Use of cidofovir in polyomavirus BK viral nephropathy in two renal allograft recipients

Polyomavirus BK viral allograft nephropathy is a potentially reversible cause of deteriorating function of kidney allografts. Initial treatment involves reducing immunosuppressive medications, with low-dose cidofovir an effective alternative in refractory cases. We describe two cases of BK viral allograft nephropathy responding to low-dose cidofovir after a reduction in immunosuppressive medications failed to clear the virus or stabilize the deterioration in renal function. There were no significant side-effects from this treatment in either patient.     

Repeated rating improves value of diagnostic dopaminergic challenge tests in Parkinson's disease

Summary. Clinicians use acute challenges with levodopa (LD) and/or apomorphine (A) for diagnostic dopaminergic response tests in Parkinson's disease (PD) patients. We consecutively compared the value of both drugs with performance of repeated ratings and adverse effect recording. Oral administration of 200 mg LD was superior to subcutaneous injection of 4 mg A in terms of tolerability and onset of temporary UPDRS motor score decline ([previously untreated PD patients] LD: 4.02 [mean] ± 2.45 [SD] {significant decrease: p = 1.42E-07} vs. A: 1.58 ± 3.38 {not significant decrease: p = 0.14}, p = 0.0009; [treated PD patients] LD: 7.71 ± 4.35 {significant decrease: p = 2.48E-06} vs. A: 5.19 ± 4.32 {significant decrease: p = 7.83E-05}, p = 0.07). We suggest diagnostic acute challenge test performance with LD as first- and A as second choice due to better tolerability and valuation in combination with repeated scoring procedures to improve sensitivity and specifity. Received December 12, 2002; accepted January 20, 2003 Published online April 7, 2003 Authors' address: Prof. Dr. Th. Müller, Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany, e-mail: thomas.mueller@ruhr-uni-bochum.de     

Epidemiology of congenital hearing loss in Victoria, Australia

The aim of this study was to report the incidence, prevalence and clinical characteristics of congenital hearing loss sufficient to require hearing aid fitting in the first 6 years of life for the 1993 birth cohort of the state of Victoria (population 4.4 million), Australia. In 1993, 64,116 infants born in the state of Victoria survived the neonatal period. Subjects included all children with congenital hearing loss for which hearing aids were fitted, at any time up to and including 31 December 1999, when the youngest member of the cohort reached 6 years of age. Data on the degree, type and etiology of hearing loss were available from the Australian Hearing database for all subjects. Sociodemographic and health data were available from the Victorian Infant Hearing Screening Program (VIHSP) and parent questionnaires. The known prevalence of identified congenital hearing loss increased as the cohort aged. By the time the youngest member had reached the age of 6 years, 134 children (78 boys, 56 girls) had been fitted with hearing aids for permanent congenital hearing loss of any degree (2.09/1000). Fifty-four (40%) of these had known mild losses (20-40 dB HL). The prevalence of known moderate or greater loss (> 40 dB HL) was 1.12/1000; the data suggest that over 90% could have been detectable by neonatal hearing screening. A further seven children from the birth cohort were fitted with hearing aids due to acquired forms of hearing loss (0.11/1000). The etiology was known in only 57 (43%) congenital cases, with known non-syndromal genetic causes accounting for 21 (37%) of these. This study reports on the prevalence of congenital hearing loss requiring hearing aid fitting for an entire birth cohort. These data indicate the possible yield from neonatal screening, and hence the likely benefit of such screening. For a large proportion of cases, the etiology remains unknown. These data have implications for health service delivery and illustrate the usefulness of a population database in monitoring the prevalence of congenital hearing loss.     

Apolipoprotein E genotype, vascular risk and early cognitive impairment in an African Caribbean population

A reduced risk of Alzheimer's disease (AD) associated with the apolipoprotein E (APOE) epsilon4 allele is reported in populations of African origin. In order to clarify possible reasons for this, we examined the association between APOE genotype and early cognitive impairment in a community-based African Caribbean UK population aged 55-75 years. APOE genotype was available for 202 participants, 57 (28%) of whom were classified as having relative cognitive impairment on a battery of neuropsychological tests. Cognitive impairment was negatively associated with epsilon2 and positively but more weakly associated with epsilon4. Effects of both alleles increased markedly after age 70. The effect of epsilon4 was increased in combination with hypertension, diabetes or lower educational attainment, but these factors did not influence epsilon2 effects. Cholesterol and triglyceride levels partially explained effects of epsilon2, but did not account for those of epsilon4. A reduced association between epsilon4 and later AD in populations of African origin is unlikely to be explained by reduced cognitive effects or by differential mortality. However, it may be accounted for by vascular comorbidity. The different patterns of association between epsilon2 and epsilon4 alleles suggest different pathways of effect.     

