Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most down-regulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis.

No abstract

No abstract

Prognosis of systemic sclerosis (SSc) depends on internal organ involvement. We assessed the value of renal function reserve (RFR) for the detection of preclinical nephropathy in scleroderma. Thirty SSc patients with normal serum creatinine and 30 healthy controls were included. Medsger disease severity score, glomerular filtration rate (GFR), and microalbuminuria were measured. Tc-99m DTPA was utilized for GFR measurement at baseline and after oral protein overload (stimulated GFR). RFR was calculated as the percentile increase of stimulated GFR. SSc patients had lower means of baseline GFR (P=0.001), stimulated GFR (P=0.004), RFR (P=0.046), and higher microalbuminuria (P=0.009) than controls. According to baseline GFR, SSc patients showed three categories-normal baseline GFR (n=12), hyperfiltration GFR (n=3), and reduced baseline GFR (n=15). In the former category, RFR was normal in 6/12 patients and abnormal in the remainders (50%). Hyperfiltration patients and those with reduced baseline GFR showed abnormal RFR. A statistically significant negative association was found between microalbuminuria versus stimulated GFR and RFR (r= -0.5, P=0.007 and r= -0.45, P=0.013, respectively). The majority of SSc patients with abnormal RFR had disease duration of ≥48 months (60% vs. 20%, P=0.008). All SSc patients with pulmonary hypertension had abnormal RFR, while reduced baseline GFR was noted in only 60%. A significant negative correlation was found between reduced baseline GFR and cumulative dose of corticosteroids in SSc patients (r= -0.4, P=0.022). RFR estimation could be a useful predictive marker for preclinical renal involvement in SSc patients so that early prophylactic measures and therapy modifications could be considered.

There has been a gradual decrease in inpatient surgical treatment for both NTT and ATT, presumably as a result of increased outpatient and/or non-operative management of these children. Concerningly, TL patterns have not improved; targeted interventions such as parental and adolescent male health education may lead to timely recognition/intervention in children at-risk for ATT. We noted no regional/racial disparities in contrast to earlier studies.

No abstract

No abstract

The aim of this study is to evaluate Protein Z (PTZ) and protein C (PTC) levels in newborns suffering from RDS, healthy preterm and full term newborns and to compare PTZ serum levels in RDS preterm infants with healthy preterm before and after recovery. Sixty newborn infants, recruited from the neonatal unit, were enrolled in the study and divided into 3 groups: Group (I): 20 preterm with RDS, Group (II): 20 healthy preterm control newborns (CPT) and Group (III): 20 healthy full term control newborns (CFT). Protein Z and C were measured using ELISA kits. The results of the study showed lower levels of protein Z were obtained in RDS group compared to preterm controls whose levels were significantly lower than in full-term controls. A significant increase in PTZ levels in RDS' group after recovery, when compared to preterm controls. In RDS, no significant correlations existed between PTZ levels (before and after recovery) and routine investigations except for a significant negative correlation with platelets count. No significant differences were found in PTC levels between the 3 studied groups. To conclude: premature newborns suffering from RDS showed decreased serum protein Z levels than normal preterm control newborns with further increase in its pattern after recovery. Further studies are recommended to evaluate the role of PTZ on outcome in premature newborns with RDS and to evaluate the relationship between protein PTZ and PTC and other coagulation factors incriminated in the development of RDS.