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1.
Folia Morphol (Warsz) ; 82(2): 256-260, 2023.
Article in English | MEDLINE | ID: mdl-35187635

ABSTRACT

BACKGROUND: The course of the spinal accessory nerve in the neck is long and superficial rendering it at high risk of injury during procedures performed in the posterior triangle. The majority of spinal accessory nerve injuries are iatrogenic in nature. This is associated with significant morbidity including reduction in shoulder movements, drooping of the shoulder, winging of the scapula and neuropathic pain. Knowledge of the nerve anatomy reduces the risk of intra-operative nerve injury. Traditional teaching describes the point of entry into the posterior triangle as the intersection between the upper and middle third of the posterior border of sternocleidomastoid. The aim of this study was to determine whether this is in fact the case and if so, whether this landmark can reliably be used to identify the spinal accessory nerve in order to improve patient outcomes. MATERIALS AND METHODS: The spinal accessory nerve was identified unilaterally in 26 cadavers. The total length of sternocleidomastoid was measured as well as the length along the posterior border from the inferior aspect of the mastoid process to the point at which the accessory nerve enters the posterior triangle of the neck. These measurements were used to calculate the ratio of the entry point of the nerve into the posterior triangle along the length of the posterior border of sternocleidomastoid from its superior insertion point. The mean ratio was 0.35 with 95% confidence intervals of 0.33 to 0.36. RESULTS AND CONCLUSIONS: Our findings confirm the traditional description of the entry point of the spinal accessory nerve into the posterior triangle of the neck. We describe a so-called 'safe zone' inferior to the midpoint of the posterior border of sternocleidomastoid within which the spinal accessory nerve is unlikely to be found, thereby reducing the risk of iatrogenic injury.


Subject(s)
Accessory Nerve Injuries , Accessory Nerve , Humans , Accessory Nerve/anatomy & histology , Accessory Nerve/surgery , Neck , Neck Muscles/innervation , Iatrogenic Disease
2.
Foot Ankle Surg ; 28(8): 1177-1182, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35798617

ABSTRACT

BACKGROUND: Talus fractures are rare (<1% of all fractures), and their rarity limits the number of studies available to guide management. In instances such as this, cadaveric studies can play an important role. The purpose of this scoping review was to identify and describe the current body of literature on cadaveric studies of fractures of the talus. METHODS: Through multiple electronic database searches (Medline, Embase, Scopus) we identified a broad body of cadaveric research into talus fractures, and these were classified into 4 main themes. Study characteristics were summarised along with any descriptive results and conclusions. RESULTS: The search yielded 484 articles of which 19 met the inclusion criteria. They provide valuable insights into benefits and drawbacks of surgical approaches to the talus, particularly with regard to direct visualisation of anatomic reduction, and risks of neurovascular or tendon compromise. For talar neck fractures it is clear that cannulated screws offer superior fixation over plates, however, are inferior when considering anatomic reduction of the fracture. Direct visualisation of fracture reduction is far superior to intraoperative radiographic assessment, and mal-reduction leads to reduced subtalar joint range of motion, midfoot deformity, and increased joint contact pressures. CONCLUSIONS: This study provides a summary of the existing literature surrounding the use of cadaver studies in fractures of the talus. We have identified gaps in the literature, particularly surrounding strength of fixation of new locking plate fixation techniques.


Subject(s)
Ankle Fractures , Fractures, Bone , Talus , Humans , Fracture Fixation, Internal/methods , Bone Screws , Ankle Fractures/surgery , Talus/diagnostic imaging , Talus/surgery , Fractures, Bone/diagnostic imaging , Fractures, Bone/surgery , Bone Plates
3.
Br J Oral Maxillofac Surg ; 59(8): 898-904, 2021 10.
Article in English | MEDLINE | ID: mdl-34420783

ABSTRACT

The intraoral vertical ramus osteotomy (IVRO) is an orthognathic procedure that is used to correct dentofacial abnormalities, and is performed by approaching the lateral aspect of the mandibular ramus. This approach, however, precludes visualisation of the inferior alveolar nerve (IAN) on the medial side, thereby placing it at risk of iatrogenic damage. The antilingula, a bony prominence on the lateral mandibular ramus, has been proposed as a landmark for prediction of the IAN's location during IVRO. The current study aimed to evaluate the variation in incidence and position of the antilingula, and therefore to determine its suitability as a surgical landmark during IVRO. The study included 480 dry hemimandibles from eight geographical populations from the Duckworth Collection in Cambridge. Skulls were sexed by visual analysis of dimorphic traits. Positional relations were determined through the digitisation of nine anatomical landmarks. The antilingula was identified in all specimens. No significant difference was identified in the positional relation between the antilingula and mandibular foramen between sexes, but multiple differences were identified in this relation between geographical populations. Our data showed that, irrespective of geographical variation, an osteotomy performed 8mm posterior to the antilingula would avoid the mandibular foramen in 98.8% of cases.


