In Vivo Curative and Protective Potential of Orally Administered 5-Aminolevulinic Acid plus Ferrous Ion against Malaria

5-Aminolevulinic acid (ALA) is a naturally occurring amino acid present in diverse organisms and a precursor of heme biosynthesis. ALA is commercially available as a component of cosmetics, dietary supplements, and pharmaceuticals for cancer diagnosis and therapy. Recent reports demonstrated that the combination of ALA and ferrous ion (Fe²⁺) inhibits the in vitro growth of the human malaria parasite Plasmodium falciparum. To further explore the potential application of ALA and ferrous ion as a combined antimalarial drug for treatment of human malaria, we conducted an in vivo efficacy evaluation. Female C57BL/6J mice were infected with the lethal strain of rodent malaria parasite Plasmodium yoelii 17XL and orally administered ALA plus sodium ferrous citrate (ALA/SFC) as a once-daily treatment. Parasitemia was monitored in the infected mice, and elimination of the parasites was confirmed using diagnostic PCR. Treatment of P. yoelii 17XL-infected mice with ALA/SFC provided curative efficacy in 60% of the mice treated with ALA/SFC at 600/300 mg/kg of body weight; no mice survived when treated with vehicle alone. Interestingly, the cured mice were protected from homologous rechallenge, even when reinfection was attempted more than 230 days after the initial recovery, indicating long-lasting resistance to reinfection with the same parasite. Moreover, parasite-specific antibodies against reported vaccine candidate antigens were found and persisted in the sera of the cured mice. These findings provide clear evidence that ALA/SFC is effective in an experimental animal model of malaria and may facilitate the development of a new class of antimalarial drug.     

Rat subthalamic nucleus and zona incerta share extensively overlapped representations of cortical functional territories

The subthalamic nucleus (STN) and the zona incerta (ZI) are two major structures of the subthalamus. The STN has strong connections between the basal ganglia and related nuclei. The ZI has strong connections between brainstem reticular nuclei, sensory nuclei, and nonspecific thalamic nuclei. Both the STN and ZI receive heavy projections from a subgroup of layer V neurons in the cerebral cortex. The major goal of this study was to investigate the following two questions about the cortico‐subthalamic projections using the lentivirus anterograde tracing method in the rat: 1) whether cortical projections to the STN and ZI have independent functional organizations or a global organization encompassing the entire subthalamus as a whole; and 2) how the cortical functional zones are represented in the subthalamus. This study revealed that the subthalamus receives heavy projections from the motor and sensory cortices, that the cortico‐subthalamic projections have a large‐scale functional organization that encompasses both the STN and two subdivisions of the ZI, and that the group of cortical axons that originate from a particular area of the cortex sequentially innervate and form separate terminal fields in the STN and ZI. The terminal zones formed by different cortical functional areas have highly overlapped and fuzzy borders, as do the somatotopic representations of the sensorimotor cortex in the subthalamus. The present study suggests that the layer V neurons in the wide areas of the sensorimotor cortex simultaneously control STN and ZI neurons. Together with other known afferent and efferent connections, possible new functionality of the STN and ZI is discussed. J. Comp. Neurol. 522:4043–4056, 2014. © 2014 Wiley Periodicals, Inc.     

Impact of statin therapy on late target lesion revascularization after sirolimus-eluting stent implantation (from the CREDO-Kyoto Registry Cohort-2)

Therapeutic strategies preventing late target lesion revascularization (TLR) after drug-eluting stent implantation have not been yet adequately investigated. In 13,087 consecutive patients undergoing first percutaneous coronary intervention in the CREDO-Kyoto Registry Cohort-2, we identified 10,221 patients who were discharged alive after implantation of sirolimus-eluting stents (SESs) only (SES stratum 5,029) or bare-metal stents (BMSs) only (BMS stratum 5,192). Impact of statin therapy at time of discharge from the index hospitalization on early (within the first year) and late (1 year to 4 years) TLR, was assessed in the SES stratum (statin group 2,735; nonstatin group 2,294) and in the BMS stratum (statin group 2,576; nonstatin group 2,616). Despite a significantly lower incidence of early TLR (7.8% vs 22.2%, p <0.0001), SES use compared to BMS use was associated with a significantly higher incidence of late TLR (7.7% vs 3.0%, p <0.0001). In the SES and BMS strata, the incidence of early TLR was similar regardless of statin use. In the SES stratum, the incidence of late TLR was significantly lower in the statin group than in the nonstatin group (6.1% vs 9.6%, p = 0.002), whereas no significant difference was found in the BMS stratum (2.6% vs 3.3%, p = 0.38). After adjusting confounders, risk for late TLR significantly favored statin use in the SES stratum (hazard ratio 0.73, 95% confidence interval 0.54 to 0.98, p = 0.04), whereas the risk decrease was not significant in the BMS stratum (hazard ratio 0.74, 95% confidence interval 0.46 to 1.20, p = 0.23). In conclusion, statin therapy at hospital discharge was associated with a significantly lower risk for late TLR after SES implantation.     

Human FcγRIIA induces anaphylactic and allergic reactions

IgE and IgE receptors (FcεRI) are well-known inducers of allergy. We recently found in mice that active systemic anaphylaxis depends on IgG and IgG receptors (FcγRIIIA and FcγRIV) expressed by neutrophils, rather than on IgE and FcεRI expressed by mast cells and basophils. In humans, neutrophils, mast cells, basophils, and eosinophils do not express FcγRIIIA or FcγRIV, but FcγRIIA. We therefore investigated the possible role of FcγRIIA in allergy by generating novel FcγRIIA-transgenic mice, in which various models of allergic reactions induced by IgG could be studied. In mice, FcγRIIA was sufficient to trigger active and passive anaphylaxis, and airway inflammation in vivo. Blocking FcγRIIA in vivo abolished these reactions. We identified mast cells to be responsible for FcγRIIA-dependent passive cutaneous anaphylaxis, and monocytes/macrophages and neutrophils to be responsible for FcγRIIA-dependent passive systemic anaphylaxis. Supporting these findings, human mast cells, monocytes and neutrophils produced anaphylactogenic mediators after FcγRIIA engagement. IgG and FcγRIIA may therefore contribute to allergic and anaphylactic reactions in humans.     

Radicular cyst in a patient with untreated Wiskott–Aldrich syndrome: A case report

Wiskott–Aldrich syndrome (WAS) is a condition with variable expression, which causes persistent thrombocytopenia and, in its complete form, also causes small platelets and humoral immunodeficiency. A 14-year-old boy, diagnosed with WAS but never treated, presented with symptoms of heart and renal failure. His right buccal region was swollen and his right first molar showed a cyst-like image on dental X-ray films. The boy's symptoms were attributed to an infected cyst, greatly aggravated by WAS-related immunodeficiency. The boy was sedated and the affected tooth and cyst were enucleated. Invasive treatment was safely achieved by paying close attention to whole-body management.