A clinical study of patients with novel CDHR1 genotypes associated with late-onset macular dystrophy

PurposeTo describe the clinical and electrophysiological features of adult-onset macular dystrophy, due to novel combinations of CDHR1 alleles, and compare the associated phenotypes with previous reports.MethodsThe clinical records of patients with macular dystrophy and biallelic variants in CDHR1 were reviewed. Data analysed included best corrected visual acuity (BCVA), fundus images: autofluorescence (AF) and optical coherence tomography (OCT); full field electroretinography (ERG) and pattern ERG (PERG).ResultsSeven patients from six pedigrees were ascertained. One patient was homozygous for a known synonymous variant p.(Pro261=), four were compound heterozygous for the p.(Pro261=) variant and a novel allele of CDHR1: p.(Gly188Ser), p.(Met1?), or p.(Val458Asp); one patient was compound heterozygous for two previously unreported variants: c.297+1G>T in trans with p.(Pro735Thr). The range of BCVA at the last clinic review was (6/5–6/60). Autofluorescence showed macular flecks of increased AF in mild cases and patches of reduced AF in severe cases. The OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and the outer nuclear layer in severe cases; one patient had subfoveal hyporeflective region between the EZ and the retinal pigment epithelium. The full field ERG was normal or borderline subnormal in all cases, and the PERG was subnormal in mild cases or undetectable in severe cases.ConclusionsThis report corroborates previous observations that genotypes distinct from those causing pan-retinal dystrophy can cause a milder phenotype, predominantly affecting the macula, and expands the spectrum of these genotypes. The findings in this cohort suggest a potential macular susceptibility to mild perturbations of the photoreceptor cadherin.Subject terms: Hereditary eye disease, Disease genetics     

Drug interaction studies between paclitaxel (Taxol) and OC144-093--a new modulator of MDR in cancer chemotherapy.

The MDR modulator, OC144-093, is a potential candidate for use in cancer therapy and exhibits potent biological activity in vitro and in vivo when combined with anticancer agents such as paclitaxel. Its inhibitory interaction with P-glycoprotein (Pgp), the mdr1 gene product and a mechanistic participant in multidrug resistance, underlies its activity as a modulator of MDR. Having previously shown that OC144-093 is not a substrate for CYP3A we first examined the effects of OC144-093 on paclitaxel metabolism in vitro. Using human liver microsomes, we have demonstrated that OC144-093 inhibited the CYP3A mediated metabolism of paclitaxel at high concentrations only (Ki = 39.8 +/- 5.1 microM, n=3). Pharmacokinetic results also show that an oral dose of OC144-093, co-administered with paclitaxel caused negligible disturbance of the pharmacokinetic profile for paclitaxel when injected intravenously. In contrast, AUC values were elevated approximately 1.5-fold in all groups treated orally with paclitaxel and OC144-093. Cmax was enhanced approximately 2-fold in the co-dosed group. These characteristics are consistent with Pgp blockade in the gut enhancing oral bioavailability. Elimination properties of paclitaxel were affected only upon multiple dosing of OC 144-093. These results warrant the further clinical assessment of OC144-093 as an MDR reversing agent.     

Symptomatic and quality of life outcomes after site-specific fascial reattachment for pelvic organ prolapse repair

The aim of this study was to assess symptomatic and quality of life outcome scores following site specific fascial reattachment surgery for pelvic organ prolapse using the validated Prolapse Quality of Life (P-QOL) questionnaires. One hundred and ninety two women underwent surgery for pelvic organ prolapse; ninety four underwent anterior repair (thirty four of them had vaginal hysterectomy), and ninety eight had posterior repair. Patients filled P-QOL questionnaires 24 hours prior to surgery and a postal P-QOL questionnaire six months post operatively. Pre and post operative questionnaires were paired. Quality of life and symptoms scores were calculated using Wilcoxon signed rank test. One hundred and one women returned their questionnaires and were suitable to include in the study. Forty nine underwent anterior repair (fifteen had vaginal hysterectomy) and 52 underwent posterior repair. Quality of life scores showed significant improvement in the anterior and posterior repair groups with the exception of general health in the anterior repair group and general health and prolapse impact in the posterior repair group. Anterior repair significantly improved urinary voiding and storage symptoms. Posterior repair group showed significant improvement in defecatory symptoms. Both groups showed improvement in sexual function and general prolapse symptoms. Prolapse repair with site specific fascial reattachment results in significant improvement in quality of life scores six months after surgery. Anterior repair improves urinary voiding and storage symptoms and posterior repair improves defecatory dysfunction and urinary voiding. Sexual function improves following prolapse repair with site specific fascial reattachment. Presentation information: British Society of Urogynaecology Annual Scientific Meeting, Royal College of Obstetricians and Gynaecologists, London, UK. November 17th 2006.     

