Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families.

The hereditary breast cancer gene BRCA2 was recently cloned and is believed to account for almost half of site-specific breast cancer families and the majority of male breast cancer families. We screened 49 site-specific breast cancer families for mutations in the BRCA2 gene using single strand conformation analysis (SSCA) followed by direct sequencing. We found mutations in eight families, including all four families with male breast cancer. The eight mutations were small deletions with the exception of a single nonsense mutation, an all were predicted to interrupt the BRCA2 coding sequence and to lead to a truncated protein product. Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03). Two mutations were seen twice, including a 8535delAG, which was detected in two French Canadian families. Our results suggest the possibility that the proportion of site-specific breast cancer families attributable to BRCA2 may be overestimated.

BRCA2 mutations in primary breast and ovarian cancers.

The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.

Spirituality and personality: understanding their relationship to health resilience.

A growing body of research suggests there are important relationships among spirituality, certain personality traits, and health (organismic) resilience. In the present study, 83 college students from two southeastern universities completed a demographic questionnaire, the NEO Five Factor Inventory, and the Resilience Questionnaire. The Organismic resilience and Relationship with something greater subscales of the Resilience Questionnaire were used for analyses. Health resilience was associated with four of the Big Five personality variables and the spirituality score. Health resilience was positively correlated with ratings of extraversion, agreeableness, conscientiousness, and spirituality and negatively correlated with neuroticism. Forty-three percent of the variance of the health resilience score was accounted for by two of the predictor variables: spirituality and neuroticism. These findings are consistent with the literature and provide further support for the idea that spirituality and health protective personality characteristics are related to and may promote better health resilience.

Clinical trial management: a profession in crisis?

Clinical trial managers play a vital role in the design and conduct of clinical trials in the UK. There is a current recruitment and retention crisis for this specialist role due to a complex set of factors, most likely to have come to a head due to the COVID-19 pandemic. Academic clinical trial units and departments are struggling to recruit trial managers to vacant positions, and multiple influences are affecting the retention of this highly skilled workforce. Without tackling this issue, we face major challenges in the delivery on the Department of Health and Social Care's Future of UK Clinical Research Delivery implementation plan. This article, led by a leading network of and for UK Trial Managers, presents some of the issues and ways in which national stakeholders may be able to address this.

Auricular cartilage: harvest technique and versatility in rhinoplasty.

OBJECTIVES/HYPOTHESIS: This study aims to present an improved technique for auricular cartilage harvest that maximizes graft volume while preserving auricular cosmesis. Also discussed is the versatility of auricular cartilage utilization in rhinoplasty. STUDY DESIGN: A retrospective review of a single surgeon's experience. METHODS: All auricular cartilage harvest and rhinoplasty operations performed by the senior author (CSC) from December 2006 through December 2009 cartilage were reviewed. RESULTS: Twenty-two cases were identified in which the described technique was used to harvest auricular cartilage for the purpose of functional or aesthetic rhinoplasty. There was sufficient tissue harvested in all operations, and no patients required costal cartilage harvest. Pain at the donor site after surgery was minimal and well controlled with oral medication. There were no donor-site complications and no cases of wound infection. CONCLUSIONS: The proposed technique allows for optimal auricular cartilage harvest. By applying this method, the ear retains the preoperative appearance while the surgeon is able to obtain the largest graft possible. Auricular cartilage is a versatile source of grafting material in primary and secondary rhinoplasty.

Lateral Domal Translocation and Medial Crural Transection: A Reliable Method for Nasal Tip Deprojection.

SUMMARY: Nasal tip deprojection is a common goal in rhinoplasty. Several techniques have been described, many of which require destructive techniques that compromise the intrinsic integrity and morphology of the lateral crura. Through lateral translocation of the domes and shortening of the medial crura, nasal tip deprojection can be achieved without disrupting the integrity of the lateral crura. The domes are recreated lateral to the intrinsic domes with a standard transdomal suture, and excess length of the middle and medial crura is managed through transection and shortening of the medial crura. This technique preserves the morphology of the nasal base without altering the position of the medial crural footplates. Deprojection of 4 to 5 mm can be readily achieved with this technique.

A Simplified Approach to Nasal Tip Shaping: The Five-Suture Technique.