Subject(s)
Orthognathic Surgical Procedures , Prognathism , Humans , Mandible/surgery , Mandibular Nerve , Reproducibility of Results , Sex Characteristics
4.
Br J Oral Maxillofac Surg ; 59(3): 380-383, 2021 04.
Article in English | MEDLINE | ID: mdl-33495045

ABSTRACT

Fractures of the mandibular condyle are common and include diacapitular fractures that affect the condylar head. The medial part of the condylar head is least commonly fractured, possibly due to decreased propensity for lines of force to run in the region. Micro-computed tomography (X-ray microtomography) of five temporomandibular joint specimens was conducted to explore whether trabecular bone structure correlates positively with fracture prevalence, which could reflect adaptation in response to lower exposure to physiological loads throughout life. Models of trabecular bone, and graphic representation of bone density indicated least dense bone medially, but a statistically significant ANOVA result was not obtained. Further study is required to verify whether a relationship between bone microstructure and fracture frequency exists, and whether or not this is the product of association between the directions of physiological and traumatic forces.


Subject(s)
Mandibular Condyle , Mandibular Fractures , Bone Density , Humans , Mandibular Condyle/diagnostic imaging , Mandibular Fractures/diagnostic imaging , Temporomandibular Joint/diagnostic imaging , X-Ray Microtomography
5.
BMJ Mil Health ; 167(6): 383-386, 2021 Dec.
Article in English | MEDLINE | ID: mdl-32122999

ABSTRACT

INTRODUCTION: Haemorrhage is the major cause of early mortality following traumatic injury. Patients suffering from non-compressible torso haemorrhage are more likely to suffer early death. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) can be effective in initial resuscitation; however, establishing swift arterial access is challenging, particularly in a severe shock. This is made more difficult by anatomical variability of the femoral vessels. METHODS: The femoral vessels were characterised in 81 cadaveric lower limbs, measuring specifically the distance from the inferior border of the inguinal ligament to the distal part of the origin of the profunda femoris artery (PFA), and from the distal part of the origin of the PFA to where the femoral vein lies posterior to and is completely overlapped by the femoral artery. RESULTS: The femoral vein lay deep to the femoral artery at a mean distance of 105 mm from the inferior border of the inguinal ligament. The PFA arose from the femoral artery at a mean distance of 51.1 mm from the inguinal ligament. From the results, it is predicted that the PFA originates from the common femoral artery approximately 24 mm from the inguinal ligament, and the femoral vein is completely overlapped by the femoral artery by 67.7 mm distal from the inguinal ligament, in 95% of subjects. CONCLUSIONS: Based on the results, proposed is an 'optimal access window' of up to 24 mm inferior to the inguinal ligament for common femoral arterial catheterisation for pre-hospital REBOA, or more simply within one finger breadth.


Subject(s)
Balloon Occlusion , Endovascular Procedures , Aorta, Abdominal , Cadaver , Femoral Artery , Humans
8.
Folia Morphol (Warsz) ; 77(4): 693-697, 2018.
Article in English | MEDLINE | ID: mdl-29500893

ABSTRACT

BACKGROUND: The carotid sinus (CS) is a dilatation in the carotid bifurcation usually at the origin of proximal internal carotid artery (ICA). It contains baroreceptors which influence blood pressure. Variations in the location of the CS are of importance as atheromatous plaque commonly forms in this area and procedures such as carotid endarterectomy are performed to reduce the risk of stroke. Inadvertent stimulation of the CS baroreceptors during interventions can have profound effects on the patient's haemodynamic status both intra- and postoperatively, causing serious complications. The aim of this study is to determine the inter- and intra-individual variations in the location of the CS. MATERIALS AND METHODS: Eighty-two carotid arteries were dissected bilaterally from 41 cadavers. The locations of the CS were noted and divided into four potential sites. RESULTS: The commonest site is the origin of the ICA (74.3%), but the CS can also be found in the distal part of the common carotid artery (CCA) inferior to the bifurcation (17.1%); at the bifurcation involving the distal CCA and origins of both the external carotid artery (ECA) and ICA (7.32%); and at the origin of the ECA (1.22%). In individual cadavers, the CS was located at the origin of the ICA in 97.6% on at least one side. The sites of the CS were asymmetrical in 34.1%. CONCLUSIONS: Clinicians performing carotid interventions should be aware of these anatomical variations to avoid inadvertent stimulation of the CS which can cause profound bradycardia and hypotension.


