Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites

Pregnant women are highly susceptible to malaria infection because of their low immunity and are at increased risk of maternal illness or death, in addition to spontaneous abortion, stillbirth, premature delivery, and low birth weight. However, the detailed pathogenesis of maternal malaria remains unclear. In this study, we evaluated a mouse model that shows similar severe pathological features of pregnant women during Plasmodium falciparum infection and investigated the pathogenesis of maternal malaria. Pregnant mice immunized by infection with an attenuated parasite, Plasmodium berghei XAT, were more susceptible to virulent P. berghei NK65 challenge/infection than were nonpregnant mice and showed high levels of parasitemia and a poor pregnancy outcome associated with placental pathology, such as accumulation of parasitized red blood cells, in the late phase of pregnancy. Notably, the pregnant immune mice challenged/infected with P. berghei NK65 developed liver injury associated with microvesicular fatty infiltration in late pregnancy. The pathological features were similar to acute fatty liver of pregnancy. Higher levels of gamma interferon and nitric oxide (NO) were found in plasma from pregnant immune mice infected with P. berghei NK65 than in plasma from nonpregnant mice. These findings suggest that development of liver injury and placental pathology in pregnant immune mice challenged/infected with P. berghei NK65 is accompanied by enhanced production of proinflammatory cytokines.     

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.     

A neuropsychological and neuroimaging study of a patient before and after treatment for paretic neurosyphilis

Abstract

A 41-year-old woman suffering from paretic neurosyphilis was treated successfully with high-dose penicillin. Detailed neuropsychological and neuroimaging studies were performed before and after treatment. The patient initially presented with presbyophrenia-like features of an amnesic-confabulatory state with a hypomanic mood. Pre-treatment neuropsychological examination revealed deficits in general intelligence, attention, memory, and frontal lobe executive function. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated severe hippocampa/parahippocampal damage, in addition to fronto-temporal atrophy and ventricular dilatation. Immediately after treatment, she was no longer confabulatory or hypomanic, but remained densely amnesic. Neuropsychological examination at that time revealed a significant improvement in frontal lobe function, whereas her memory was still impaired. However, CT and MRI showed no interval change. Single-photon emission CT (SPECT) demonstrated a remarkable improvement in cerebral perfusion, but the Increase in frontal perfusion was relatively small. Seven months after treatment, clinical and neuropsychological examination revealed no evidence of memory impairment. Cerebral perfusion on SPECT in the frontal areas by this time had improved to normal. Positron emission tomography (PET), however, still showed patchy areas of hypoperfusion/hypometabolism. This study demonstrates the patient's stepwise clinical recovery following early antibiotic therapy and shows the dissociation of neuropsychological recovery and changes on SPECT and PET.     

Association between ApoE phenotypes and telomere erosion in Alzheimer's disease

Although several reports suggest that Alzheimer's disease (AD) is associated with shortened telomere length, the clinical relevance of this has not yet been fully elucidated. This study was conducted to clarify the correlation of telomere length with clinical characteristics and ApoE phenotypes in 74 AD patients. Telomere length was determined from genomic DNA extracted from whole blood by quantitative real-time polymerase chain reaction. We found no significant difference in telomere length between the AD and non-dementia elderly control (n = 35) groups. Furthermore, no significant correlation was found among telomere length and the severity of cognitive decline and disease duration, age, or gender difference. However, telomere length was significantly shorter in AD patients with the ApoE4 homozygote than in those with the ApoE4 heterozygote (p < .001) and noncarriers (p < .001). These findings suggest that shortened telomere length may be associated with the ApoE4 homozygote in AD patients.     

Coronary ostium occlusion by coronary cusp displacement in Williams syndrome

Williams syndrome is a contiguous gene deletion syndrome resulting from a heterozygous deletion on chromosome 7q11.23, and is characterized by distinctive facial features and supravalvular aortic stenosis (SVAS). This syndrome rarely presents unpredictable cardiac death, and yet, as illustrated in the present case, it is still not possible to predict it, even on close monitoring. We herein describe the case of a 6‐year‐old Japanese girl with Williams syndrome, who had sudden cardiac collapse due to cardiac infarction after pharyngitis. Cardiac failure followed a critical course that did not respond to catecholamine support or heart rest with extracardiac mechanical support. Although marked coronary stenosis was not present, the left coronary cusp abnormally adhered to the aortic wall, which may synergistically cause coronary ostium occlusion with SVAS. Altered hemodynamic state, even that caused by the common cold, may lead to critical myocardial events in Williams syndrome with SVAS.     

Complex translocations derived stepwise from standard t(15;17) in a patient with variant acute promyelocytic leukemia

We report the case of an elderly man with an acute promyelocytic leukemia variant carrying complex variant translocations. The Q-banded karyotype and spectral karyotyping method revealed a typical t(15;17), and two complex rearrangements caused by stepwise translocation derived from a typical t(15;17). Chromosomes 8 and 14 were related to these rearrangements. The patient received induction chemotherapy using all-trans retinoic acid and achieved complete remission. To our knowledge, a case with complex rearrangements, caused by apparent stepwise translocation, at diagnosis, has not been reported previously.