Techniques for nasal tip shaping have evolved from destructive to nondestructive techniques. These techniques have proven to be effective, yet they are often applied incrementally and require repeated intraoperative evaluation and manipulation to assess their efficacy. We describe a simple, effective, and reliable five-suture technique to achieve consistent results in tip shaping based on previously described ideals for nasal tip aesthetics.

A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

BRCA1 mutations in primary breast and ovarian carcinomas.

Loss of heterozygosity data from familial tumors suggest that BRCA1, a gene that confers susceptibility to ovarian and early-onset breast cancer, encodes a tumor suppressor. The BRCA1 region is also subject to allelic loss in sporadic breast and ovarian cancers, an indication that BRCA1 mutations may occur somatically in these tumors. The BRCA1 coding region was examined for mutations in primary breast and ovarian tumors that show allele loss at the BRCA1 locus. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all four mutations were germline alterations and occurred in early-onset cancers. These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele.

Tragal cartilage grafts in rhinoplasty: a viable alternative in the graft-depleted patient.

OBJECTIVE: To describe a simple technique for harvesting tragal cartilage and describe its use in rhinoplasty. STUDY DESIGN: Retrospective review. SUBJECTS AND METHODS: Rhinoplasties performed between January 2005 and June 2007 in which tragal cartilage grafts were utilized by the senior author (CSC) were reviewed to assess type of graft, preservation of tragal contour, and donor-site morbidity. RESULTS: Tragal cartilage grafts were used in three primary and three secondary rhinoplasty patients. Postoperative follow-up ranged from six months to 12 months. Tragal cartilage was used as five alar contour grafts, one lateral crural onlay graft, one dorsal onlay graft, and one infratip lobule graft. Tragal cartilage was used to close the septal perforation of one patient. Tragal contour was preserved in all patients, and there were no complications noted with this procedure. CONCLUSION: The tragus provides a simple, convenient alternative source of cartilage for rhinoplasty in graft-depleted patients.

Current concepts in the postoperative care of the rhinoplasty patient.

This is a systematic review of the available literature and our own personal experience regarding the optimal management of the rhinoplasty patient. The routine utilization of nasal splinting, casting and perioperative antibiotics is supported. The management of a number of common early complications is also discussed. Meticulous technique based on sound structural principles and coupled with preoperative planning and attention to wound care will result in a favorable outcome in most individuals undergoing rhinoplasty.

Glucose utilization in a patient with hepatoma and hypoglycemia. Assessment by a positron emission tomography.

Tumor glucose use in patients with non-islet-cell tumors has been difficult to measure, particularly in hepatoma, because of hepatic involvement by neoplasm. We studied a patient with nonhepatic recurrence of hepatoma after successful liver transplantation. Tumor tissue contained messenger RNA for insulin-like growth factor-II (IGF-II), and circulating high molecular weight components and E-peptide of IGF-II were increased. Glucose use measured by isotope dilution with [3-3H]glucose was 7.94 mg/kg fat-free mass per min, and splanchnic glucose production was 0.93 mg/kg fat-free mass per min. Glucose uptake and glucose model parameters were independently measured in tissues by positron emission tomography with 18F-fluoro-2-deoxy-D-glucose. Glucose uptake by heart muscle, liver, skeletal muscle, and neoplasm accounted for 0.8, 14, 44, and 15% of total glucose use, respectively. Model parameters in liver and neoplasm were not significantly different, and glucose transport and phosphorylation were twofold and fourfold greater than in muscle. This suggests that circulating IGF-II-like proteins are partial insulin agonists, and that hypoglycemia in hepatoma with IGF-II production is predominantly due to glucose uptake by skeletal muscle and suppression of glucose production.

Restorative rhinoplasty in the aging patient.

