Prospectus

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Rapid Selection of Plasmodium falciparum Chloroquine Resistance Transporter Gene and Multidrug Resistance Gene-1 Haplotypes Associated with Past Chloroquine and Present Artemether-Lumefantrine Use in Inhambane District,Southern Mozambique

Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P ≤ 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246 haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased use of CQ and large-scale use of AL. In the absence of a clear AL-resistance marker and the (almost) continent-wide use of AL in sub-Saharan Africa, and when considering CQ reintroduction, continued monitoring of these markers is needed.     

Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells

Protective protein/cathepsin A (PPCA), a lysosomal carboxypeptidase, is deficient in the neurodegenerative lysosomal disorder galactosialidosis (GS). PPCA(-/-) mice display a disease course similar to that of severe human GS, resulting in nephropathy, ataxia, and premature death. Bone marrow transplantation (BMT) in mutant animals using transgenic BM overexpressing the corrective enzyme in either erythroid cells or monocytes/macrophages has proven effective for the improvement of the phenotype, and encouraged the use of genetically modified BM cells for ex vivo gene therapy of GS. Here, we established stable donor hematopoiesis in PPCA(-/-) mice that received hematopoietic progenitors transduced with a murine stem cell virus (MSCV)-based, bicistronic retroviral vector overexpressing PPCA and the green fluorescent protein (GFP) marker. We observed complete correction of the disease phenotype in the systemic organs up to 10 months after transplantation. PPCA(+) BM-derived cells were detected in all tissues, with the highest expression in liver, spleen, BM, thymus, and lung. In addition, a lysosomal immunostaining was seen in nonhematopoietic cells, indicating efficient uptake of the corrective protein by these cells and cross-correction. Expression in the brain occurred throughout the parenchyma but was mainly localized on perivascular areas. However, PPCA expression in the central nervous system was apparently sufficient to delay the onset of Purkinje cell degeneration and to correct the ataxia. The long-term expression and internalization of the PPCA by cells of systemic organs and the clear improvement of the neurologic phenotype support the use of this approach for the treatment of GS in humans. (Blood. 2002;99:3169-3178)     

Prevalence effect in a laboratory environment

PURPOSE: To measure observer performance at various levels of prevalence. MATERIALS AND METHODS: A multiobserver multiabnormality receiver operating characteristic (ROC) study to assess the effect of prevalence on observer performance was conducted. Fourteen observers, including eight faculty members, two fellows, and four residents, interpreted 1,632 posteroanterior chest images with five prevalence levels by using a nested study design. Performance comparisons were accomplished by using a multireader multicase approach to assess the effect of prevalence from 28% (69 of 249) to 2% (31 of 1,577) on diagnostic accuracy. The mean times required to review and report a case were analyzed and compared for different levels of prevalence and readers' experience. RESULTS: Area under the ROC curve demonstrated that, with the study experimental conditions, no significant effect could be measured as a function of prevalence (P >.05) for any abnormality, group of cases, or readers. There were no significant differences (P >.05) in the mean times required to review and report cases at different prevalence levels and with different groups of readers. CONCLUSION: The consistency in the results and the size of this study suggest that with laboratory conditions, if a prevalence effect exists, it is quite small in magnitude; hence, it will not likely alter conclusions derived from such studies.     

A humid corridor across the Sahara for the migration of early modern humans out of Africa 120,000 years ago

It is widely accepted that modern humans originated in sub-Saharan Africa approximately 150-200 thousand years ago (ka), but their route of dispersal across the currently hyperarid Sahara remains controversial. Given that the first modern humans north of the Sahara are found in the Levant approximately 120-90 ka, northward dispersal likely occurred during a humid episode in the Sahara within Marine Isotope Stage (MIS) 5e (130-117 ka). The obvious dispersal route, the Nile, may be ruled out by notable differences between archaeological finds in the Nile Valley and the Levant at the critical time. Further west, space-born radar images reveal networks of-now buried-fossil river channels that extend across the desert to the Mediterranean coast, which represent alternative dispersal corridors. These corridors would explain scattered findings at desert oases of Middle Stone Age Aterian lithic industries with bifacial and tanged points that can be linked with industries further to the east and as far north as the Mediterranean coast. Here we present geochemical data that demonstrate that water in these fossil systems derived from the south during wet episodes in general, and penetrated all of the way to the Mediterranean during MIS 5e in particular. This proves the existence of an uninterrupted freshwater corridor across a currently hyperarid region of the Sahara at a key time for early modern human migrations to the north and out of Africa.