Subject(s)
Anatomic Variation , Carotid Sinus/anatomy & histology , Aged , Aged, 80 and over , Dissection , Female , Humans , Male
9.
Clin Anat ; 31(2): 293-300, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29205513

ABSTRACT

Dermatomes are an important component of medical curricula and clinical practice. In addition to the intrinsic complexity of dermatome maps, their discrepancies in the literature make their learning among students even more difficult. These discrepancies are particularly evident in the lower deltoid ("regimental badge" area) and upper back. The aims of our study were firstly to identify and compare published versions of the dermatome map focusing on depictions of the "regimental badge" area and upper back, secondly to assess the perceived confidence and knowledge of dermatomes among medical students, and finally to create and introduce a simplified dermatome map. For the first part of the study, depictions of dermatome maps that included the "regimental badge" area and upper back in webpages and books were compared. For the second part, a dermatome exercise was given to 177 medical students who were asked to draw and label the dermatomes on blank figures. A total of 45 sources depicting dermatomes of the "regimental badge" area and upper back were included in the study and showed significant discrepancies in both areas. In the dermatome exercise, the mean perceived confidence was 3.64 ± 1.58 (scale 1-10). Based on our pre-set assessment criteria, upper limb, lower limb, nipple, umbilicus, and perineum dermatomes were labeled correctly by 57.1%, 43.5%, 52.6%, 60%, and 75.7% students, respectively. In light of our results, we propose a map of autonomous regions of clinically relevant dermatomes that can be used instead of whole dermatome maps for teaching purposes. Clin. Anat. 31:293-300, 2018. © 2017 Wiley Periodicals, Inc.


Subject(s)
Anatomy/education , Education, Medical/standards , Skin/anatomy & histology , Analysis of Variance , Curriculum/standards , Humans , Internet , Students, Medical/statistics & numerical data , Surveys and Questionnaires , Textbooks as Topic
10.
Clin Radiol ; 73(2): 185-190, 2018 02.
Article in English | MEDLINE | ID: mdl-29032801

ABSTRACT

AIMS: To investigate the current use of radiology in anatomy teaching across the UK, and to determine the level of interest expressed in expanding its role in medical education. MATERIALS AND METHODS: A 22-question electronic survey was distributed to the organisers of anatomy teaching at 35 UK medical schools. The questionnaire explored the use of radiology in their anatomy course, the different kinds of available resources, and attitudes towards integrating radiology into anatomy teaching. RESULTS: Responses were received from 29/35 (83%) medical schools. Among the respondents, radiological anatomy featured in all but one of their curricula. Of those schools using radiology to aid anatomy teaching, 20/28 expressed a wish for more radiology in the curriculum. Timetabling constraints constituted one of the main difficulties in further implementation. In addition, 22/28 medical schools had already fostered collaborative links with local radiology departments, with 18 of these expressing a wish for further cooperation. Of the remaining six schools without current collaboration, four would like to establish connections. CONCLUSION: Compared with previous studies, this national survey shows a definite increase in radiological anatomy in medical school curricula with a stronger presence of radiologists in anatomy teaching. Despite this, most anatomy departments still express a desire to increase the radiological component in their courses.


Subject(s)
Anatomy/education , Curriculum , Education, Medical, Undergraduate/methods , Radiology/education , Schools, Medical , Humans , Surveys and Questionnaires , United Kingdom
11.
Br J Oral Maxillofac Surg ; 55(10): 1035-1041, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29122337