OBJECTIVE: The objective of this study is to review our favorable experience in performing rhinoplasty in aging patients. METHODS: All patients aged 65 years or greater who underwent rhinoplasty, either esthetic or functional, by the senior author (Y.D.) from August 1997 to July 2005 with a minimum follow up of 1 year were retrospectively reviewed. RESULTS: A total of 51 patients met the inclusion criteria and had complete records available for review. The average age was 69.5 years (range, 65-82 years) with 24 female and 27 male patients. All but two patients underwent open rhinoplasty. Eighteen procedures represented secondary rhinoplasties. Seven patients required auricular cartilage grafts, and 11 patients required costal cartilage grafts. One costal cartilage graft was aborted as a result of excessive calcification. All patients underwent columellar strut placement, 92% underwent internal valve grafts, and 80.4% underwent grafting of the external nasal valves. Nasal osteotomies were performed in only 23.5% of patients, all with the percutaneous technique. Revision surgery was necessary in only three (5.8%) patients, all of whom required grafting of the external valve (not performed primarily). In each of these cases, no significant external valve collapse was noted preoperatively. Premaxillary augmentation with diced or crushed cartilage grafts was performed in 81.8% (n = 18) of patients with an edentulous maxillary arch. CONCLUSIONS: Aging patients present unique technical challenges in rhinoplasty that warrant a comprehensive approach to restore internal and external valve competency and tip support. Consideration of prophylactic external valve grafts in addition to the routine use of internal valve grafts and columellar struts may help decrease the need for revision surgery in this patient population. Reasonable functional and esthetic outcomes can be expected in the aging patient.

Rethinking nasal osteotomies: an anatomic approach.

OBJECTIVES: To review our experience with our anatomic (medial, transverse, and lateral) nasal osteotomy technique for correcting the asymmetric bony nasal vault in esthetic and functional rhinoplasty. METHODS: All patients undergoing anatomic nasal osteotomy technique by the senior author (y.d.) from August 1997 to August 2005 with a minimum follow-up of 6 months were reviewed. Preoperative and postoperative photographs and clinical examination were analyzed to determine restoration of a symmetric bony nasal vault configuration. RESULTS: A total of 322 patients met the inclusion criteria. Percent of patients who had favorable results with restoration of a symmetric bony nasal vault configuration was 98.1%. Six (1.9%) patients required revision surgery at the level of the nasal bones with repeat osteotomies or dorsal rasping. All six of these patients had favorable outcomes after revision surgery. CONCLUSIONS: The anatomic nasal osteotomy technique represents an effective, simple, and logical approach for correcting asymmetric bony nasal vault.

External auditory canal hemangioma: case report.

A patient with a hemangioma completely within the external auditory canal is reported.

Insulinoma induced hypoglycaemia in a Jamaican patient.

Herein reported is the case of a young woman who had hyperinsulinaemic hypoglycaemia which was biochemically consistent with an insulinoma. Initial imaging was negative and definitive treatment was delayed until repeat imaging localized the tumour several years later. This case demonstrates the importance of clinical judgment and biochemical testing in the diagnosis of insulinoma despite negative imaging.

Extended Alar Contour Grafts: An Evolution of the Lateral Crural Strut Graft Technique in Rhinoplasty.

Modification of the lower lateral cartilage complex is the sine qua non of modern rhinoplasty, and the open approach to rhinoplasty has expanded the number of techniques available to help achieve an aesthetically pleasing tip. The ideal tip has been described as having a diamond-shaped configuration, with the lateral points formed by the tip-defining points, the superior point by the supratip, and the inferior point by the columellar break point. Over the years, various techniques have been described to minimize isolation of the tip and to help achieve the ideal tip configuration: lateral crural strut grafts, alar contour grafts (i.e., rim grafts), alar strut grafts, subdomal grafts, and suturing techniques such as alar flaring sutures. The authors present their technique of the extended alar contour graft, which represents an evolution of the lateral crural strut graft and its marriage with the alar contour graft. Lateral crural abnormalities do not usually occur singularly, but rather are the result of an interplay of several factors. Nevertheless, the recurring theme of orientation and alar support to prevent isolation of the tip by extended alar grooves remains. Extended alar contour grafts are a versatile technique to optimize tip shape and orientation by combining the many positive attributes of lateral crural strut grafts and alar contour grafts.

Congenital midline cervical cleft: a practical approach to Z-plasty closure.

