A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen

Stickler syndrome (hereditary arthro-ophthalmopathy) is the commonest inherited cause of retinal detachment and one of the commonest autosomal dominant connective tissue dysplasias. There is clinical and locus heterogeneity with about two thirds of families linked to the gene encoding type II procollagen (COL2A1). Families with Sticklers syndrome type 1 have a characteristic congenital vitreous anomaly and are linked without recombination to markers at the COL2A1 locus. In contrast families with the type 2 variety have a different vitreo- retinal phenotype and are not linked to the COL2A1 gene. Type XI collagen is a quantitatively minor fibrillar collagen related to type V collagen and associated with the more abundant type II collagen fibrils. A mutation in COL11A2, the gene for alpha 2 (XI) procollagen, has recently been found in a family described as having Stickler syndrome, although there was no ocular involvement. Here we show for the first time that a family with the full Type 2 Stickler syndrome including vitreous and retinal abnormalities is linked to the COL11A1 gene and characterise the mutation as a Glycine to Valine substitution at position 97 of the triple helical domain caused by a single base G-- >T mutation. These results are the first to provide confirmation that type XI collagen is an important structural component of human vitreous. They also support previous work suggesting that mutations in the genes encoding collagen XI can give rise to some manifestations of Stickler syndrome, but of these, only mutations in COL11A1 will give the full syndrome including the vitreo-retinal features.      

Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer.

Using permanent-section immunohistochemistry, we investigated the role of HER-2/neu in the development and progression of human breast cancer by measuring its overexpression in a series of hyperplastic (n = 30), dysplastic (n = 15), and malignant neoplastic (n = 708) lesions of ductal epithelium and by evaluating the relationships between overexpression and clinicopathologic features known to have prognostic significance in these lesions. The neoplasms included pure ductal carcinoma in situ (DCIS; n = 59) and infiltrating ductal carcinoma (IDC; n = 649). The latter were all node negative and stratified into IDC combined (n = 237) or not combined (n = 412) with a "significant amount" of DCIS (defined as DCIS greater than or equal to 10% of total tumor cellularity). Overexpression of HER-2/neu was not observed in any of the hyperplastic or dysplastic lesions. In contrast, it was present in 56% of pure DCIS and in 77% of the comedo subtype of this group. Only 15% of IDC overexpressed HER-2/neu. However, the rate of overexpression was significantly higher in the subset of IDC combined with DCIS compared with the subset of IDC not combined with DCIS (22% v 11%, respectively; P less than .0001). These results are consistent with the hypothesis that HER-2/neu plays a more important role in initiation than in progression of ductal carcinomas. They also suggest that overexpression decreases within individual tumors as they evolve from in situ to increasingly invasive lesions or, alternatively, that many invasive carcinomas arise de novo (ie, without progressing through a significant in situ stage) by mechanisms not involving HER-2/neu. In addition, overexpression of HER-2/neu was associated with several poor prognostic features (younger patient age, premenopause, negative estrogen receptor status, negative progesterone receptor status, and high nuclear grade) in the subset of IDC combined with DCIS. With one exception (negative estrogen receptor status) these associations were lost in IDC not combined with DCIS, also suggesting that the role of HER-2/neu changes during the progression of human breast cancer.     

Semaphorin/neuropilin signaling influences the positioning of migratory neural crest cells within the hindbrain region of the chick.

Within the hindbrain region, neural crest cell migration is organized into three streams that follow the segmentation of the neuroepithelium into distinct rhombomeric compartments. Although the streaming of neural crest cells is known to involve signals derived from the neuroepithelium, the molecular properties underlying this process are poorly understood. Here, we have mapped the expression of the signaling component of two secreted class III Semaphorins, Semaphorin (Sema) 3A and Sema 3F, at time points that correspond to neural crest cell migration within the hindbrain region of the chick. Both Semaphorins are expressed within rhombomeres at levels adjacent to crest-free mesenchyme and expression of the receptor components essential for Semaphorin activity by neural crest cells suggests a function in restricting neural crest cell migration. By using bead implantation and electroporation in ovo, we define a role for both Semaphorins in the maintenance of neural crest cell streams in proximity to the neural tube. Attenuation of Semaphorin signaling by expression of soluble Neuropilin-Fc resulted in neural crest cells invading adjacent mesenchymal territories that are normally crest-free. The loss or misguidance of specific neural crest cell populations after changes in Semaphorin signaling also affects the integration of the cranial sensory ganglia. Thus, Sema 3A and 3F, expressed and secreted by the hindbrain neuroepithelium contributes to the appropriate positioning of neural crest cells in proximity to the neural tube, a process crucial for the subsequent establishment of neuronal connectivity within the hindbrain region.     

Ossiculoplasty with intact stapes and absent malleus: the silastic banding technique.

