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PubMed2006

Comparison of 'whoosh' and modified 'swoosh' test for identification of the caudal epidural space in children.

BACKGROUND: Caudal analgesia is widely used in pediatric anesthesia practice. The 'whoosh' test which uses air to identify the epidural space, has been recommended as a guide for successful needle placement. However, the use of air may be associated with an incidence of neurological complications. The 'swoosh' test avoids the injection of air and was originally performed using injection of a local anesthetic solution. A comparison was made between the 'whoosh' test and a modified 'swoosh' test using saline to identify the caudal epidural space in children. METHODS: We studied 60 children of either sex in the age group of 2-8 years undergoing inguinal herniotomy. During insertion of the caudal block, a stethoscope was placed over the lower lumbar spine to note the presence or absence of 'whoosh' or 'swoosh', by an independent observer who was blinded to the injection of 1 ml of air or saline which was given simultaneously by the operator into the caudal space. The operator's clinical impression of successful insertion of the needle was also recorded and correlated with the presence or absence of 'whoosh' or 'swoosh'. In addition, the need for supplemental intraoperative analgesia was noted. RESULTS: Overall success rate of caudal block using the 'whoosh' and modified 'swoosh' tests was found to be 96.6% and 93.3%, respectively as judged by the lack of supplementary perioperative analgesia. The sensitivity, specificity and positive predictive value of the 'whoosh' test and clinical predictors of caudal placement was found to be 100% whereas the modified 'swoosh' test had a sensitivity of 93%, specificity of 50% and a positive predictive value of 96%. However, statistically there was no significant difference between the clinical predictors, 'whoosh' and the modified 'swoosh' test for identification of the caudal epidural space. CONCLUSIONS: The modified 'swoosh' test is as reliable as the 'whoosh' test and we recommend it for identification of the caudal epidural space in children as it avoids injection of air into the caudal space.

Air↗
PubMed2006

Disease modifying therapy for AD?

Alzheimer's disease (AD) is the most common form of dementia in industrialized nations. If more effective therapies are not developed that either prevent AD or block progression of the disease in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Only two types of drugs are currently approved for the treatment of AD: inhibitors of acetyl cholinesterase, which symptomatically enhance cognitive state to some degree but are not disease modifying; and the adamantane derivative, memantine. Memantine preferentially blocks excessive NMDA receptor activity without disrupting normal receptor activity and is thought to be a neuroprotective agent that blocks excitotoxicty. Memantine therefore may have a potentially disease modifying effect in multiple neurodegenerative conditions. An improved understanding of the pathogeneses of AD has now led to the identification of numerous therapeutic targets designed to alter amyloid beta protein (Abeta) or tau accumulation. Therapies that alter Abeta and tau through these various targets are likely to have significant disease modifying effects. Many of these targets have been validated in proof of concept studies in preclinical animal models, and some potentially disease modifying therapies targeting Abeta or tau are being tested in the clinic. This review will highlight both the promise of and the obstacles to developing such disease modifying AD therapies.

Alzheimer Disease↗
PubMed2006

Engineering of vascular grafts with genetically modified bone marrow mesenchymal stem cells on poly (propylene carbonate) graft.

Bone marrow mesenchymal stem cells (MSCs) have demonstrated their pluripotency to differentiate into different cell lineages and may be an alternative cell source for vascular tissue engineering. The objective of this study is to create small diameter vessels by seeding and culture of genetically modified MSCs onto a synthetic polymer scaffold produced by an electrospinning technique. A tubular scaffold (2 mm in diameter) with a microstructure of nonwoven fibers was produced by electrospinning of poly (propylene carbonate) (PPC). Rat MSCs obtained from bone marrow were expanded in culture and modified with vasculoprotective gene endothelial nitric oxide synthase (eNOS) or marker gene green fluorescent protein (GFP). These MSCs were seeded onto the electrospun fibrous grafts (internal diameter = 2 mm), and cultured in 5% CO(2) at 37 degrees C. The growth of MSCs in the scaffold was analyzed with scanning electron microscopy (SEM) and hematoxylin and eosin (H&E) staining. The gene transfer and transgenic gene expression were examined with fluorescence-activated cell sorting (FACS), immunochemical staining, reverse transcriptase-polymerase chain reaction (RT-PCR), and western blot. The production of nitric oxide (NO) by the engineered vessels was measured with an NO detection kit. Our data showed that the seeded cells integrated with the microfibers of the scaffold to form a three-dimensional cellular network, indicating a favorable interaction between this synthetic PPC scaffold with MSCs. High transduction efficiency was obtained with the use of concentrated retrovirus in the gene transfection of MSCs. The eNOS gene transcripts and protein were detected in the grafts seeded with eNOS-modified MSCs by RT-PCR and immunochemical staining. The amount of NO produced by grafts seeded with eNOS-modified MSCs was comparable to that produced by native blood vessels, and it was significantly higher than that in the grafts seeded with nonmodified MSCs. In summary, the vascular graft produced by culture of eNOS gene-modified MSCs onto the electrospun tubular scaffolds shows promising results in terms of function. The use of MSCs and therapeutic genes in tissue engineering of blood vessels could be helpful in improving vessel regeneration and patency.

