The nonnucleoside reverse transcriptase inhibitor MIV-150 in carrageenan gel prevents rectal transmission of simian/human immunodeficiency virus infection in macaques.

Development of a microbicide that prevents rectal transmission of human immunodeficiency virus (HIV) is a vital component in reducing HIV spread. We recently demonstrated that a formulation of the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 in carrageenan reduced vaginal infection of macaques with simian immunodeficiency virus SIVmac239 with HIV-1(HxB2) reverse transcriptase (SHIV-RT). Herein, we performed the first testing of MIV-150-carrageenan against rectal infection. Rhesus macaques were treated rectally with MIV-150-carrageenan or methyl cellulose (MC) placebo gel up to 4 h prior to rectal challenge with 10³ or 10(4) 50% tissue culture infective doses (TCID50) of SHIV-RT. Infection was assessed by measuring plasma virus RNA as well as T and B cell responses. MIV-150-carrageenan protected all animals challenged with 10³ TCID(50 when gel was applied either 30 min or 4 h prior to challenge, while 100% of the MC-treated animals became infected (n = 4 each; P < 0.03). Partial protection (2 of 4 animals) by MIV-150-carrageenan was observed for rectal challenge with 10-fold more virus applied 4 h after the gel. Sequencing of the RT gene from plasma virus RNA isolated at peak viremia confirmed that both of these animals (like infected MC controls) were infected with wild-type virus. Infection correlated with the development of SIV-specific T and B cell responses. MIV-150 was detected in the rectal fluids and tissues 4 h after gel application but was not detected in the blood at any time (0.5 to 24 h). These data are promising for the development of NNRTI-containing gels to prevent rectal HIV transmission.

A fusion inhibitor prevents spread of immunodeficiency viruses, but not activation of virus-specific T cells, by dendritic cells.

Dendritic cells (DCs) play a key role in innate immune responses, and their interactions with T cells are critical for the induction of adaptive immunity. However, immunodeficiency viruses are efficiently captured by DCs and can be transmitted to and amplified in CD4(+) T cells, with potentially deleterious effects on the induction of immune responses. In DC-T-cell cocultures, contact with CD4(+), not CD8(+), T cells preferentially facilitated virus movement to and release at immature and mature DC-T-cell contact sites. This occurred within 5 min of DC-T-cell contact. While the fusion inhibitor T-1249 did not prevent virus capture by DCs or the release of viruses at the DC-T-cell contact points, it readily blocked virus transfer to and amplification in CD4(+) T cells. Higher doses of T-1249 were needed to block the more robust replication driven by mature DCs. Virus accumulated in DCs within T-1249-treated cocultures but these DCs were actually less infectious than DCs isolated from untreated cocultures. Importantly, T-1249 did not interfere with the stimulation of virus-specific CD4(+) and CD8(+) T-cell responses when present during virus-loading of DCs or for the time of the DC-T-cell coculture. These results provide clues to identifying strategies to prevent DC-driven virus amplification in CD4(+) T cells while maintaining virus-specific immunity, an objective critical in the development of microbicides and therapeutic vaccines.

Dendritic cells and HIV infection: activating dendritic cells to boost immunity.

Dendritic cells (DCs) are white blood cells that coordinate innate and adaptive immunity. They are distributed within epithelia and mucosal-associated lymphoid tissues, positioned to entrap incoming pathogens or vaccines. Human immunodeficiency virus (HIV) and the non-human primate equivalent (SIV) exploit DCs to amplify infection, underscoring the need to harness strategies that promote presentation of virus by DCs to stimulate potent anti-viral immunity instead of virus transmission. Two main subsets of DCs need to be considered: myeloid (MDC) and plasmacytoid (PDC) subsets. Using the SIV-macaque system to advance oral vaccine research, we examined macaque PDC and MDC biology, identifying ways to activate DCs and boost antiviral immunity. Immunostimulatory oligodeoxyribonucleotides (ISS-ODNs) stimulated PDC/MDC mixtures to up-regulate co-stimulatory molecule expression and to secrete both IFN-alpha and IL-12. Additionally, ISS-ODNs augmented SIV-specific IFN-gamma responses induced by virus-bearing DCs. ISS-ODN-driven DC activation is being pursued to improve oral/nasopharyngeal mucosal vaccines and therapies against HIV.

Lethal multiple pterygium syndrome: suggestion for a consistent pathological workup and review of reported cases.

We report on 2 brothers with lethal multiple pterygium syndrome (LMPS) born to non-consanguineous parents as late spontaneous abortions. Both fetuses presented with massive nuchal edema, and facial anomalies including cleft palate and broad ribs. Apparently, several subgroups of LMPS exist. Differentiation is difficult, as there is no consistent agreement on a workup protocol for autopsies. We compared the findings in the literature on cases with LMPS, and we suggest a standardized workup as an initial step for more efficient differentiation between various subgroups.

