Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes.

We investigated hearing impairment (HI) in 51 families from Ghana with at least two affected members that were negative for GJB2 pathogenic variants. DNA samples from 184 family members underwent whole-exome sequencing (WES). Variants were found in 14 known non-syndromic HI (NSHI) genes [26/51 (51.0%) families], five genes that can underlie either syndromic HI or NSHI [13/51 (25.5%)], and one syndromic HI gene [1/51 (2.0%)]. Variants in CDH23 and MYO15A contributed the most to HI [31.4% (16/51 families)]. For DSPP, an autosomal recessive mode of inheritance was detected. Post-lingual expression was observed for a family segregating a MARVELD2 variant. To our knowledge, seven novel candidate HI genes were identified (13.7%), with six associated with NSHI (INPP4B, CCDC141, MYO19, DNAH11, POTEI, and SOX9); and one (PAX8) with Waardenburg syndrome. MYO19 and DNAH11 were replicated in unrelated Ghanaian probands. Six of the novel genes were expressed in mouse inner ear. It is known that Pax8-/- mice do not respond to sound, and depletion of Sox9 resulted in defective vestibular structures and abnormal utricle development. Most variants (48/60; 80.0%) have not previously been associated with HI. Identifying seven candidate genes in this study emphasizes the potential of novel HI genes discovery in Africa.

Etiologies of Childhood Hearing Impairment in Schools for the Deaf in Mali.

Objectives: To identify the etiologies of hearing impairment (HI) in schools for students who are deaf and to use a systematic review to summarize reports on the etiologies and clinical and genetic features of HI in Mali. Methods: We included individuals with HI that started before the age of 15 years old. Patients were carefully evaluated under standard practices, and pure-tone audiometry was performed where possible. We then searched for articles published on HI in the Malian population from the databases' inception to March 30, 2020. Results: A total of 117 individuals from two schools for the deaf were included, and a male predominance (sex ratio 1.3; 65/52) was noted. HI was pre-lingual in 82.2% (n = 117), and the median age at diagnosis was 12 years old. The etiologies were environmental in 59.4% (70/117), with meningitis being the leading cause (40%, 20/70), followed by cases with genetic suspicion (29.3%, 21/117). In 11.3% (8/117) of patients, no etiology was identified. Among cases with genetic suspicion, three were syndromic, including two cases of Waardenburg syndrome, while 15 individuals had non-syndromic HI. An autosomal recessive inheritance pattern was observed in 83.3% of families (15/18), and consanguinity was reported in 55.5% (10/18) of putative genetic cases. Conclusion: This study concludes that environmental factors are the leading causes of HI in Mali. However, genetic causes should be investigated, particularly in the context of a population with a high consanguinity rate.

Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice.

Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·µmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity.

Antiplasmodial activity of cucurbitacin glycosides from Datisca glomerata (C. Presl) Baill.

The traditionally used antimalarial plant, Datisca glomerata (C. Presl) Baill, was subjected to antiplasmodial assay guided fractionation. This led to the isolation of seven cucurbitacin glycosides, datiscosides I-O, along with two known compounds, datiscoside and datiscoside B, from the aerial parts of D. glomerata. Their structures and relative stereochemistry were determined on the basis of mass spectrometry, 1D and 2D NMR spectroscopic data. Antiplasmodial IC(50) values were determined for all isolated compounds against a chloroquine sensitive strain of Plasmodium falciparum (D10), which were also evaluated in vitro for their antileishmanial activity against Leishmania tarentolae. Cytotoxicity was evaluated against rat skeletal muscle cells (L6) and Chinese ovarian hamster cells (CHO). The antiplasmodial activity of the compounds was moderate and ranged from 7.7 to 33.3 µM. None of the compounds showed appreciable antileishmanial activity. The compounds displayed cytotoxicity against L6 but not CHO mammalian cells.

Antiparasitic compounds from Cornus florida L. with activities against Plasmodium falciparum and Leishmania tarentolae.

AIM OF THE STUDY: The objective of this study was to identify the antiplasmodial constituents from the bark of Cornus florida L., a plant traditionally used in North America for the treatment of malaria. METHODS AND MATERIALS: Dried and powdered bark was extracted with 95% ethanol. The resultant extract was subjected to in vitro antiplasmodial-guided fractionation against Plasmodium falciparum (D10 strain). Antiplasmodial IC(50) values were calculated for pure compounds. Compounds were also assayed against Leishmania tarentolae, and rat skeletal myoblast L6 cells to assess antileishmanial activity and cytotoxicity, respectively. RESULTS: Antiplasmodial-guided fractionation afforded 8 compounds: betulinic acid (1), ursolic acid (2), ß-sitosterol (3), ergosta-4,6,8,22-tetraene-3-one (4), 3ß-O-acetyl betulinic acid (5), 3-epideoxyflindissol (6), 3ß-O-cis-coumaroyl betulinic acid (7), 3ß-O-trans-coumaroyl betulinic acid (8), of which, (6) is for the first time here isolated from a natural product and (4), (7) and (8) are reported for the first time from this genus. In vitro IC(50) values against P. falciparum for (4) (61.0 µM) (6) (128.0 µM), (7) (10.4 µM), (8) (15.3 µM) are reported for the first time. Antileishmanial IC(50) values are reported here for the first time for (4) (11.5 µM), (6) (1.8 µM), (7) (8.3 µM) and (8) (2.2 µM). Cytotoxicity against L6 cells is reported for all compounds. CONCLUSIONS: The compounds isolated in this study, while displaying moderate in vitro antiplasmodial activity, do not fully support the historical importance of C. florida as an antimalarial remedy in North America. The traditional remedy may exert its well documented effects by mechanisms unrelated to direct antiplasmodial action. While not traditionally used to treat Leishmania, this work shows that several constituents of C. florida possess promising in vitro antileishmanial activity.