Animals↗
PubMedDate not supplied

Biomechanical and clinical evaluation of a modified 3-loop pulley suture pattern for reattachment of canine tendons to bone.

OBJECTIVE: To describe a modified 3-loop pulley suture pattern for the reattachment of canine tendons to bone along with a biomechanical comparison with the locking-loop suture. STUDY DESIGN: In vitro biomechanical study and clinical case report. ANIMALS OR SAMPLE POPULATION: Biomechanical study: 10 paired gastrocnemius tendons and calcaneii harvested from 5 canine cadavers. CASE REPORT: a Doberman with avulsion of the gastrocnemius tendon of insertion. METHODS: Biomechanical study: paired tendons were reattached to the calcaneus with either a modified 3-loop pulley pattern or a locking-loop pattern. Tensile loading to failure was performed. A direct, non-contact, method of gap measurement, using digital video, was used to measure gap formation. Load required to initiate gap formation (defined as load at a 1 mm gap) and to produce a 3 mm gap was evaluated in addition to maximum load and gap at failure. RESULTS: Mean (+/-SEM) 1 mm gap loads were 31.0+/-4.2 and 17.2+/-2.5 N, mean 3 mm gap loads were 49.1+/-2.4 and 28.9+/-3.2 N, and mean maximum loads were 72.9+/-4.3 and 55.8+/-2.2 N for the modified 3-loop pulley suture and the locking-loop suture, respectively. These differences were statistically significant (P<.05). The gap at failure was similar for both repairs. The clinical case remained sound 7 months postoperatively. CONCLUSIONS: A modified 3-loop pulley pattern is biomechanically superior to a locking-loop pattern for reattachment of the canine gastrocnemius tendon to bone and may be suitable for clinical use. CLINICAL RELEVANCE: Tendon repairs with a gap >3 mm are reported to be at increased risk of rupture during the first 6 weeks postoperatively. A modified 3-loop pulley pattern resists gap formation better than a locking-loop pattern.

Animals↗
PubMedDate not supplied

A modified lateral approach to the canine cervical spine: procedural description and clinical application in 16 dogs with lateralized compressive myelopathy or radiculopathy.

OBJECTIVE: To describe a modified lateral surgical approach to the cervical spine in dogs and evaluate clinical outcomes of dogs with neurologic disorders treated with this technique. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: Sixteen dogs with lesions involving the cervical spine. METHODS: Medical records (1998-2002) of dogs that had a modified lateral approach to the cervical spine were reviewed. To reduce procedural morbidity, the surgical approach was modified from original descriptions of the technique by minimizing disruption of epaxial and extrinsic thoracic limb musculature and limiting the size of the operative field to the affected vertebral segment. Signalment, neurologic status on admission; onset, progression, and duration of clinical signs; diagnostic testing, etiologic diagnosis, surgical site(s), intra- and postoperative complications, hospitalization, time to optimum recovery, neurologic status at discharge, final neurologic status, and outcome were recorded. Neurologic status (0-5) was scored preoperatively, 1 day postoperatively, at discharge, and at recheck examination (8 dogs). Telephone interviews were used to obtain additional follow-up information. RESULTS: None of the dogs had postoperative deterioration in neurologic status. Outcomes were good or excellent in dogs with intervertebral disc disease, 3/4 dogs with caudal cervical spondylomyelopathy, 1/2 dogs with spinal neoplasia, and in 1 dog with the vascular anomaly; long-term outcomes were unknown in 2 dogs. Intraoperative complications occurred in 3 dogs and included controllable venous plexus hemorrhage (2) and incorrect lesion localization (1). One dog was euthanatized because of postoperative complications. Hospitalization, time to optimal recovery, and overall outcome were not different from previously reported results using other surgical approaches to treat analogous neurologic conditions. CONCLUSIONS: A modified lateral approach to the cervical spine is viable for surgical treatment of cervical myelopathic or radiculopathic lesions when exposure to foraminal and lateralized lesions of the vertebral canal involving the C2-C7 vertebral articulations is desirable. CLINICAL RELEVANCE: A modified lateral approach to the cervical spine can be successfully used in dogs of all sizes to treat caudal cervical spondylomyelopathy, other anomalous conditions of the cervical spine, intervertebral disc disease, and spinal neoplasms. Although long-term follow-up was not available for all patients, outcomes were generally favorable.