Does an inflatable obstetric belt facilitate spontaneous vaginal delivery in nulliparae with epidural analgesia?

Objective To assess whether an inflatable obstetric belt, synchronised to apply uniform fundal pressure during a uterine contraction, reduces operative delivery rates when used in the second stage of labour.
Design Randomised controlled trial.
Methods Five hundred nulliparae with a singleton cephalic pregnancy at term and with an epidural in labour were recruited during the first stage and randomised at full dilatation. Standard care involved one hour passive second stage and one hour active pushing after which instrumental delivery was performed if delivery was not imminent. Those randomised to the belt group, in addition to standard care, had the inflatable obstetric belt for the whole second stage of labour.
Main outcome measure Mode of delivery.
Results One hundred and eleven of the 260 women in the belt group (42.7%) compared with 94 of the 240 in the control group (39.2%) had a spontaneous vertex delivery (   P = 0.423  ). The lift-out instrumental delivery rate was similar between the two groups: 108 belts (41.5%), compared with 101 controls (42.1%) (   P = 0.902  ), whereas rotational instrumental deliveries in the belt group were 26 belts (10%) compared with 36 controls (15%) (   P = 0.09  ). Fifteen women (5.8%) in the belt group and nine women (34%) in the control group had a caesarean section in the second stage (   P = 0.292  ). An intact perineum was more likely in the belt group (16.5% compared with 9–6%,   P = 0.022  ) as was a third degree tear (6.5% compared with 0.4%,   P = 0.001  ).
Conclusion The inflatable obstetric belt did not significantly reduce operative delivery rates when used in this clinical setting in the second stage of labour.     

Analysis of Epstein–Barr virus (EBV) type and variant in spontaneous lymphoblastoid cells and Hu-SCID mouse tumours

Epstein–Barr virus (EBV) type and strain variations were examined using both lymphoblastoid cell lines (LCLs), spontaneously derivedin vitrofrom peripheral blood mononuclear cells (PBMC) of 15 HIV-1-seropositive individuals, and SCID mouse tumours induced by inoculation of PBMC from 11 healthy human donors (Hu-SCID tumours). Polymerase chain reaction (PCR) analysis disclosed that all but one of the 26 EBV+ samples harboured EBV nuclear antigen (EBNA) 2 and 3C type A virus. On the other hand, single strand conformation polymorphism (SSCP) analysis using Epstein–Barr encoded RNA (EBER) specific primers detected an AG876-like (type B) band pattern in 21 of the 26 EBV+ samples. Three Hu-SCID tumours scored as B95.8-like (type A), and two showed neither a type A nor a type B SSCP migration pattern. Sequence analysis of the amplified EBER fragments confirmed the PCR-SSCP findings; moreover, additional mutations were present not only in the two EBV+ samples with anomalous SSCP pattern, but also in two other samples with a standard SSCP profile. Thus, EBER analysis did not correlate with EBNA typing, and appeared to be unsuitable for EBV type assessment. Latent membrane protein (LMP) analysis disclosed, on the whole, seven size variants: as expected, the differences were due to the variable numbers of a 33-bp repeat in the amplified fragment, as assessed by direct sequencing. The broader variability detected by LMP analysis should prove more useful than typing for assessing the presence of single and/or mixed variants resulting from EBV reactivation and/or reinfection.