OBJECTIVE: To report an original method of ossicular reconstruction with intact stapes and absent malleus. Ossiculoplasty is performed with a total ossicular replacement prosthesis positioned from the stapes footplate to the under-surface of the tympanic membrane, using a Silastic banding technique to stabilize the prosthesis. STUDY DESIGN: A prospective study of ossicular reconstruction using the Silastic banding technique. A consecutive series of cases with intact stapes superstructure and missing malleus handle (Austin-Kartush Group C) is presented. SETTING: One tertiary referral center. PATIENTS: Ninety-nine patients who underwent total ossicular reconstruction with Silastic banding technique were enrolled in the study from January 2000 to December 2002. INTERVENTIONS: Ossiculoplasty with total ossicular replacement prostheses with Silastic Rubber Band for chronic otitis media and non-inflammatory disease. MAIN OUTCOME MEASURES: Preoperative and postoperative audiometric evaluation using conventional audiometry. Air-bone gap, bone-conduction threshold, and air-conduction threshold were assessed. Postoperative audiometry was performed at the 6th, 9th, 12th, 18th, 24th, and 36th months. RESULTS: Overall, a postoperative air-bone gap closed to within 10 dB was achieved in 61.5% of cases. An air-bone gap smaller than 20 dB was obtained in 77% of cases. Postoperative improvement of air-conduction thresholds by at least 20 dB was found in 51% of cases. There was no case of postoperative sensorineural hearing loss. One case of extrusion of the prosthesis was seen (1%). CONCLUSION: Stabilizing the total ossicular replacement prosthesis with the Silastic banding technique when performing ossicular reconstruction is a safe, effective method when the stapes supra-structure is present and the malleus absent.     

Diagnostic accuracy of magnetic resonance cholangiopancreatography and ultrasound compared with direct cholangiography in the detection of choledocholithiasis

AIM: To determine the diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) and trans-abdominal ultrasound in the detection of choledocholithiasis, and to compare bile duct stone characteristics using endoscopic retrograde cholangiopancreatography (ERCP), MRCP and ultrasound. MATERIALS AND METHODS: Of 191 consecutive patients referred for diagnostic ERCP, choledocholithiasis was diagnosed in 34 patients using direct cholangiography. The latter took the form of ERCP (n = 29), intraoperative cholangiography (n = 3) or percutaneous transhepatic cholangiography (n = 2). All patients underwent MRCP and ultrasound examinations and their findings for choledocholitiasis were compared with those at direct cholangiography. Finally, in the 29 patients with choledocholithiasis diagnosed under ERCP, stone characteristics were compared across the three investigations of ERCP, MRCP and ultrasound. RESULTS: Compared with direct cholangiography, MRCP showed a sensitivity, specificity and diagnostic accuracy of 91%, 98% and 97%, respectively, in the diagnosis of choledocholithiasis. MRCP resulted in three false-negative and three false-positive findings, four of which occurred due to confusion with lesions at the ampulla. Ultrasound showed a sensitivity, specificity and diagnostic accuracy of 38%, 100% and 89%, respectively, in the diagnosis of choledocholithiasis. ERCP revealed a greater number of stones and these were more proximally distributed within the bile ducts when compared to MRCP. CONCLUSIONS: MRCP is highly accurate in the diagnosis of choloedocholithiasis and has the potential to replace diagnostic ERCP. MRCP underestimates the number of bile duct stones present.     

The musculocutaneous nerve

We have analysed the results of repair of traumatic lesions of the musculocutaneous nerve in 85 patients, which were graded by Seddon's modification of the Medical Research Council system into three types of injury: open 'tidy', open 'untidy' and closed 'traction'. They were also correlated with associated arterial injury. There were 57 good, 17 fair and 11 poor results. The type of injury was the most important factor in determining the result; 12 of 13 open-tidy lesions gave good results compared with 30 of 48 closed-traction lesions. The results were better when the nerves were repaired within 14 days of injury and when grafts were less than 10 cm long. They were worse in the presence of associated arterial or bony injury.     

The Role of the Contextual Cohort to Resolve Some Challenges and Limitations of Comparisons in Pharmacoepidemiology

Drug Safety - In pharmacoepidemiology, comparison studies can provide a useful estimate of the level of increased or decreased risk of specific events with a medication (through a measure of...     

Dopamine DRD2/Cys311 is not associated with chronic schizophrenia

A mutation in the DRD2 receptor gene has been reported in association with schizophrenia in Japanese and Caucasian populations. The variation, Ser to Cys at codon 311, occurs in the third intracellular loop of the receptor and is therefore putatively functional. We report the results of screening US Caucasian schizophrenic and nonschizophrenic populations. We detected the occurrence of the DRD2 Cys311 variant in both schizophrenics and controls. Our data demonstrates no significant difference between the frequency of Cys311 in Caucasian schizophrenic and non-schizophrenic populations, indicating no association with schizophrenia. © 1996 Wiley-Liss, Inc.