Diaphragmatic defects, limb deficiencies, and ossification defects of the skull: a distinctive malformation syndrome.

We report on prenatal and postnatal findings in 4 consecutive fetuses with a pattern of severe congenital anomalies who were born to a healthy nonconsanguineous couple. The spectrum of malformations includes diaphragmatic defects, hypoplastic lungs, omphalocele, limb deficiencies, syndactyly of toes, and ossification defects of the skull. This specific spectrum of anomalies is not fully compatible with that of any established syndrome. No prenatal exposure to any possible teratogen was found. Family history is suggestive for autosomal recessive inheritance, even though germ-line mosaicism in one of the parents cannot completely be excluded.

[Placental site trophoblastic tumor. Morphology, differential diagnosis and prognosis]. / Placental site trophoblastic tumor. Morphologie, Differentialdiagnose und Prognose.

A placental-site trophoblastic tumor is a rare neoplasia that is derived from the cells of the intermediate trophoblast. Morphological, biochemical, and Doppler ultrasound findings are presented regarding differential diagnosis using material from three recent cases. Essentially, placental-site trophoblastic tumors can be diagnosed if infiltration of the myometrium is seen by a monomorphic trophoblastic proliferation that is not interrupted by decidual cells. Necrosis and hemorrhages are not features of placental-site trophoblastic tumors. However, there is a peculiar behavior towards the uterine vasculature as spiral arteries are dilated and transformed the same way as occurs at the site of physiological implantation of pregnancy. It appears that as a result of this phenomenon there is a characteristic finding in ultrasound. Examination of this type of tumor demonstrates cystic spaces that can be defined as blood vessels by their Doppler signal. In two of the three cases a hysterectomy was performed, and criteria for the assumption of malignant placental-site tumors are therefore presented. However, only the mitosis rate seems to possess some predictive value.

[Transvaginal ultrasound of "placental-site trophoblastic tumor"]. / Transvaginalsonographie eines "Placental Site Trophoblastic Tumor".

The case of a placental-site trophoblastic tumor (PSTT) is described. Transvaginal sonography revealed a vascularized tumor mass with a deep invasion of the myometrium, partly with echogenic, solid parts and partly multiple echo-free cystic lesions. The maximum size of an echo-free cystic lesion was 4.4 cm. Doppler exploration indicated the presence of blood flow in all these cystic lesions. Distinctly abnormal low flow indices were prominent in the whole tumor area. According to the clinical results and the slightly positive levels of human chorionic beta-gonadotropin (100-1,000 IU/l postpartum), this tumor was classified as malignant trophoblastic disease, most likely PSTT. The authors conclude that, in the case of a patient with suspected trophoblastic disease and in view of the sonographic findings, PSTT may be a valid differential diagnosis, particularly if larger cystic lesions of more than 3 cm in diameter are found in the tumor bed together with evident blood flow at a low vascular resistance.

[Blood pressure: knowledge and behavior]. / Blutdruck: Wissen und Verhalten.

Knowledge about blood pressure and practice in terms of its measurement are two important indicators for problem areas in cardiovascular disease prevention. This paper analyses these two indicators based on a representative Health Survey (SOMIPOPS) in order to illustrate the potential of such surveys. The results demonstrate that interesting clues to preventive action can indeed be obtained. In addition, time series analyses could potentially be a basis for the continuous evaluation of health services in this area.

Renal mercury content in HgCl2-induced acute renal failure in furosemide/saline-protected and nonprotected rats.

Renal mercury content, urinary mercury excretion and renal function were studied in rats with acute renal failure (ARF) induced by subcutaneous injection of 2, 3, 6, or 10 mg/kg HgCl2. Similarly poisoned rats were protected against ARF by continuous intravenous infusion of furosemide and saline. Excellent protection was obtained in rats receiving 2,3, and 6 mg/kg HgCl2, whilst some animals developed moderate azotemia after 10 mg/kg HgCl2. Renal mercury content 48 h after HgCl2 injection did not differ appreciably between protected and nonprotected groups of rats and showed no relation to the dose of HgCl2 injected or to the degree of renal failure. Urinary Hg excretion was variable during the first 24 h after HgCl2 injection and tended to be higher with higher dosage unless the animals became anuric early on. Hg excretion during the second 24 h was independent of dosage, but was comparatively high in functionally well protected rats and low in oliguric animals with severe renal failure. Attempts at detoxication with the potent chelating agent complexon I after 6 mg/kg HgCl2 failed completely: Renal mercury content was similar to that in the other groups of rats and every single rat so treated developed severe anuric renal failure. Although dose-dependent functional injury after HgCl2 may be related to the amount of Hg reaching the kidney during the initial phase, we have to conclude that HgCl2 toxicity is unrelated to the amount of Hg found in renal tissue at 48 h. Furthermore, furosemide/saline protection does not act through increasing urinary Hg excretion or decreasing the amount of toxin accumulating in renal tissue.