Animals↗
PubMed1989

Contact allergy due to colophony. (V). Patch test results with different types of colophony and modified-colophony products.

The results of patch tests with colophony in the standard series between 1983 and 1987 were analyzed. 5521 patients were tested in the Department of Dermatology, Hamburg, while 354 were tested in other clinics and private practices. Colophony was positive in 2.4% and 11.9%, respectively. Out of 62 patients in the 1st group and 75 in a 2nd group tested subsequently with 6 unmodified types of colophony and 12 types of modified-colophony products, 17 did not react to the unmodified material. However, most of them responded to 1 or more of the modified products. In the enlarged group (n = 75), reactions to Abitol and the maleic-modified products were the most frequently obtained. As the authors are convinced that the actual incidence of allergic reactions to modified-colophony products is underestimated, they propose to test a mixture of 3 materials: Chinese colophony (today 50% of the world market) and 2 derivatives (modified colophony), instead of the 60% mix of unmodified colophony, in the standard series.

Dermatitis, Contact↗
PubMed1990

Contact allergy due to colophony (VI). The sensitizing capacity of minor resin acids and 7 commercial modified-colophony products.

3 minor resin acids and 7 commercial modified-colophony products of different origins were studied by experimental sensitization by means of a modified FCA method. All 3 resin acids were almost negative. The commercial products gave different results. While the maleic-modified product of Greek origin showed a strong sensitizing power, the fumaric-modified, terpene-phenol-modified and a disproportioned rosin were only moderate. A remarkable difference was obtained with the Swedish and Finnish tall oil rosins, which, in contrast to the previously studied French product, exhibited only a weak sensitizing capacity.

Animals↗
PubMedDate not supplied

Expression and in vitro evaluation of rhesus macaque wild type (wt) and modified CC chemokines.

Several human CC chemokines have been shown to inhibit HIV/ SIV infection in vitro, providing the rationale for their potential use in vivo. However, because of their inherent physiological effect, such chemokines are reasoned to be of limited therapeutic value due to potential side effects. The knowledge that amino terminus modified or deleted human RANTES retains its receptor binding properties but loses its signaling properties has provided a means to use such modified chemokines in vivo for possible therapeutic benefits. In efforts to test the efficacy of such modified chemokines, our laboratory has cloned, sequenced, and prepared recombinant forms of wild-type (wt) and amino-terminus modified rhesus macaque chemokines MIP-1alpha, MIP-1beta, and RANTES. These sets of chemokines were tested for their potential to inhibit SIV infection and induce signaling. The data showed that whereas wt chemokines retained both virus inhibitory and signaling functions, corresponding amino-terminus modified chemokines only showed virus inhibitory effects without detectable signaling effects. Such reagents will be valuable for evaluation of their therapeutic potential in vivo, either alone or as adjuncts to other chemotherapeutic drugs.

Amino Acid Sequence↗
PubMed2005

Effectiveness of scaling and root planing versus modified Widman flap on nitric oxide synthase and arginase activity in patients with chronic periodontitis.

