VAMP1 mutation causes dominant hereditary spastic ataxia in Newfoundland families.

Our group previously described and mapped to chromosomal region 12p13 a form of dominantly inherited hereditary spastic ataxia (HSA) in three large Newfoundland (Canada) families. This report identifies vesicle-associated membrane protein 1 (VAMP1), which encodes a critical protein for synaptic exocytosis, as the responsible gene. In total, 50 affected individuals from these families and three independent probands from Ontario (Canada) share the disease phenotype together with a disruptive VAMP1 mutation that affects a critical donor site for the splicing of VAMP1 isoforms. This mutation leads to the loss of the only VAMP1 isoform (VAMP1A) expressed in the nervous system, thus highlighting an association between the well-studied VAMP1 and a neurological disorder. Given the variable phenotype seen in the affected individuals examined here, we believe that VAMP1 should be tested for mutations in patients with either ataxia or spastic paraplegia.

Subscapularis tendon tears: a common sonographic finding in symptomatic postarthroplasty shoulders.

PURPOSE: Subscapularis tendon tears can complicate shoulder arthroplasty because the subscapularis tendon is typically divided surgically to gain access to the joint. The purpose of this study is to document the prevalence of subscapularis tears on sonography of symptomatic postarthroplasty shoulders. METHODS: We retrospectively reviewed official reports of shoulder sonograms performed over an 11-year period by one experienced radiologist. Sonographic findings in 112 (mean age, 61.7 years; age range, 38-87 years; 40% female) symptomatic patients who had undergone either total shoulder arthroplasty or hemiarthroplasty were compared with findings in both a symptomatic control group consisting of 209 patients (mean age, 55.2 years; age range, 32-79 years; 37% female) who had undergone surgery for rotator cuff repair but no arthroplasty, and an asymptomatic control group consisting of 11 (mean age, 66 years; age range, 61-77 years; 45% female) volunteers who had shoulder arthroplasty but were without complaints. RESULTS: The prevalence of subscapularis tears in arthroplasty patients (51%, 57/112) was higher (p < 0.0001) than that of rotator cuff repair patients (16%, 33/209). In the asymptomatic volunteers, subscapularis tears (9%, 1/11) were less common (p < 0.01) than in the symptomatic patients. CONCLUSIONS: Subscapularis tendon tears are a common sonographic finding in symptomatic postarthroplasty shoulders.

Independent predictors of acute appendicitis on CT with pathologic correlation.

RATIONALE AND OBJECTIVES: To assess computed tomographic (CT) signs that have been described in published studies for the diagnosis of appendicitis to identify independent findings that predict appendicitis. METHODS AND MATERIALS: A retrospective database search identified 67 patients with a CT scan of the abdomen/pelvis and pathologic evaluation of the appendix, including 41 with appendicitis and 26 with a normal appendix on pathologic examination. Each computed tomogram was re-evaluated by three independent, blinded observers who evaluated appendix diameter, enhancement of the appendix, thickening of the appendix, presence of an appendicolith, infiltration of peri-appendiceal fat, focal cecal thickening, local lymphadenopathy, fluid collections, non-appendiceal bowel thickening, non-periappendiceal infiltration of fat, and comparison of peri-appendiceal fat infiltration to thickening of adjacent bowel loops. RESULTS: Mean diameter of the normal appendix (6.7 +/- 2.2 mm) was significantly lower than that of the inflamed appendix (12.1 +/- 4.3 mm; P < .001). Significant univariate predictors of appendicitis included appendix diameter >8 mm (odds ratio [OR] 34.8), enhancement of the appendix (OR 4.4), thickening of the appendix (OR 4.3), infiltration of peri-appendiceal fat (OR 5.5), focal cecal thickening (OR 5.1), non-appendiceal bowel thickening (OR 0.4), and non-periappendiceal infiltration of fat (OR = 0.3). Of these variables, only appendix diameter and enhancement of the appendix were significant independent predictors of appendicitis on multivariate analysis. An overall diagnostic impression based on all secondary signs was less accurate than a diagnosis based on appendix diameter alone (receiver-operating characteristic analysis: Az = 0.80 vs. Az = 0.91, P = .02). Sensitivity/specificity of appendix diameter was 84%/87% using a cutoff between 8 and 9 mm and 97%/48% using a cutoff between 6 and 7 mm. CONCLUSION: Appendix diameter is the best single diagnostic criterion for appendicitis on CT scan. A cutoff between 8 and 9 mm provided the best balance of sensitivity/specificity in our study population, whereas a cutoff between 6 and 7 mm improved sensitivity at the expense of specificity. The presence of appendiceal enhancement provided additional diagnostic information, but other secondary signs of appendicitis did not improve diagnostic accuracy.

