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"Lekstrom-Himes, Julie"
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Mikhail and Margarita
It is 1933 and Mikhail Bulgakov's enviable career is on the brink of being dismantled. His friend and mentor, the poet Osip Mandelstam, has been arrested, tortured, and sent into exile. Meanwhile, a mysterious agent of the secret police has developed a growing obsession with exposing Bulgakov as an enemy of the state. To make matters worse, Bulgakov has fallen in love with the dangerously candid Margarita. Facing imminent arrest, and infatuated with Margarita, he is inspired to write his masterpiece, The Master and Margarita, a scathing novel critical of both power and the powerful. Ranging between lively readings in the homes of Moscow's literary elite to the Siberian Gulag, Mikhail and Margarita recounts a passionate love triangle while painting a portrait of a country whose towering literary tradition is at odds with a dictatorship that does not tolerate dissent. Margarita is a strong, idealistic, seductive woman who is fiercely loved by two very different men, both of whom will fail in their attempts to shield her from the machinations of a regime hungry for human sacrifice. Debut novelist Julie Lekstrom Himes launches a rousing defense of art and the artist during a time of systematic deception, and she movingly portrays the ineluctable consequences of love for one of history's most enigmatic literary figures.
Book
CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia
Two patients, one with transfusion-dependent β-thalassemia and the other with sickle cell disease, received autologous CD34+ cells edited with CRISPR-Cas9 targeting of
BCL11A
. Their clinical course over the following 16 to 18 months supports further experimental testing of CRISPR-Cas9 gene editing to treat these diseases.
Journal Article
Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del
Patients with homozygous Phe508del cystic fibrosis were assigned to receive combination tezacaftor–ivacaftor or placebo for 24 weeks. The combination resulted in an FEV
1
that was 4 percentage points higher and a pulmonary-exacerbation rate that was 35% lower than with placebo.
Journal Article
Tezacaftor–Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis
Approximately 5% of patients with cystic fibrosis express one allele with some retained CFTR function. In a prospective trial, tezacaftor–ivacaftor had a greater effect on increasing FEV
1
than ivacaftor alone, and both ivacaftor alone and the combination were more effective than placebo.
Journal Article
Pharmacokinetic and Drug–Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor
Drug–drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P‐gp) substrate. The effects of steady‐state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P‐gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP3A inhibitors on tezacaftor/ivacaftor PKs were also determined. Tezacaftor/ivacaftor increased digoxin area under the curve (AUC) by 30% but did not affect midazolam, ethinyl estradiol, or norethindrone exposures. Itraconazole increased the AUC of tezacaftor 4‐fold and ivacaftor 15.6‐fold. Ciprofloxacin had no significant effect on tezacaftor or ivacaftor exposure. Coadministration of tezacaftor/ivacaftor may increase exposure of sensitive P‐gp substrates. Tezacaftor/ivacaftor is unlikely to impact exposure of drugs metabolized by CYP3A, including hormonal contraceptives. Strong CYP3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor.
Journal Article
Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del / F508del-CFTR or F508del / G551D-CFTR
Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor.
To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D.
This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 to 150 mg) every day alone or in combination with ivacaftor (150 mg every 12 h) in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D, taking physician-prescribed ivacaftor, received tezacaftor (100 mg every day).
Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV
(ppFEV
) from baseline through Day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV
in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV
in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all).
These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).
Journal Article
Immunodeficiency Diseases Caused by Defects in Phagocytes
Primary phagocytic defects must be included in the differential diagnosis of recurrent infection and fever in a child and occasionally in an adult. Early diagnosis is essential, because manifestations of infection are usually blunted and rapid intervention can be lifesaving. In general, patients are identified at a young age on the basis of their susceptibility to normally nonpathogenic bacteria or fungi. In some cases, the infectious agents point to the disorder (Table 1): catalase-positive microorganisms and aspergillosis species are characteristic of chronic granulomatous disease,
1
and atypical mycobacteria suggest a defect in the interferon-γ–interleukin-12 axis.
2
These bacterial infections contrast with the . . .
Journal Article
Association of Major Histocompatibility Complex Determinants with the Development of Symptomatic and Asymptomatic Genital Herpes Simplex Virus Type 2 Infections
The clinical spectrum of herpes simplex virus (HSV) infections, ranging from asymptomatic to frequently distressing outbreaks, suggests that there may be immunologic determinants of disease severity that are associated with human leukocyte antigen (HLA) expression. A controlled, prospective study identified several major histocompatibility complex (MHC) class I and II antigens whose frequencies are associated with HSV-2 infection or with frequent symptomatic genital recurrences. Previous studies were hampered by the inability to serologically identify patients with asymptomatic HSV-2 infection. Clinical evaluation and Western blot assay were used to identify 3 subject cohorts: 1 with no prior HSV infections, 1 with HSV-2 antibodies but no recognized symptoms, and 1 with HSV-2 antibodies and frequent genital recurrences. Statistical comparisons of HLA frequencies among these cohorts showed associations of HLA-B27 and -Cw2 with symptomatic disease. Also, HLA-Cw4 was significantly associated with HSV-2 infection. These associations indicate that immunologic factors linked to the MHC influence the risk of HSV-2 infection and disease expression.
Journal Article
Periodic Illness Associated with Epstein-Barr Virus Infection
A 15-year-old boy with a 13-year history of periodic fevers, lymphadenopathy, and leukocytosis showed virological, serological, immunohistologic, and molecular evidence of persistent, active, Epstein-Barr virus (EBV) infection. Acyclovir and several other agents failed to alter his clinical course. Comprehensive immunological studies could not identify a defined immune deficiency syndrome to explain the persistent infection, although he does continue to have circulating polymeric EBV-specificimmunoglobulin type A, as is seen in individuals during acute EBV infections. In vitro work suggests that this polymeric antibody prevents B cell infection by EBV. Cumulative data suggest that this patient suffers from a novel form of EBV infection.
Journal Article
Impaired Granulopoiesis, Myelodysplasia, and Early Lethality in CCAAT/Enhancer Binding Protein ε -deficient Mice
Polymorphonuclear leukocytes are essential for host defense to infectious diseases. CCAAT/enhancer binding protein ε (C/EBPε ) is preferentially expressed in granulocytes and lymphoid cells. Mice with a null mutation in C/EBPε develop normally and are fertile but fail to generate functional neutrophils and eosinophils. Opportunistic infections and tissue destruction lead to death by 3-5 months of age. Furthermore, end-stage mice develop myelodysplasia, characterized by proliferation of atypical granulocytes that efface the bone marrow and result in severe tissue destruction. Thus, C/EBPε is essential for terminal differentiation and functional maturation of committed granulocyte progenitor cells.
Journal Article