BACKGROUND: Nitric oxide (NO) is synthesized from the conversion of L-arginine to L-citrulline by NO synthase (NOS). Arginase, which is an arginine-depleting enzyme, can compete with NOS for the common substrate L-arginine and thus inhibit NO production. OBJECTIVES: In the present study, we aimed to examine the correlation between the arginase and NOS activity in patients with chronic periodontitis and to compare the effects of scaling and root planing and modified Widman flap procedures on enzyme activity. MATERIAL AND METHODS: The study included 13 patients diagnosed with chronic periodontitis. Using a split-mouth design, the defects showing>or=7 mm of attachment loss were treated either with scaling and root planing or with modified Widman flap. Gingival biopsies from both sites were obtained at baseline and 2 months after periodontal treatment. Immunohistochemical staining was performed for evaluating NOS expression and specific arginase activity was determined spectrophotometrically. RESULTS: Although inflamed periodontal tissues demonstrated a strong inducible NOS (iNOS) expression at baseline, immunostaining decreased after periodontal treatment. iNOS expression intensity and the number of inflammatory cells showing iNOS expression were found to be higher in the scaling and root planing group compared to the modified Widman flap group. The specific activity of arginase was measured as 0.18+/-0.07 IU/mg protein in the modified Widman flap group and 0.25+/-0.11 IU/mg protein in the scaling and root planing group at baseline. After periodontal therapy, the enzyme level was increased to 0.68+/-0.14 IU/mg protein in the modified Widman flap and to 1.10+/-0.23 IU/mg protein in the scaling and root planing group. CONCLUSION: This study was the first report of evaluating the involvement of the arginine-NO pathway in chronic periodontitis and this might be considered to be of value in understanding the periodontal disease mechanisms.

Adult↗
PubMed2005

Bone tissue responses to surface-modified zirconia implants: A histomorphometric and removal torque study in the rabbit.

BACKGROUND: Zirconia ceramics are biocompatible and have mechanical properties that make them suitable as materials for dental implants. Little is known about how surface modification influences the stability and bone tissue response to zirconia implants. PURPOSE: The objective of the investigation was to histologically and biomechanically evaluate the bone tissue response to zirconia implants with two different surface modifications in comparison with machined, nonmodified zirconia implants and oxidized titanium implants. MATERIALS AND METHODS: Threaded zirconia implants with a diameter of 3.75 mm with either a machined surface (Zr-Ctr) or one of two surface modifications (Zr-A and Zr-B) were manufactured. Oxidized titanium (Ti-Ox) implants 3.75 mm in diameter were also used. The implants were characterized with regard to surface topography using an interferometer. Twelve rabbits received 96 implants using a rotational scheme, two in each tibia and two in each femur. The implants in six rabbits were subjected to removal torque (RTQ) tests after a healing period of 6 weeks. The implants in the remaining six animals were removed en bloc for light microscopic analysis. Back-scatter scanning electron microscopic (BS-SEM) analyses were used to evaluate the state of the bone-implant interface at the modified zirconia implants after RTQ testing. RESULTS: The Ti-Ox and Zr-A implants showed the highest surface roughness, followed by the Zr-B implants and, finally, the Zr-Ctr implants. The nonmodified ZrO2 implants showed statistically significant lower RTQs than all other implants. No significant differences in bone-implant contact or bone area filling the threads were observed. BS-SEM showed intact surface layers of the surface-modified implants after RTQ testing and revealed fracture of the interface bone rather than a separation. CONCLUSION: The present study showed a strong bone tissue response to surface-modified zirconia implants after 6 weeks of healing in rabbit bone. The modified zirconia implants showed a resistance to torque forces similar to that of oxidized implants and a four- to fivefold increase compared with machined zirconia implants. The findings suggest that surface-modified zirconia implants can reach firm stability in bone.

Animals↗
PubMed2001

Evaluation of a modified version of the index of Oral Impacts On Daily Performances (OIDP) in elderly populations in two European countries.

OBJECTIVE: To examine the psychometric properties of a modified version of the index of Oral Impacts on Daily Performance (OIDP) in elderly populations in two European countries, namely Great Britain and Greece. The psychometric properties examined in this study refer to internal consistency and face, content, criterion and construct validity. DESIGN AND SETTING: Cross-sectional epidemiologic surveys of independently living people aged 65 years or older. Data were collected by interviewers through structured questionnaires. The British sample consisted of the randomly selected independently living persons that participated in the dental component of the National Diet and Nutrition Survey (NDNS) of adults aged 65 years or over. The Greek sample is an opportunity sample drawn from eligible people living in two municipalities of the Athens region. SUBJECTS: 753 people participated in the British and 681 in the Greek sample. RESULTS: Through pilot work in both countries, the OIDP index was modified and both Greek and British modified versions demonstrated satisfactory face and content validity. In the main studies, Cronbach's alpha of the modified OIDP was 0.77 for the Greek and 0.69 for the British sample. In both samples, the index showed very significant associations with perceived dental treatment need (p<0.001), perceived general health (p<0.001 in Greek, p=0.002 in British) and intermediate oral impacts (p<0.001), as well as with satisfaction with oral health in the Greek sample (p<0.001). CONCLUSIONS: Overall, this study has demonstrated that the modified OIDP is a valid and reliable measure of oral health related quality of life in elderly people in Great Britain and Greece.

