The ciliopathy Joubert syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear1–3. In order to investigate Joubert syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert syndrome gene4,5. These mice exhibit cerebellar hypoplasia with a vermis/midline fusion defect early in development. This defect is concomitant with expansion of the roof plate and is also evident in a mouse mutant for another Joubert syndrome gene, Cep2906,7. Further, fetal magnetic resonance imaging (MRI) from human subjects with Joubert syndrome reveals a similar midline cleft suggesting parallel pathogenic mechanisms. Previous evidence has suggested a role for Jouberin (Jbn), the protein encoded by Ahi1, in canonical Wnt signaling8. Consistent with this, we found decreased Wnt reporter activity at the site of hemisphere fusion in the developing cerebellum of Ahi1 mutant mice. This decrease was accompanied by reduced proliferation at the site of fusion. Finally, treatment with lithium, a Wnt pathway agonist9, partially rescued this phenotype. Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome, which can be overcome with Wnt stimulation.

No abstract

Heart disease affects 1 in 3 individuals in the United States, and the prevalence of heart failure (HF) is increasing exponentially. Although our understanding of the disease progression of congestive HF (CHF) has advanced, refining the areas of diagnosis, risk stratification, prognosis, and treatment is still needed. The natriuretic peptides, specifically B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), have shown promise in clinical practice. Brain natriuretic peptide is released from cardiac ventricular myocytes in response to volume or pressure overload. Rapid measurement of plasma BNP or NT-proBNP has been shown to increase the diagnostic accuracy of HF exacerbations. A cutoff value of 100 pg/mL has a sensitivity and specificity of 90% and 73%, respectively, according to the Breathing Not Properly Study. In addition, BNP and NT-proBNP have been considered independent predictors of adverse outcome. One study calculated a 35% increase in risk of death due to HF for every 100-pg/mL increase in BNP level. Lastly, natriuretic peptides have been known to decrease following medical therapy of HF, suggesting the role of their measurement in monitoring inpatient disease progression and outpatient medical programs. The future of natriuretic peptides lies in risk stratification in other cardiac diseases, such as acute coronary syndrome, and possibly determining severity of valvular disease. Although there is substantial work done in elucidating the power of natriuretic peptides in clinical practice, more research is necessary to reach a consensus regarding how to appropriately utilize them in treatment regimens.

No abstract