Quantitative computed tomography perfusion of prostate cancer: correlation with whole-mount pathology.

PURPOSE: Microvessel density within the prostate is associated with presence of cancer, disease stage, and disease-specific survival. We evaluated multidetector computed tomography (CT) to estimate prostate perfusion and localize prostate cancer. PATIENTS AND METHODS: Ten subjects were evaluated with contrast enhanced CT before radical prostatectomy with the Mx8000IDT 16-slice scanner. Following baseline pelvic scan, 100 cc of Optiray 300 was administered intravenously (4 cc per second). Repeated dynamic scans through the prostate were obtained at 20, 30, 40, 50, and 60 seconds following initiation of contrast injection. Computed tomography perfusion was compared with pathologic findings of Gleason score and tumor volume on whole-mount prostatectomy specimens. RESULTS: Conventional adenocarcinoma (Gleason score, 6-10) was present in all subjects, including one who also demonstrated a mucinous variant of prostate cancer. Visible focal CT enhancement was noted in 1 patient with a high-volume tumor and a Gleason score of 10. A positive correlation between local estimates of CT perfusion and percent of prostate volume occupied by tumor in each sextant was found for half of the subjects (Pearson correlation coefficient, 0.3-0.95; mean, 0.48) but statistically significant correlation (P < 0.05; Pearson coefficient, 0.9-0.95) was present in only the 2 subjects with the highest Gleason scores (8 and 10) and the highest tumor volume (> or = 50% in > or = 1 sextant region). CONCLUSION: Visible enhancement of prostate cancer during dynamic CT is present in a minority of subjects. Correlation between quantitative CT perfusion and tumor location is statistically significant only in subjects with localized high-volume, poorly differentiated prostate cancer.

Characterization of a new full length TMPRSS3 isoform and identification of mutant alleles responsible for nonsyndromic recessive deafness in Newfoundland and Pakistan.

BACKGROUND: Mutant alleles of TMPRSS3 are associated with nonsyndromic recessive deafness (DFNB8/B10). TMPRSS3 encodes a predicted secreted serine protease, although the deduced amino acid sequence has no signal peptide. In this study, we searched for mutant alleles of TMPRSS3 in families from Pakistan and Newfoundland with recessive deafness co-segregating with DFNB8/B10 linked haplotypes and also more thoroughly characterized the genomic structure of TMPRSS3. METHODS: We enrolled families segregating recessive hearing loss from Pakistan and Newfoundland. Microsatellite markers flanking the TMPRSS3 locus were used for linkage analysis. DNA samples from participating individuals were sequenced for TMPRSS3. The structure of TMPRSS3 was characterized bioinformatically and experimentally by sequencing novel cDNA clones of TMPRSS3. RESULTS: We identified mutations in TMPRSS3 in four Pakistani families with recessive, nonsyndromic congenital deafness. We also identified two recessive mutations, one of which is novel, of TMPRSS3 segregating in a six-generation extended family from Newfoundland. The spectrum of TMPRSS3 mutations is reviewed in the context of a genotype-phenotype correlation. Our study also revealed a longer isoform of TMPRSS3 with a hitherto unidentified exon encoding a signal peptide, which is expressed in several tissues. CONCLUSION: Mutations of TMPRSS3 contribute to hearing loss in many communities worldwide and account for 1.8% (8 of 449) of Pakistani families segregating congenital deafness as an autosomal recessive trait. The newly identified TMPRSS3 isoform e will be helpful in the functional characterization of the full length protein.

Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15.

