Burden of Malaria during Pregnancy at the Time of IPTp/SP Implementation in Gabon

The new recommendations to prevent malaria in pregnant women have recently been implemented in Gabon. There is little information on the pregnancy indicators that are useful for their evaluation. A cross-sectional study for the assessment of the prevalence of peripheral, placental, and cord malaria and anemia among delivering women was performed at the largest public hospital of Gabon. Malaria prevalence was 34.4%, 53.6%, and 18.2% for maternal peripheral, placental, and cord blood respectively, with no difference between primigravidae and multigravidae. Submicroscopic infections were frequent and concerned all the positive cord samples. Maternal peripheral, late placental, and cord infections were all associated with a reduced mean birth weight in primigravidae (P = 0.02). Anemia prevalence was 53%, low birth rate was 13%, and prematurity was 25%. The use of intermittent preventive treatment with sulfadoxine-pyrimethamine (greater than or equal to one dose) combined with bed net was associated with a reduction in infection only in multigravidae and with a reduced risk of maternal anemia.     

Transgenic rhesus monkeys produced by gene transfer into early-cleavage–stage embryos using a simian immunodeficiency virus-based vector

The development of transgenic technologies in monkeys is important for creating valuable animal models of human physiology so that the etiology of diseases can be studied and potential therapies for their amelioration may be developed. However, the efficiency of producing transgenic primate animals is presently very low, and there are few reports of success. We have developed an improved methodology for the production of transgenic rhesus monkeys, making use of a simian immunodeficiency virus (SIV)-based vector that encodes EGFP and a protocol for infection of early-cleavage–stage embryos. We show that infection does not alter embryo development. Moreover, the timing of infection, either before or during embryonic genome activation, has no observable effect on the level and stability of transgene expression. Of 70 embryos injected with concentrated virus at the one- to two-cell stage or the four- to eight-cell stage and showing fluorescence, 30 were transferred to surrogate mothers. One transgenic fetus was obtained from a fraternal triple pregnancy. Four infant monkeys were produced from four singleton pregnancies, of which two expressed EGFP throughout the whole body. These results demonstrate the usefulness of SIV-based lentiviral vectors for the generation of transgenic monkeys and improve the efficiency of transgenic technology in nonhuman primates.     

Management of migraine in adolescents

Headaches in children and adolescents are still under-diagnosed. 75% of children are affected by primary headache by the age of 15 with 28% fitting the ICHD2 criteria of migraine. Migraine is considered a chronic disorder that can severely impact a child's daily activities, including schooling and socializing. Early recognition and aggressive therapy, with acute and prophylactic treatments, as well as intensive biobehavioral interventions, are essential to control the migraine attacks and reverse the progression into intractable disabling headache.     

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.     

Role and Localization of Urokinase Receptor in the Formation of New Microvascular Structures in Fibrin Matrices

Fibrin or a fibrinous exudate can facilitate angiogenesis in many pathological conditions. In vitro, the outgrowth of capillary-like structures in fibrin can be mimicked by exposing human microvascular endothelial cells (hMVECs) to an angiogenic growth factor and tumor necrosis factor (TNF)-alpha. Urokinase-type plasminogen activator (u-PA) and plasmin activities are required for this angiogenic process. This study focuses on the role and localization of the u-PA receptor (u-PAR) in newly formed microvascular structures. The u-PAR-blocking monoclonal antibody (MAb) H-2 completely inhibited the formation of capillary-like tubular structures induced by exposure of hMVECs to basic fibroblast growth factor and TNF-alpha. This was accompanied by a several-fold increase in u-PA accumulation in the conditioned medium. The effect of MAb H-2 was not caused by blocking cellular activation by u-PA/u-PAR interaction, as the amino-terminal fragment (ATF) of u-PA, which also activates u-PAR, prevented tube formation. In addition, the inhibition by MAb H-2 was not due to an effect of the antibody on u-PAR-vitronectin binding. These data show that inhibition of tube formation can be caused not only by inhibition of u-PA or plasmin activities but also by unavailability of the u-PAR for cell-bound proteolysis. Immunohistochemical analysis showed that in in vitro angiogenesis u-PAR and u-PA were localized on the invading, tube-forming hMVECs and not on the endothelial cells that are located on top of the fibrin matrix. u-PAR and u-PA were also prominently expressed on endothelial cells of neovessels present in an atherosclerotic plaque. These data may give more insight into the role of u-PAR in repair-associated angiogenesis.     

Endocrine and bone consequences of cyclic nutritional changes in the calcium, phosphate and vitamin D status in the rat: an in vivo depletion-repletion-redepletion study

Hypocalcemia secondary to vitamin D3 (D3) depletion (D-Ca-) perturbs extra- and intracellular calcium (Ca). To study the effect of cyclic nutritional changes in the D3 and calcium (Ca) repletion state, we investigated the lasting effects of calcium or D3 repletion on calcium and bone metabolism using a novel depletion-repletion-redepletion protocol. D-Ca- rats presenting osteomalacia without rickets and a significant impairment in whole body mineral content (BMC) accretion were repleted with either calcium alone [3% (Ca+3) or 0.5% (Ca+0.5)] or D3 and then switched back to the original D-Ca- diet. All repletion protocols, except Ca+0.5, normalized serum (S) Ca and parathyroid hormone (PTH) but Ca+3 exhibited growth retardation and hypophosphatemia. D3 normalized BMC in D-Ca- and healed osteomalacia while Ca+0.5 led to 50% normalization. In contrast, rickets with no BMC accretion was observed in Ca+3 most likely secondary to hypophosphatemia. Upon redepletion, S Ca rapidly decreased while S PTH and phosphate increased. D3 and Ca+0.5 survived the redepletion protocols but all Ca+3 died within 5 days upon sudden Ca withdrawal whereas progressive Ca redepletion significantly delayed the death rate. Data indicate that during the calcium redepletion period, correction of hypophosphatemia in Ca+3 allowed calcification of the enlarged growth plates thus resulting in an increased demand for calcium. It is postulated that this increased demand for calcium, in conjunction with low dietary calcium and the bone calcium reservoir incapacity to provide sufficient calcium to sustain S Ca, led to the observed acute hypocalcemia which was most likely the cause of death. This hypothesis is further supported by the observation that Ca+3 submitted to a progressive Ca deprivation exhibited a delay in death rate, a progressive involution of rickets and survival only upon return to the D-Ca- phenotype. Furthermore, in Ca+3, increasing dietary phosphate by 0.6% to achieve a Ca/P ratio similar to Ca+0.5 or D3 prevented the development of hypophosphatemia, slightly increased S Ca, significantly increased BMC, prevented the development of rickets and allowed 100% survival during rapid calcium withdrawal. Collectively, data clearly demonstrate the importance of the dietary Ca/P ratio to maintain S Ca/P at optimum concentrations for bone health.