Can prognostic indicators be identified in a fetus with an encephalocele?

Encephaloceles, like other congenital malformations of the brain diagnosable in utero, can be either complicated (there being an associated chromosomal abnormality, abnormalities in the remainder of the central nervous system (CNS) and/or other organs), or isolated (no abnormalities in the chromosomes, the remainder of the CNS or other organs). Complicated cases invariably have a poor prognosis but amongst those with isolated lesions the outcome is variable with some affected children having poor mental and physical development but others who are only mildly or moderately disabled. To be able to make an informed decision about how to manage their pregnancy parents need to know what the prognosis is likely to be for their fetus with an encephalocele. To see if the necessary information could be reliably gathered by prenatal assessment of affected fetuses, a review was carried out of the medical records and ultrasound scans of 31 fetuses with encephaloceles referred to the Fetal Management Unit at St. Mary's Hospital in Manchester between January 1991 and December 1997. Eighteen of the cohort were classified as having a complicated encephalocele. Thirteen of the pregnancies were terminated; there were three intrauterine deaths, and one neonatal death. There is only one surviving child who is severely disabled. Thirteen fetuses were classified as having isolated encephaloceles, six had a mass of neural tissue in the encephalocele sac and were terminated, one died in utero and six had a cystic lesion or only a nubbin and have survived with few or no abnormalities. This study has shown that it is possible to identify fetuses with an encephalocele with a favourable outcome.

Identification of a calcium channel modulator using a high throughput yeast two-hybrid screen.

The interaction of the N-type calcium channel beta3 subunit with the alpha1B subunit alters the activation/inactivation kinetics and the maximal conductance of the channel. The defined protein-protein interaction of the human alpha1B and beta3 subunits provides a target for small-molecule modulation of N-type channel activity. We describe a high throughput screen based on a counterselection yeast two-hybrid assay, which was used to identify small molecules that disrupt alpha1B-beta3 subunit interactions and inhibit N-type calcium channel activity. These small molecules may be a new class of calcium channel antagonists with therapeutic potential.

Divergent expression of EtA and EtB receptors in response to cyclosporine in mesangial cells.

We examined the effects of cyclosporine (Cy) on preproendothelin-1 (prepro Et-1) and both Et receptors, A-type (EtA) and B-type (EtB), in rat glomerular mesangial cells. Cy at 10(-5) mol/L, the concentration relevant to tissue levels in vivo, increased mRNA for prepro Et-1 after both 1 and 3 hours to 183 +/- 14% (n = 8) and 147 +/- 12% (n = 9) of levels seen in control cells. A similar pattern was observed at a lower dose of Cy (10(-6) mol/L, the concentration relevant to plasma levels in vivo): at 1 hour, expression increased to 146 +/- 15% (n = 5); at 3 hours, expression was 159 +/- 25% (n = 8). Concomitant with these changes in expression of prepro Et-1 mRNA, the Et-1 protein nearly doubled at 3 hours. Both EtA and EtB mRNA were expressed in unstimulated mesangial cells and were affected differently by Cy. Little change was observed in the EtA mRNA. In contrast, EtB mRNA increased with Cy (10(-5) mol/L) up to 129 +/- 8% (n = 6) at 1 hour and 265 +/- 62% (n = 3) at 3 hours. A similar effect was seen with the lower dose of Cy: EtB expression increased to 129 +/- 9% (n = 6) of control value at 1 hour and 253 +/- 74% (n = 4) at 3 hours. These results indicate that Cy enhances expression of mRNA for prepro Et-1 and production of mature Et-1 by glomerular mesangial cells. Further, Cy has differential effects on EtA and EtB, affecting EtA minimally while markedly increasing the expression of EtB. These results constitute the first demonstration that Et receptor subtypes are modulated in a pathophysiological setting. The divergent modulation of EtA and EtB raises the possibility that there are differences in contribution of each of the receptor subtypes to pathophysiological mechanisms of Cy toxicity.

Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity.

Endothelin (Et) has been implicated in cyclosporine A (CsA) nephrotoxicity. We have previously shown that CsA treatment in rats results in up-regulation of Et receptors specifically within the kidney. The role of Et in vivo CsA nephrotoxicity was therefore studied further with a new competitive antagonist, BQ-123, specific for Et(A) receptors (EtRA). Systemic administration of CsA in Munich-Wistar rats resulted in marked glomerular hypoperfusion and hypofiltration, with RPF in left and right kidneys falling by some 40% to 1.60 +/- 0.25 and 1.73 +/- 0.38 ml/min and GFR decreasing by some 20% to 0.61 +/- 0.05 and 0.67 +/- 0.11 ml/min, respectively. Selective infusion of EtRA into the left renal artery following systemic CsA treatment had no effect on this hemodynamic pattern (RPF 1.58 +/- 0.29 and 1.92 +/- 0.34 ml/min and GFR 0.60 +/- 0.09 and 0.70 +/- 0.08 ml/min in left and right kidneys, respectively, P = NS vs. CsA period). By contrast, intrarenal infusion of EtRA prior to systemic administration of CsA resulted in a strikingly different pattern of renal hemodynamics. Thus, EtRA pretreatment in the left kidney protected against glomerular dysfunction following CsA: RPF was maintained, 3.23 +/- 0.28 ml/min versus 2.96 +/- 0.31 (P = NS EtRA vs. EtRA + CsA), as was the GFR, 1.04 +/- 0.16 ml/min versus 1.12 +/- 0.09 (P = NS). However, the contralateral right kidneys of these rats, not pretreated with EtRA, showed no protective effect: RPF decreased from 3.15 +/- 0.34 ml/min to 2.39 +/- 0.19 and GFR from 1.04 +/- 0.10 ml/min to 0.85 +/- 0.07 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Reconstruction of the upper extremity in tetraplegia: functional assessment, surgical procedures and rehabilitation.

The results of 22 procedures (8 for elbow extension, 14 for hand rehabilitation) on the upper limb in tetraplegia are reported. To evaluate the effect of surgery an objective hand function test is presented. The few complications after surgery must be attributed to the material used.