We studied a consanguineous family (Family A) from the island of Newfoundland with an autosomal recessive form of prelingual, profound, nonsyndromic sensorineural hearing loss. A genome-wide scan mapped the deafness trait to 10q21-22 (max LOD score of 4.0; D10S196) and fine mapping revealed a 16 Mb ancestral haplotype in deaf relatives. The PCDH15 gene was mapped within the critical region and was an interesting candidate because truncating mutations cause Usher syndrome type IF (USH1F) and two missense mutations have been previously associated with isolated deafness (DFNB23). Sequencing of the PCDH15 gene revealed 33 sequencing variants. Three of these variants were homozygous exclusively in deaf siblings but only one of them was not seen in ethnically matched controls. This novel c.1583 T>A transversion predicts an amino-acid substitution of a valine with an aspartic acid at codon 528 (V528D). Like the two DFNB23 mutations, the V528D mutation in Family A occurs in a highly conserved extracellular cadherin (EC) domain of PCDH15 and is predicted to be more deleterious than the previously identified DFNB23 missense mutations (R134G and G262D). Physical assessment, vestibular and visual function testing in deaf adults ruled out syndromic deafness because of Usher syndrome. This study validates the DFNB23 designation and supports the hypothesis that missense mutations in conserved motifs of PCDH15 cause nonsyndromic hearing loss. This emerging genotype-phenotype correlation in USH1F is similar to that in several other USH1 genes and cautions against a prognosis of a dual sensory loss in deaf children found to be homozygous for hypomorphic mutations at the USH1F locus.

Effect of dutasteride therapy on Doppler US evaluation of prostate: preliminary results.

PURPOSE: To prospectively determine the effect of short-term therapy with dutasteride on the suppression of Doppler ultrasonographic (US) signal in benign prostate tissue and thus on improvement in the depiction of prostate cancer with Doppler US-guided core-needle biopsy. MATERIALS AND METHODS: After institutional review board approval and informed consent were obtained as part of this HIPAA-compliant study, 11 men (age range, 59-77 years) were evaluated with gray-scale, color, and power Doppler US at baseline and weekly for up to 3 weeks while taking 0.5 mg of dutasteride per day. Flow intensity in the periurethral, transition, and peripheral zones was subjectively scored by using a four-point scale. The Wilcoxon matched-pairs signed-ranks test was used to compare pre- and posttherapy scores. After flow was reduced to "diminished" or "none" with at least a 1-score difference on the four-point scale, up to four targeted cores were obtained from areas of persistent flow within the peripheral zone, followed by laterally directed sextant biopsy. RESULTS: Doppler US flow suppression occurred in 11 of 11 patients after 1 week of dutasteride therapy (P < .01). Further suppression was noted after 2 weeks in eight of 10 patients (P = .04) and after 3 weeks in two of two patients. Biopsy was performed after 1 (n = 1), 2 (n = 8), or 3 (n = 2) weeks of therapy. Flow suppression was greatest in the peripheral zones (mean decrease: 0.64 and 0.76 after weeks 1 and 2, respectively) and least in the periurethral zones (mean decrease: 0.30 after 1 week). Cancer was detected in eight (20%) of 40 targeted cores and in five (8%) of 66 sextant cores. Four patients had cancer at targeted biopsy, and three of these four patients had cancer at sextant biopsy. In the four men with cancer, targeted cores were 5.9 times more likely to be positive (P = .027). Selective suppression of flow in benign tissue was observed in two of the four men with cancer. CONCLUSION: Short-term dutasteride therapy reduces Doppler US flow in the prostate and may improve depiction of hypervascular cancer.

Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) presents with visceromegaly, macroglossia, tumor predisposition and other congenital abnormalities, and is usually associated with abnormalities of chromosome 11p15. A number of identical twin pairs, mostly female, have been reported to be discordant for BWS. We show here that the incidence of female monozygotic twins among patients with BWS is dramatically increased over that of the general population. A cluster of imprinted genes within 11p15 is thought to be coordinately regulated via the imprinted expression of KCNQ1OT1, which encodes an untranslated RNA. In skin fibroblasts from five monozygotic twin pairs discordant for BWS, each affected twin had an imprinting defect at KCNQ1OT1 on 11p15, whereas the unaffected twin did not. Five additional monozygotic twin pairs, for whom only blood was available, also displayed an imprinting defect at KCNQ1OT1. It is possible that discordance for BWS in MZ twins is due to unequal splitting of the inner cell mass during twinning, thereby causing differential maintenance of imprinting at KCNQ1OT1. Alternatively, we propose that KCNQ1OT1 is especially vulnerable to a loss of imprinting event, caused by a lack of maintenance DNA methylation at a critical stage of preimplantation development, and that this loss of imprinting predisposes to twinning as well as to discordance for BWS. These data underscore the importance of continued surveillance of children born following assisted reproductive technologies that impact the preimplantation embryo.