Vaginal Delivery After Dührssen Incisions in a Patient With Bladder Exstrophy and Uterine Prolapse.

BACKGROUND: Bladder exstrophy is a rare congenital anomaly affecting the lower abdominal wall, pelvis, and genitourinary structures. Pregnant women with bladder exstrophy present a unique challenge to the obstetrician. CASE: The patient is a 35-year old pregnant woman with bladder exstrophy, an extensive surgical history, and uterine prolapse with an abnormal, rubbery consistency to her cervix. Prenatally, she was counseled on the potential use of Dührssen incisions to facilitate vaginal delivery. Labor was induced at 36 4/7 weeks of gestation after her pregnancy was complicated by recurrent pyelonephritis. Vaginal delivery was achieved 8 minutes after the creation of Dührssen incisions. CONCLUSION: The care of pregnant women with bladder exstrophy requires multidisciplinary management and careful delivery planning. Successful vaginal delivery can be attained in these patients.

Diagnosis and Management of Hyperthyroidism in Pregnancy: A Review.

IMPORTANCE: Hyperthyroidism has important implications for pregnancy, affecting both mother and fetus. Appropriate maternal and fetal management iscritical to avoiding adverse pregnancy outcomes and requires a multidisciplinary approach. OBJECTIVE: To describe maternal diagnosis and management of hyperthyroidism, across all stages of pregnancy. In addition, to review clinical signs of fetal thyroid dysfunction due to maternal Graves disease and discuss management considerations. EVIDENCE ACQUISITION: Review of published articles on PubMed and guidelines by recognized governing organizations regarding the diagnostic and management considerations for hyperthyroidism in pregnancy, from preconception to the postpartum period. RESULTS: Diagnosis of maternal hyperthyroidism involves both clinical symptoms and laboratory findings. Antithyroid medications are the mainstay of therapy, with trimester-specific pregnancy goals. Hyperthyroidism due to Graves disease has important diagnostic and management considerations for the fetus and neonate. CONCLUSIONS AND RELEVANCE: Hyperthyroidism in pregnancy affects mother, fetus, and neonate. Interpretation of thyroid tests and understanding the appropriate use of antithyroid drugs are fundamental. Proper education of physicians providing care to women with hyperthyroidism is essential and starts before pregnancy. Postpartum follow-up is an essential part of the care. A systematic approach to management will ensure optimal pregnancy outcomes.

Liposome-mediated delivery of iminosugars enhances efficacy against dengue virus in vivo.

A key challenge faced by promising antiviral drugs, such as iminosugars, is in vivo delivery to achieve effective levels of drug without toxicity. Four iminosugars, all deoxynojirimycin (DNJ) derivatives-N-butyl DNJ (NB-DNJ), N-nonyl DNJ, N-(9-methoxynonyl) DNJ, and N-(6'-[4″-azido-2″-nitrophenylamino]hexyl)-1-DNJ (NAP-DNJ)-potently inhibited both the percentage of cells infected with dengue virus and release of infectious virus from primary human monocyte-derived macrophages, demonstrating their efficacy in primary cells. In a lethal antibody-dependent enhancement mouse model of dengue pathogenesis, free NB-DNJ significantly enhanced survival and lowered viral load in organs and serum. Liposome-mediated delivery of NB-DNJ, in comparison with free NB-DNJ, resulted in a 3-log(10) reduction in the dose of drug sufficient to enhance animal survival. The optimizing of the effective dose in this way could liberate the therapeutic potential of many cytotoxic antivirals against both dengue virus and a wide array of other viruses.

Characterization of a model of lethal dengue virus 2 infection in C57BL/6 mice deficient in the alpha/beta interferon receptor.

Dengue virus (DENV) causes dengue fever and dengue haemorrhagic fever/dengue shock syndrome, both considered major public-health problems worldwide. We generated a lethal DENV-2 strain (D220) by 10 additional cycles of subcutaneous inoculation of mice with supernatant from mosquito cells infected with the previously characterized strain D2S10, followed by harvesting of serum. D220 induces mortality at ten-fold lower doses than D2S10 in mice lacking only the alpha/beta interferon (IFN-α/ß) receptor in C57BL/6 or 129 backgrounds under both non-enhanced and antibody-enhanced conditions. Sequence analysis of the complete viral genome revealed five amino acid changes between D220 and D2S10, of which two (K122I in envelope and V115A in NS4B) appear to account for the observed phenotypic differences between the viruses. By causing mortality at lower doses in C57BL/6 mice lacking only the IFN-α/ß receptor, D220 constitutes an improved tool for study of DENV-induced pathogenesis, as well as for testing potential vaccines and antiviral drugs against DENV.

Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification.

Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcgamma receptors (FcgammaR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcgammaR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue.