FGF-4 signaling is involved in mir-206 expression in developing somites of chicken embryos.

The microRNAs (miRNAs) are recently discovered short, noncoding RNAs, that regulate gene expression in metazoans. We have cloned short RNAs from chicken embryos and identified five new chicken miRNA genes. Genome analysis identified 17 new chicken miRNA genes based on sequence homology to previously characterized mouse miRNAs. Developmental Northern blots of chick embryos showed increased accumulation of most miRNAs analyzed from 1.5 days to 5 days except, the stem cell-specific mir-302, which was expressed at high levels at early stages and then declined. In situ analysis of mature miRNAs revealed the restricted expression of mir-124 in the central nervous system and of mir-206 in developing somites, in particular the developing myotome. In addition, we investigated how miR-206 expression is controlled during somite development using bead implants. These experiments demonstrate that fibroblast growth factor (FGF) -mediated signaling negatively regulates the initiation of mir-206 gene expression. This may be mediated through the effects of FGF on somite differentiation. These data provide the first demonstration that developmental signaling pathways affect miRNA expression. Thus far, miRNAs have not been studied extensively in chicken embryos, and our results show that this system can complement other model organisms to investigate the regulation of many other miRNAs.     

Clinical findings in four children with biotinidase deficiency detected through a statewide neonatal screening program

Four children with biotinidase deficiency were identified during the first year of a neonatal screening program for this disease in the Commonwealth of Virginia. Two unrelated probands were identified among the 81,243 newborn infants who were screened. In addition, two siblings of one of these infants were found to be affected. Both probands had mild neurologic symptoms at two and four months, respectively, and the two older children had more severe neurologic abnormalities, cutaneous findings, and developmental delay at two and three years of age. However, none of the affected children had acute metabolic decompensation. Previous studies have shown that the administration of biotin to affected children can be a lifesaving procedure that can reverse acute symptoms and prevent irreversible neurologic damage. Our findings demonstrate that subtle neurologic abnormalities may appear as early as at two months of age and that developmental abnormalities may occur even in the absence of episodes of overt metabolic decompensation. Since screening and treatment are both inexpensive and effective and the incidence of the disease is well within the range of that of other metabolic diseases for which screening is performed, biotinidase deficiency should be added to the group of metabolic diseases for which screening is done in the neonatal period.     

"Crack" cocaine-associated stroke

We present three cases of "crack" cocaine-associated stroke, together with a review of cocaine-associated cerebrovascular complications. Unlike previously reported cases tentatively associating ischemic stroke with cocaine, our patients had no other potential causes for their strokes. Although the exact mechanism of cocaine-related stroke remains uncertain, both disordered neurogenic control of the cerebral circulation as well as systemic factors (ie, acute hypertension) may play a role.     

Effect of QT interval prolongation on cardiac arrest following liver transplantation and derivation of a risk index

Liver transplantation (LT) has a 4-fold higher risk of periprocedural cardiac arrest and ventricular arrhythmias (CA/VAs) compared with other noncardiac surgeries. Prolongation of the corrected QT interval (QTc) is common in patients with liver cirrhosis. Whether it is associated with an increased risk of CA/VAs following LT is unclear. Rates of 30-day CA/VAs post-LT were assessed in consecutive adults undergoing LT between 2010 and 2017. Pretransplant QTc was measured by a cardiologist blinded to clinical outcomes. Among 408 patients included, CA/VAs occurred in 26 patients (6.4%). QTc was significantly longer in CA/VA patients (475 ± 34 vs 450 ± 34 ms, P < .001). Optimal QTc cut-off for prediction of CA/VAs was ≥480 ms. After adjustment, QTc ≥480 ms remained the strongest predictor for the occurrence of CA/VAs (odds ratio [OR] 5.2, 95% confidence interval [CI] 2.2-12.6). A point-based cardiac arrest risk index (CARI) was derived with the bootstrap method for yielding optimism-corrected coefficients (2 points: QTc ≥480, 1 point: Model for End-Stage Liver Disease [MELD] ≥30, 1 point: age ≥65, and 1 point: male). CARI score ≥3 demonstrated moderate discrimination (c-statistic 0.79, optimism-corrected c-statistic 0.77) with appropriate calibration. QTc ≥480 ms was associated with a 5-fold increase in the risk of CA/VAs. The CARI score may identify patients at higher risk of these events. Whether heightened perioperative cardiac surveillance, avoidance of QT prolonging medications, or beta blockers could mitigate the risk of CA/VAs in this population merits further study.     

Spinal cord dysfunction in Paget's disease of bone. Has medical treatment a vascular basis?

The medical treatment of eight patients with paraparesis associated with Paget's disease of the vertebrae is described. Treatment, for 3 to 87 months, with calcitonin or with diphosphonates produced marked clinical improvement in seven of these patients. From this series and a review of 19 additional case reports it is concluded that favourable clinical response is seen in about 90 per cent of patients, and that this may occur very rapidly. Results are as good or better than those obtained by surgical decompression. It seems possible that paraparesis in some cases may be due to diversion of blood supply from the spinal cord to the highly vascular Pagetic bone giving rise to a vascular "steal" syndrome. It is suggested that medical treatment should be used more widely to avoid or delay the need for operation and reduce the risks of recurrence. These patients, however treated, require lifelong follow-up because relapses are common.     

Vascular endothelial growth factor accelerates renal recovery in experimental thrombotic microangiopathy

BACKGROUND: Renal microvascular injury characterizes thrombotic microangiopathy (TMA). The possibility that angiogenic growth factors may accelerate recovery in TMA has not been studied. METHODS: TMA was induced in rats by the selective right renal artery perfusion of antiglomerular endothelial cell IgG (30 mg/kg). Twenty-four hours later, rats received vascular endothelial growth factor (VEGF121, 100 microg/kg/day) or vehicle (control) daily until day 14. To evaluate renal function, the unperfused left kidney was removed at day 14, and rats were sacrificed at day 17. RESULTS: The induction of TMA was associated with loss of glomerular and peritubular capillary endothelial cells and decreased arteriolar density at day 1. Some spontaneous capillary recovery was present by day 17; however, repair was incomplete, and severe tubulointerstitial damage occurred. The lack of complete microvascular recovery was associated with reduced VEGF immunostaining in the outer medulla. VEGF-treated rats had more glomeruli with intact endothelium, less glomerular ischemia (collapsed glomeruli), and greater peritubular capillary density with less peritubular capillary loss. This was associated with less tubulointerstitial fibrosis, less cortical atrophy, and improved renal function. CONCLUSIONS: VEGF accelerates renal recovery in this experimental model of TMA. These studies suggest that angiogenic growth factors may provide a new therapeutic strategy for diseases associated with endothelial cell injury.