ABSTRACT

Dissection on to the facial aspect of the zygoma is common in procedures of the midface for trauma, craniofacial deformity, and cosmesis. These procedures carry the risk of injury to the neurovascular structures that exit from the zygomaticofacial foramen (ZFF). The purpose of this study was to map the ZFF, and to establish reliable reference points from which to identify it before and during operation. We also aimed to compare the anatomy of the ZFF between sexes and among geographical populations. A total of 429 adult skulls from nine geographical sites were used. A cross-line laser was superimposed on to each zygoma to generate consistent landmarks (lines 1 and 2) from which to measure the ZFF, and the number of ZFF on each zygoma was recorded. The site and incidence of ZFF differed significantly among geographical populations, but not between sexes. Of all 858 sides, no foramina were found in 16.3%, one foramen in 49.8%, two foramina in 29%, three in 3.4% and four in 1.4%. A total of 93% of foramina were within a 25mm diameter zone (ZFF zone) centred 5mm anterior to the intersection of lines 1 and 2 on the right zygoma, and 94% were within equivalent measurements on the left. Using these landmarks, we propose a new method of identifying a ZFF zone that is irrespective of sex or geographical population. This technique may be useful in the prevention of iatrogenic damage to the ZFF neurovascular bundle during procedures on the midface and in local nerve blocks.


Subject(s)
Anatomic Variation , Zygoma/anatomy & histology , Cadaver , Female , Humans , Male , Racial Groups , Surgical Procedures, Operative
12.
Folia Morphol (Warsz) ; 76(4): 742-747, 2017.
Article in English | MEDLINE | ID: mdl-28553852

ABSTRACT

BACKGROUND: In this study, 82 forearms from 41 cadavers were dissected to establish the incidence of variant additional radial wrist extensors. Three variants have been described in the literature: extensor carpi radialis intermedius (ECRI), extensor carpi radialis accessorius (ECRA) and extensor carpi radialis tertius (ECRT). MATERIALS AND METHODS: Of the 41 cadavers studied, 5/41 (12%) had an additional radial wrist extensor. Of these 5 individuals, 2 had bilateral additional muscles and 3 were unilateral. Of the 82 forearms, 7/82 (9%) had additional radial wrist extensors. RESULTS: We found 4 examples of ECRI and 3 examples of ECRA. We did not find any examples of ECRT. One specimen of ECRA had an atypical, previously undescribed, course. CONCLUSIONS: These accessory muscles are of clinical relevance, as they may be a contributing factor in tennis elbow and nerve entrapment, or cause diagnostic confusion, especially in ultrasound scans. However, they may also be used for tendon transfer. Of the 7 muscles found in the current study, 3 would have been suitable for such procedures.

13.
Ann R Coll Surg Engl ; 97(6): 439-44, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26274737

ABSTRACT

INTRODUCTION: Locoregional variation in the human colon is important in surgical practice; the length and mobility of different colonic regions impacts on laparoscopic and endoscopic colorectal procedures. The aim of this study was to refine anatomical understanding of the colon in terms of segmental length and mobility. METHODS: The colons of 35 cadavers were examined to determine lengths of caecum as well as ascending, transverse, descending and rectosigmoid colon, and to characterise colonic mobility at each location in terms of the mesenteric attachments. The presence of Jackson's membrane (a congenital peritoneal band of the right colon) was also documented. RESULTS: The mean total colonic length was 131.2cm (standard deviation [SD]: 13.4cm). There was no correlation with height, age or sex; the best predictor of total colonic length was the length of the rectosigmoid segment. The mean height of the transverse mesocolon was 7.4cm (SD: 3.6cm) and that of the sigmoid mesocolon was 6.3cm (SD: 2.6cm). Two-thirds of the subjects had a mobile portion of the ascending colon and nearly one-third had a mobile descending colon. A mobile ascending colon was significantly more common in females. Jackson's membrane was present in 66% of the subjects. CONCLUSIONS: This cadaveric study suggests that rectosigmoid length accounts for most of the variability in total colonic length. The significant proportion of colons with mobility of the ascending and descending segments prompts revision of the traditional anatomical teaching of these segments as fixed and retroperitoneal. Mobility of the ascending colon may account for the anecdotal finding that colonoscopy is more challenging in female patients. Jackson's membrane was identified in most colons.


Subject(s)
Colon/anatomy & histology , Colon/physiology , Gastrointestinal Motility/physiology , Aged , Aged, 80 and over , Cadaver , Colon/abnormalities , Colon, Sigmoid/anatomy & histology , Colon, Sigmoid/physiology , Female , Humans , Male , Mesentery/anatomy & histology , Mesentery/physiology , Middle Aged , Sex Characteristics
14.
J Med Genet ; 36(9): 678-82, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10507723