A congenital midline cervical cleft (CMCC) is a rare developmental abnormality with several common features of variable severity: a midline defect of anterior neck skin, a superior nipple-like skin projection, and a subcutaneous fibrous cord. Congenital midline cervical clefts have important functional and cosmetic implications as cicatrical contracture with subsequent deformity may result without early surgical intervention. Treatment involves excision of all abnormal tissue, and reconstruction with Z-plasty techniques is favored because linear closure results in hypertrophic scarring and recurrent contracture. Z-plasty allows broken-line closure, reorientation of the defect in the horizontal plane with re-creation of a cervicomental angle, and most importantly, a lengthening of the anterior neck skin that aids in preventing recurrent contracture. We present our experience managing a congenital cervical midline cleft in a 3-month-old patient and describe a simple technique for planning the ideal Z-plasty closure. No simple description for planning the ideal closure for this defect could be found in the otolaryngology literature.

Genetic alterations of p53 and ras genes in 1,3-butadiene- and 2',3'-dideoxycytidine-induced lymphomas.

Mutations of p53 and ras genes were analyzed in 40 and 31 1,3-butadiene (BD)-induced lymphomas of B6C3F1 mice (BLFs), respectively, and in 63 2',3'-dideoxycytidine-induced lymphomas, which were collected from B6C3F1 (n = 16) or NIH Swiss mice (DLSs; n = 47). The frequencies of K- and N-ras mutations in BLFs (32 and 13%, respectively) were higher than those in DLSs (13 and 2%, respectively). Seven of 10 K-ras-mutated BLFs contained codon 13 CGC mutations, whereas no mutation in K-ras codon 13 was detected in DLSs, suggesting that the codon 13 CGC mutation is specific for BD exposure. Interestingly, 8 of 13 BLFs with ras mutations were from low-dose (< or = 200 ppm) or stop-exposure (26 weeks) groups. These results suggest that ras mutations play an important role in the development of BD-induced lymphoma and may represent an early event. Analysis of genetic alterations in exons 5-8 of the p53 gene revealed mutations in seven of the BLFs and three of the DLSs. All seven BLFs carrying p53 mutations were collected from the high-dose (625 ppm) continuous exposure group, which might indicate that p53 is involved in the progression of BD-induced lymphoma and in late stage of lymphomagenesis. Mutations in ras and p53 genes are relatively infrequent in 2',3'-dideoxycytidine-induced lymphomas, suggesting that other genes must be involved.

Allelotype analysis of 2',3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas in B6C3F1 mice.

To identify potential tumor suppressor genes involved in lymphoma development, we generated allelotypes of 16 2',3'-dideoxycytidine (ddC and 31 1,3-butadiene (BD)-induced lymphomas from C57BL/6 x C3H/He F1 (hereafter called B6C3F1) mice. Two or more anonymous simple sequence length polymorphisms per autosome were examined for loss of heterozygosity (LOH). Allelic losses throughout the genome were generally infrequent, except for markers on chromosome 2, 4, 11 and 12. The highest frequency of allelic losses was observed on chromosome 12, with 38 and 39% in ddC and BD-induced lymphomas, respectively. The most prevalent LOH was localized to the distal region bounded by markers D12Mit263 and D12Nds2. No known tumor suppressor genes have been mapped to this region, and no obvious candidates could be identified, suggesting the presence of novel suppressor gene(s). LOH on chromosome 2 was observed in 31% of ddC-induced lymphomas but in only 3% (1/31) of BD-induced lymphomas, suggesting a ddC-specific genetic effect. Detailed analysis localized a potential tumor suppressor gene residing on the distal region of chromosome 2, between markers D2Mit147 and D2Mit148. Twenty-five % of ddC-induced and 23% of BD-induced lymphomas showed LOH on chromosome 4, and two discrete regions were identified. One of the regions includes the IFN gene cluster and is syntenic to human chromosome 9p2l-22. Candidate tumor suppressor genes, Mts1 (multiple tumor suppressor 1) and Mts2 have been mapped to this region. The second region is located on the distal part of chromosome 4, which is homologous to human chromosome 1p35-36, a region that is frequently deleted in various types of human tumors. Finally, 19% of ddC-induced and 29% of BD-induced lymphomas revealed LOH on chromosome 11 at the Acrb locus, which lies within 1 cM of p53, suggesting that the p53 tumor suppressor gene also plays a role in lymphomagenesis. These results suggest that multiple potential suppressor loci contribute to lymphoma development in B6C3F1 mice.