Potent stimulation and inhibition of the CFTR Cl(-) current by phloxine B

The effects of the fluoresceine derivative, phloxine B, on the Cl(-) current through the cystic fibrosis transmembrane conductance regulator (CFTR) were examined in XENOPUS: oocytes expressing human CFTR. In whole oocytes, the CFTR Cl(-) current (I(CFTR)) was activated by superfusion with isobutylmethylxanthine and forskolin. I(CFTR) was stable during activation and deactivated rapidly upon washout of the activation solution. Phloxine B slowed deactivation and, at high concentrations, inhibited I(CFTR) weakly. In excised inside-out macropatches, I(CFTR) was activated by the catalytic subunit of protein kinase A (cPKA) and MgATP. Phloxine B (0.01 - 3 microM), applied after activation, increased I(CFTR) within 30 s followed by a slow decrease which became dominant at high concentrations. Slowing of deactivation of the CFTR was observed at all concentrations. The effect of phloxine B after 30 s had a bell-shaped concentration-dependence with midpoints at 45 and 1600 nM for the stimulatory and the inhibitory limb, respectively; maximum stimulation was about 1.8 times. The slow inhibitory component, measured after 6 min, occurred with an IC(50) value of approximately 1 microM. In the absence of cPKA, phloxine B did not stimulate I(CFTR). In the presence of cPKA and MgATP, the effects of phloxine B were more prominent at low (0.02 mM) than at high ATP (2 mM). The data show that phloxine B modulates I(CFTR) by increasing channel activity and slowing channel deactivation; at high concentrations inhibition dominates. The effects may be mediated by direct interactions with CFTR from the inside of the cell.     

Characterization of a mutant sulfonylurea receptor SUR2B with high affinity for sulfonylureas and openers: differences in the coupling to Kir6.x subtypes.

ATP-dependent K(+) channels are composed of pore-forming subunits of the Kir6.x family and of sulfonylurea receptors (SURs). SUR1, expressed in pancreatic beta-cells, has a higher affinity for sulfonylureas, such as glibenclamide, than SUR2B, expressed in smooth muscle. This difference is mainly caused by serine 1237 in SUR1 corresponding to tyrosine 1206 in SUR2B. To increase the affinity of SUR2B for glibenclamide, the mutant SUR2B(Y1206S) was constructed. In whole-cell patch-clamp experiments, glibenclamide inhibited the channel formed by coexpression of mutant SUR2B with Kir6.1 or 6.2 in human embryonic kidney cells with IC(50) values of 2.7 and 13 nM, respectively (wild-type, 43 and 167 nM). In intact cells, [(3)H]glibenclamide bound to mutant SUR2B with a K(D) value of 4.7 nM (wild-type, 32 nM); coexpression with Kir6.1 or 6.2 increased affinity by 4- and 8-fold, respectively. Binding of the opener [(3)H]P1075 to SUR2B(Y1206S) was the same as to wild-type and was unaffected by coexpression. In cells, the ratio of glibenclamide:P1075 sites was approximately 1:1; in membranes, it varied with the MgATP concentration. Heterologous competition curves were generally biphasic; the shape of the curve depended on the Kir-subtype. The effects of coexpression were weakened or abolished when binding assays were conducted in membranes. It is concluded that the mutation Y1206S increases the affinity of SUR2B for and the channel sensitivity toward glibenclamide by 7- to 15-fold. The interaction of glibenclamide (but not opener) with mutant SUR2B is modified by coexpression with Kir6.x in a manner depending on the Kir subtype and on the integrity of the cell.     

Biochirurgie – Sind Fliegenmaden wirklich die besseren Chirurgen?

Vom 1.10.96 bis zum 31.12.98 wurden 123 Patienten (74 M?nner, 43 Frauen) mit akuten (n = 17) und chronischen (n = 21) Infektionen sowie chronischen Wunden (n = 85) mit sterilen Fliegenlarven (Lucilia sericata) zun?chst ausschlie?lich station?r, sp?ter auch ambulant behandelt. Es handelte sich vorwiegend um bislang therapieresistente Wunden. Die akuten Infekte kamen alle zur Ausheilung, bei den chronischen Infektionen zeigten sich überzeugende Anfangserfolge. Bei den chronischen Wunden erbrachten die diabetischen Wundheilungsst?rungen die besten Ergebnisse, bei den ?tiologisch heterogenen Ulcera cruris führte ein eher polypragmatischer Therapieansatz zum Erfolg. Die arterielle Verschlu?krankheit (AVK) im Stadium 4 zeigte die meisten Therapieversager. Begrenzte Erfahrung mit der „Biochirurgie“ verbunden mit hochgradiger Patientenselektion und kurzer Nachbeobachtungsdauer relativieren unsere Behandlungsergebnisse; dennoch ist die Therapie mit sterilen Fliegenlarven ein neuer Hoffnungstr?ger für Probleml?sungen im Gesamtkonzept der chirurgischen Wundbehandlung.