ABSTRACT

Germline mutations in the MSH2 and MLH1 mismatch repair genes account for most cases of hereditary non-polyposis colon cancer syndrome (HNPCC). In addition, germline MSH2 and MLH1 mutations have been detected in patients with non-HNPCC early onset colorectal cancer. Germline MSH6 mutations appear to be rare in classical HNPCC families, but their frequency in young colorectal cancer cases has not been studied previously. In a population based study of early onset colorectal cancer (<50 years) investigated for tumour microsatellite instability (MSI), we identified a subgroup of tumours with MSI for mono- but not dinucleotide repeat markers (m-MSI+ group). In contrast to tumours with classical MSI for dinucleotide markers (d-MSI+), the m-MSI+ group cancers were mainly left sided (6/7). As MSH6 mutations in yeast and human cell lines are associated with weak (and preferential mononucleotide) MSI, the complete MSH6 gene coding region was sequenced in blood DNA from the five m-MSI+ cases available for analysis. A germline nonsense mutation was identified in an isolated case of early onset colorectal cancer (age 43 years). These results support previous findings that germline MSH6 mutations may not be associated with classical MSI and suggest a role for germline MSH6 mutations in isolated early onset colorectal cancer.


Subject(s)
Colorectal Neoplasms/genetics , DNA-Binding Proteins/genetics , Proto-Oncogene Proteins/genetics , Adult , Age of Onset , Base Pair Mismatch , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Germ-Line Mutation , Humans , Microsatellite Repeats , Middle Aged , MutS Homolog 2 Protein
15.
J Med Genet ; 36(2): 97-102, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10051005

ABSTRACT

The frequency, origin, and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated. The mutation (A-->T at nt943+3) disrupts the 3' splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported. Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England, more extensive analysis has reduced the frequency to four of 52 (8%) English HNPCC kindreds analysed. In contrast, the MSH2 mutation was identified in 10 of 20 (50%) separately identified colorectal families from Newfoundland. To investigate the origin of this mutation in colorectal cancer families from England (n=4), Newfoundland (n=10), and the United States (n=3), haplotype analysis using microsatellite markers linked to MSH2 was performed. Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families. In contrast, a common haplotype was identified at the two flanking markers (CA5 and D2S288) in eight of the Newfoundland families. These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families. We calculated age related risks of all, colorectal, endometrial, and ovarian cancers in nt943+3 A-->T MSH2 mutation carriers (n=76) for all patients and for men and women separately. For both sexes combined, the penetrances at age 60 years for all cancers and for colorectal cancer were 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (p<0.01) in males than females (0.63 v 0.30 and 0.84 v 0.44 at ages 50 and 60 years, respectively). For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms/genetics , DNA-Binding Proteins , Proto-Oncogene Proteins/genetics , Age Factors , Chromosomes, Human, Pair 2/genetics , Endometrial Neoplasms/genetics , England , Female , Founder Effect , Gene Expression , Haplotypes , Humans , Male , MutS Homolog 2 Protein , North America , Ovarian Neoplasms/genetics , Phenotype , Point Mutation , Polymorphism, Single-Stranded Conformational , Risk Factors , Sequence Analysis, DNA , Sex Factors
16.
J Med Genet ; 33(12): 981-5, 1996 Dec.
Article in English | MEDLINE | ID: mdl-9004127

ABSTRACT

Hereditary non-polyposis colorectal cancer syndrome (HNPCC) is often considered to be the most common form of inherited colorectal cancer, although its precise incidence is unknown. The clinical diagnosis of HNPCC relies on a combination of family history and young age of onset of colorectal cancer, but as many familial aggregations of colorectal cancer do not fulfil the strict diagnostic criteria, HNPCC might be underdiagnosed. The majority of HNPCC families have germline mutations in mismatch repair (MMR) genes, such as MSH2 or MLH1, so that HNPCC cancers characteristically exhibit DNA replication errors (RERs) at microsatellite loci. Although an RER positive phenotype in tumours can also result from somatic mutations in an MMR gene, the prevalence of RER + tumours should provide a maximum estimate of the incidence of germline MMR gene mutations in patients with early onset and familial colorectal cancer. We investigated colorectal cancers for RERs from (1) a population based study of 33 patients with colorectal cancer aged 45 years or less, (2) 65 kindreds with familial colorectal cancer which only partially fulfilled the criteria for the diagnosis of HNPCC, and (3) 18 cancers from 12 HNPCC kindreds. Seven of 33 patients (21%) with colorectal cancer aged 45 years or less had an RER + cancer, with only two of these having a clear family history of HNPCC. A greater proportion of RER + tumours (5/7) occurred proximal to the splenic flexure than RER - tumours (4/26; chi2 = 6.14, p < 0.025). RERs were detected in all 18 cancers from HNPCC patients but in only six of 65 non-HNPCC familial colorectal cancer kindreds (9%; chi2 = 52.2, p < 0.0005). These findings suggest that most cancers in patients diagnosed at 45 years of age or less and familial aggregations of colorectal cancer which do not fulfil HNPCC diagnostic criteria do not have germline mutations in MSH2 and MLH1. Hence population screening for germline mutations in these genes is unlikely to be an efficient strategy for identifying people at high risk of developing colorectal cancer.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Fungal Proteins , Microsatellite Repeats , Adult , Age of Onset , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , DNA Repair/genetics , DNA Replication , DNA-Binding Proteins/genetics , Female , Germ-Line Mutation , Humans , Male , Middle Aged , MutS Homolog 2 Protein , Pedigree , United Kingdom/epidemiology
17.
J Med Genet ; 33(9): 726-30, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8880570

