolerance
17.
Int J Radiat Oncol Biol Phys ; 12(8): 1299-302, 1986 Aug.
Article in English | MEDLINE | ID: mdl-3759551

ABSTRACT

The drug BW12C, which increases the oxygen affinity of hemoglobin, reduces oxygen availability to tissues. This results in protection against radiation damage to the hemopoietic system and epidermal Langerhans cells in CBA mice. The drug also protects against beta-irradiation damage in pig epidermis. BW12C increases the hypoxic cell fraction in tumors and histological examination of an experimental T cell lymphoma shows that the induced hypoxia leads to tumor necrosis.


Subject(s)
Aldehydes/therapeutic use , Antineoplastic Agents/therapeutic use , Benzaldehydes , Hemoglobins/metabolism , Neoplasms, Experimental/therapy , Oxygen/physiology , Radiation-Protective Agents/therapeutic use , Animals , Combined Modality Therapy , Mice , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/radiotherapy , Oxygen/blood , Swine
19.
Genetics ; 110(4): 709-21, 1985 Aug.
Article in English | MEDLINE | ID: mdl-3839762

ABSTRACT

A mutation induced by ethylnitrosourea in a spermatogonial stem cell of a 101/H mouse has resulted in a structurally altered beta-diffuse major globin in one of his offspring. The mutant hemoglobin is associated with polycythemia, rubor, increased oxygen affinity and decreased hem-hem interaction. The mutant haplotype has been designated Hbbd4, polycythemia. Amino acid analysis of the mutant globin has shown that a single substitution beta 145 Tyr----Cys has occurred, and it is proposed that ethylnitrosourea induced an A----G transition in the tyrosine codon (TAC----TGC). This murine polycythemia is homologous with hemoglobin Rainier in man, in which the amino acid substitution is also beta 145 Tyr----Cys and which is associated with similar physiological consequences.


Subject(s)
Globins/genetics , Hemoglobins, Abnormal/genetics , Mutation , Animals , Crosses, Genetic , Ethylnitrosourea/pharmacology , Female , Genotype , Heterozygote , Homozygote , Humans , Macromolecular Substances , Male , Mice , Mice, Inbred BALB C , Mice, Inbred Strains , Recombination, Genetic , Species Specificity , Spermatogonia/drug effects
20.
Br J Haematol ; 60(2): 219-32, 1985 Jun.
Article in English | MEDLINE | ID: mdl-4005179

ABSTRACT

Having shown a haematopoietic role for Patch (Ph), especially when doubly heterozygous with the mutant Wct (Loutit & Cattanach, 1983) we have similarly examined the Rw locus, the third member of the triplet. Mature Rw/+mice have a just detectable macrocytic anaemia. When doubly heterozygous with Wct and Wv the mild anaemia of these W mutants is exaggerated but with W19H (not anaemic as single heterozygote) red cell factors are as for Rw/+. Rw/+mice are strikingly more sensitive to the lethal effects of X-irradiation (MLD 6.66 +/- 0.10 Gy) on haematopoiesis than comparable +/+ mice (MLD 8 Gy). Those mice that do recover after X-irradiation do not exhibit the delay in recovery of erythropoiesis that is evident with characteristic W mutants in both single and double dose. Furthermore the double heterozygote Wct+/+Rw has a significantly lower MLD (5.19 +/- 0.17 Gy) for X-radiation than Wct/+ (MLD 6.48 +/- 0.24 Gy). We argue that all three loci W, Ph and Rw, influence haematopoietic stem cells, leading to increased radiosensitivity when deletions or mutant genes are present.


Subject(s)
Genes , Hematopoiesis , Anemia, Macrocytic/genetics , Animals , Blood Cell Count , Chromosome Mapping , Erythrocytes/radiation effects , Erythropoiesis , Genotype , Hematopoiesis/radiation effects , Heterozygote , Mice
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