Aged↗
PubMed2003

SCNM1, a putative RNA splicing factor that modifies disease severity in mice.

The severity of many inherited disorders is influenced by genetic background. We describe a modifier interaction in C57BL/6Jmice that converts a chronic movement disorder into a lethal neurological disease. The primary mutation (medJ) changes a splice donor site of the sodium channel gene Scn8a (Nav1.6). The modifier mutation is characteristic of strain C57BL/6Jand introduces a nonsense codon into sodium channel modifier 1 (SCNM1), a zinc finger protein and a putative splice factor. An internally deleted SCNM1 protein is also predicted as a result of exon skipping associated with disruption of a consensus exonic splicing enhancer. The effect of the modifier mutation is to reduce the abundance of correctly spliced sodium channel transcripts below the threshold for survival. Our finding that genetic variation in a putative RNA splicing factor influences disease susceptibility in mice raises the possibility that a similar mechanism modifies the severity of human inherited disorders.

Alleles↗
PubMed1973

Rapid, modified Kirby-Bauer susceptibility test with single, high-concentration antimicrobial disks.

A rapid (6-7 hr), modified Kirby-Bauer disk-susceptibility method, by which derivatives of tetrazolium dyes are used to enhance delineation between areas of growth and zones of inhibition, has been developed. Inoculated petri plates, prepared by the Kirby-Bauer method, were sprayed, after 6 to 7 hr of incubation (37 C), with aqueous solutions of MTT-tetrazolium or INT-tetrazolium resulting in readily detectable zones of inhibition. Excellent correlation was obtained between the modified test and the standard Kirby-Bauer test when challenged with a variety of gram-negative bacteria and Staphylococcus aureus strains. Additionally, the modified test has demonstrated reproducibility comparable to the standard Kirby-Bauer test. It is demonstrated that the modified test is applicable to susceptibility determinations with representative, commercially available antimicrobial disks. This applicability indicates that the modified method could provide rapid in vitro guidelines for in vivo therapy.

Bacteria↗
PubMed1980

Variability of low-molecular-weight, heat-modifiable outer membrane proteins of Neisseria meningitidis.

Analysis of major outer membrane protein (MOMP) profiles of various meningococci by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (SDS-PAGE) revealed the presence of 0 to 2 low-molecular-weight, heat-modifiable MOMPs (molecular weight, 25,000 to 32,000) and 1 to 3 high-molecular-weight MOMPs (molecular weight, 32,000 to 46,000). Heat modifiability was investigated by comparing MOMP profiles after heating in SDS solutions at 100 degrees C for 5 min or at 40 degrees C for 1 h. Low-molecular-weight MOMPs shifted to higher apparent molecular weights after being heated at 100 degrees C. Heat modifiability of high-molecular-weight MOMPs varied among strains; whenever modified these proteins shifted to lower apparent molecular weights after complete denaturation. Variability of low-molecular-weight, heat-modifiable MOMPs was demonstrated when MOMP profiles were compared of (i) isolates from index cases and associated cases and carriers among contacts, (ii) different isolates from the same individual, and (iii) isolates from a small epidemic caused by serogroup W-135. In some cases high-molecular-weight MOMPs revealed quantitative differences among related strains. The observed variability and quantitative differences indicate that MOMP serotyping and typing on the basis of SDS-PAGE profiles (PAGE typing) need careful reevaluation.

Adolescent↗
PubMed1980

Major heat-modifiable outer membrane protein in gram-negative bacteria: comparison with the ompA protein of Escherichia coli.

The outer membranes of several strains of Escherichia coli, other enteric bacteria, and a variety of nonenteric gram-negative bacteria all contain a major heat-modifiable protein similar to the OmpA protein of E. coli K-12. The heat-modifiable proteins from these bacteria resemble the K-12 protein in molecular weight, in preferential release from the outer membrane by sodium dodecyl sulfate in the presence of Mg2+, and in characteristic cleavage by proteases to yield a smaller fragment which remains membrane bound. Antiserum directed against the K-12 protein precipitated the heat-modifiable protein from all strains of Enterobacteriaceae, and chemical comparison by isoelectric focusing, cyanogen bromide cleavage profiles, and proteolytic peptide analysis indicated that the proteins from the various enteric bacteria were nearly identical in primary structure. The heat-modifiable proteins from bacteria phylogenically distant from E. coli shared many of the properties of the E. coli protein but were chemically distinct. Thus, it appears that the structure (and, presumably, the function) of the heat-modifiable protein of gram-negative bacteria is strongly conserved during evolution.