ABSTRACT

Germline mutations in four human mismatch repair genes (MSH2, MLH1, PMS1, and PMS2) have been reported to cause hereditary non-polyposis colon cancer syndrome (HNPCC). The identification of germline mutations in HNPCC kindreds allows precise diagnosis and accurate predictive testing. To investigate further the genetic epidemiology of HNPCC and the nature and frequency of germline mutations in this disorder, we studied 17 English HNPCC kindreds for germline mutations in MSH2 and MLH1. A previous genetic linkage study had suggested that most English HNPCC families will have mutations in one of these genes. Mutation analysis was performed in a three step process. (1) mRNA extracted from lymphoblastoid cell lines was analysed for gross rearrangements, (2) the in vitro transcription-translation (IVTT) assay was then performed to detect protein truncating mutations, and (3) partial cDNA sequencing of MSH2 or MLH1 was undertaken in families (n = 6) linked to MSH2 or MLH1 but without a detectable mutation. Seven different germline mutations were identified in eight of 17 (47%) kindreds (five in MSH2 and three in MLH1). In three cases there was a deletion of a single exon in MSH2 mRNA, three mutations resulted in a truncated protein product, and two missense mutations were identified by direct sequencing. Six mutations were novel. No precise correlation between genotype and phenotype was observed, although a MSH2 missense (Thr905Arg) mutation was associated with a susceptibility to multiple colorectal polyps. Age related risks for colorectal and uterine cancer were similar for MSH2 and MLH1 mutations.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Repair , DNA-Binding Proteins/genetics , Fungal Proteins/genetics , RNA, Messenger/chemistry , Adaptor Proteins, Signal Transducing , Genetic Linkage , Genotype , Humans , Microsatellite Repeats , MutL Protein Homolog 1 , MutS Homolog 2 Protein , Mutagenesis , Phenotype , Saccharomyces cerevisiae Proteins , Tumor Cells, Cultured
19.
Biochim Biophys Acta ; 840(3): 383-92, 1985 Jul 05.
Article in English | MEDLINE | ID: mdl-3859336

ABSTRACT

Stopped-flow spectrometry and simple mixing techniques have been employed to investigate the detergent-induced dissociation of anthracycline antibiotics from natural and synthetic DNAs. Both daunomycin and nogalamycin dissociate more slowly from poly(dG-dC) than from poly(dA-dT) but the difference is much more marked for nogalamycin. With an equimolar mixture of poly(dG-dC) and poly(dA-dT), or with poly(dA-dC).poly(dG-dT), dissociation of nogalamycin occurs very slowly. In all cases the release of antibiotic from a synthetic polynucleotide is a one-step process following a single exponential. Dissociation of daunomycin, adriamycin and iremycin from calf thymus DNA is a more complex reaction which requires a two-exponential fit, in contrast to earlier reports, but differences between the behaviour of the three antibiotics are minor. Dissociation of nogalamycin from natural DNA requires a three-exponential fit, is in general far slower, and depends upon the base composition, the level of binding and the time allowed for the complex to equilibrate. It is concluded that sequence selectivity is minimal or lacking for daunomycin, whereas nogalamycin binding is sequence dependent and probably involves migration of the antibiotic between DNA binding sites. There is an inverse correlation between dissociation rate constants and antibacterial potency in simple tests.


Subject(s)
DNA/metabolism , Daunorubicin/analogs & derivatives , Nogalamycin/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antibiotics, Antineoplastic , Binding Sites , Cattle , In Vitro Techniques , Kinetics , Naphthacenes/metabolism , Poly dA-dT/metabolism , Polydeoxyribonucleotides/metabolism
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