Antigens, Bacterial↗
PubMed2003

p24 Antigen detection assay modified with a booster step for diagnosis and monitoring of human immunodeficiency virus type 1 infection.

We modified a p24 antigen enzyme-linked immunosorbent assay as a method for diagnosis and monitoring of human immunodeficiency virus type 1 (HIV-1) subtype E infection. This modified assay is based on the use of preheated immune complex dissociation combined with a booster step using a regular Vironostika HIV-1 p24 antigen assay (bioMerieux) to decrease the lower limit of p24 antigen detection from 10 pg/ml (lower limit achievable when using a regular p24 antigen assay) to 0.5 pg/ml (100 virions/ml) by the new method. The correlation between the values obtained by the HIV-1 RNA (Amplicor HIV-1 Monitor) assay and the p24 antigen assay modified with a booster step antigen assay in 160 frozen plasma samples with known viral load and 80 blind fresh plasma samples by Spearman rank were 0.671 (R(2) = 0.450; P < 0.01) and 0.782 (R(2) = 0.612; P < 0.01). During antiretroviral treatment, the change of p24 antigen level at >/=0.5 log correlated well with the level of HIV-1 in plasma. In order to improve the early diagnosis of HIV-1 infection in 121 infants born to HIV-1-infected mothers, a heat-denatured plasma p24 antigen assay modified with a booster step was compared with DNA-PCR and HIV RNA (nucleic acid sequence-based amplification) assays. The sensitivity of the antigen test modified with a booster step was similar to that of the HIV-1 RNA (NASBA QL) assay and better than that of the DNA-PCR assay (100 versus 61.90%) for subjects 1 to 2 months old. The overall results from this study might renew interest in p24 antigen detection as an easily affordable alternative method for diagnosis of HIV-1 infection and monitoring of disease progression in developing countries.

Antigens, Viral↗
PubMed2004

Modified colorimetric assay for susceptibility testing of azole antifungal drugs against Candida species.

We modified a rapid susceptibility assay (RSA) for antifungal susceptibility testing of azoles based upon glucose utilization. This modified RSA method provides quantitative endpoint readings in 6 h. In this study, the modified RSA and the National Committee for Clinical Laboratory Standards M27-A methods were used to determine the MICs of fluconazole and itraconazole for 118 Candida isolates. Yeast nitrogen base containing 0.12 g of glucose per liter was used for the modified RSA method. For fluconazole, agreement among assays within one or two twofold dilutions was 72.9 and 88.1%, respectively; for itraconazole, agreement within one or two twofold dilutions was 82.2 and 89.8%, respectively. These data suggest that the modified RSA method is a reliable and rapid method for azole antifungal susceptibility testing against Candida species.

Antifungal Agents↗
PubMed2002

Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes.

BACKGROUND: Familial adenomatous polyposis (FAP) is characterised by variable phenotypic expression. Part of this is attributable to a relationship between APC genotype and phenotype but there remains significant intrafamilial variation. In the Min mouse model of FAP, differences in the severity of gastrointestinal polyposis result from the action of modifier genes. AIMS: To determine whether phenotypic variation in human FAP has an inherited component consistent with the action of modifier genes. METHOD: We systematically examined polyp numbers in colectomy specimens from patients with classical FAP. Variation both between and within families was analysed. Formal modelling of the segregation of disease severity in families was performed RESULTS: There was strong evidence for a relationship between site of mutation and the number of colorectal polyps, with germline mutations in the "cluster region" causing the most severe disease and those with mutations between codons 1020 and 1169 having the mildest disease. In addition to this genotype-phenotype relationship, we found evidence for non-APC linked genetic modifiers of disease expression. First degree relatives had more similar polyp counts than more distant relatives. Formal modelling of the segregation of disease severity in families revealed further evidence for the action of modifier genes, with a best fit to a mixed model of inheritance. CONCLUSION: Our data provide good evidence to support the hypothesis that modifier genes influence the severity of FAP in humans.

Adenomatous Polyposis Coli↗