Comparison of capsule endoscopy and magnetic resonance imaging for the detection of polyps of the small intestine in patients with familial adenomatous polyposis or with Peutz-Jeghers' syndrome.

BACKGROUND AND STUDY AIMS: We have conducted a study to compare the diagnostic yields of magnetic resonance imaging (MRI) and capsule endoscopy for the detection of small-bowel polyps in patients with inherited polyposis syndromes. PATIENTS AND METHODS: MRI was performed in 20 patients, with either Peutz-Jeghers' syndrome (PJS; n = 4) or familial adenomatous polyposis (FAP; n = 16), and capsule endoscopy was done the next day. The number, size, and location of polyps were analyzed. RESULTS: Overall, 448 polyps ranging from about 1 mm to 30 mm in size were detected in eight patients by capsule endoscopy, whereas with MRI only 24 polyps all bigger than 5 mm could be seen in the four PJS patients. CONCLUSIONS: Polyps bigger than 15 mm were detected similarly with capsule endoscopy and MRI, whereas smaller polyps were seen much more often with capsule endoscopy. Polyps smaller than 5 mm were exclusively seen with capsule endoscopy. However, location of the detected polyps and determination of their exact sizes was more accurate by MRI.

E-cadherin expression is homogeneously reduced in adenoma from patients with familial adenomatous polyposis: an immunohistochemical study of E-cadherin, beta-catenin and cyclooxygenase-2 expression.

BACKGROUND AND AIMS: The adenomatous polyposis coli (APC) protein plays a crucial role in the regulation of beta-catenin, which is linked to the cell adhesion molecule E-cadherin. Furthermore, beta-catenin and cyclooxygenase-2 (COX-2) are both involved in the activation of nuclear transcription factors inducing cell proliferation. Germline mutations in the APC gene are the cause of familial adenomatous polyposis (FAP). To characterise the expression pattern of these proteins in FAP in comparison with sporadic adenomas, we studied 18 FAP-associated adenomas, 16 sporadic adenomas and seven normal colonic controls. METHODS: E-cadherin, beta-catenin, COX-2 expression and the proliferative index (Ki67) were assessed by immunohistochemistry (index of expressing cells / total number of cells) in adenomatous mucosa, adjacent non-neoplastic tissue and normal colonic controls. RESULTS: E-cadherin expression was significantly and homogeneously reduced in FAP adenomas (24%; 95%CI 16-32; sporadic adenomas 61%; 38-84; normal controls 98%; 96-100). Membraneous beta-catenin expression was significantly reduced in both FAP (30%; 11-49) and sporadic (42%; 19-65) adenomas (normal controls 96%; 88-104), whereas marked nuclear staining occurred in sporadic, but not in FAP adenomas. Stromal COX-2 expression and the proliferative index were increased only in sporadic adenomas (sporadic adenomas: COX-2 12%; 7-17, Ki67 24%; 15-33, FAP adenomas: COX-2 8%; 5-11, Ki67 5%; 2-9, normal controls: COX-2 4%; 2-7, Ki67 6%; 1-11). CONCLUSION: Proteins involved in cell adhesion and cell proliferation, especially E-cadherin, are expressed differently in FAP and sporadic adenoma, pointing to possible differences in the molecular pathways to adenoma.

Differences in pelvic floor area between African American and European American women.

OBJECTIVE: This study tests the null hypothesis that the size of the pelvic opening spanned by the pelvic floor is the same in African American and European American women. STUDY DESIGN: Forty African American female pelvises were age matched with 40 European American female pelvises from the Hamann-Todd collection at the Cleveland Museum of Natural History. The distances between the anchoring points of the pelvic floor to the bony pelvis (pubis anteriorly, ischial spines laterally, and inferior lateral angle of the sacrum posteriorly) were measured on each half of the pelvis. Measurements from left and right halves were averaged. The cross-sectional area of the pelvic floor was calculated from these dimensions. The bi-ischial line divided the total area into anterior and posterior pelvic floor areas. Analyses taking into account differences in stature by dividing individual dimensions by height were also performed. Group differences were compared with the Student t test and the Mann-Whitney rank sum test. RESULTS: African American women had a 5.1% smaller pelvic floor area than European American women (889.6 cm(2) vs 937.0 cm(2), 5.1% P =.037). This was attributable to a 10.4% smaller posterior area (365.3 cm(2) vs 407.6 cm(2), 10.4% P =.016), whereas the anterior areas were similar (524.3 cm(2) vs 529.3 cm(2), P =.61). The following measured distances were smaller in African American women: ischial spine to inferior sacral angle (5.4 cm vs 5.9 cm, P =.016) and bi-ischial diameter (10.0 cm vs 10.6 cm, P =.004). These distances remained significant after height was controlled. CONCLUSIONS: In African American women, the posterior pelvic floor area is 10.4% smaller than in European American women, resulting in a 5.1% smaller total pelvic floor area.

Detection of APC and k-ras mutations in the serum of patients with colorectal cancer.

Detection of tumor DNA in peripheral blood of patients with colorectal cancer (CRC) may allow early diagnosis of tumor disease and be of prognostic value. However, a reliable tumor marker detectable in the serum of patients with this disease is missing. Because k-ras and APC mutations occur frequently and at an early stage in CRCs, these mutations might also be detected in the serum of CRC patients and serve as tumor markers. Hence, tumor tissues of CRC patients were examined for the presence of mutations in the k-ras and APC genes. If a mutation was detected in the tumor, the serum of the patient was screened subsequently for the presence of this mutation. K-ray mutations were detected in 22 of 30 colorectal tumor tissues, but only in six patients was the mutation identified in their serum samples. Mutations of the APC gene were identified in 25 of 65 tumors: 20 of these 25 patients showed the respective mutation in their serum. Given their higher detection rate, APC mutations could be a more informative serum marker than k-ras in CRC patients.

Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families.

BACKGROUND AND AIMS: In familial adenomatous polyposis (FAP), correlations between site of mutation in the adenomatous polyposis coli (APC) gene and severity of colonic polyposis or extracolonic manifestations are well known. While mutation analysis is important for predictive diagnosis in persons at risk, its relevance for clinical management of individual patients is open to question. METHODS: We examined 680 unrelated FAP families for germline mutations in the APC gene. Clinical information was obtained from 1256 patients. RESULTS: APC mutations were detected in 48% (327/680) of families. Age at diagnosis of FAP based on bowel symptoms and age at diagnosis of colorectal cancer in untreated patients were used as indicators of the severity of the natural course of the disease. A germline mutation was detected in 230 of 404 patients who were diagnosed after onset of bowel symptoms (rectal bleeding, abdominal pain, diarrhoea). When these patients were grouped according to the different sites of mutations, mean values for age at onset of disease differed significantly: patients carrying APC mutations at codon 1309 showed a disease onset 10 years earlier (mean age 20 years) compared with patients with mutations between codons 168 and 1580 (except codon 1309) (mean age 30 years), whereas patients with mutations at the 5' end of codon 168 or the 3' end of codon 1580 were diagnosed at a mean age of 52 years. Within each group of patients however large phenotypic variation was observed, even among patients with identical germline mutations. A higher incidence of desmoids was found in patients with mutations between codons 1445 and 1580 compared with mutations at other sites, while no correlation between site of mutation and presence of duodenal adenomas was observed. CONCLUSIONS: As age at manifestation and course of the disease may be rather variable, even in carriers of identical germline mutations, therapeutic decisions should be based on colonoscopic findings in individual patients rather than on the site of mutation. However, in patients with mutations within codons 1445-1580, it may be advisable to postpone elective colectomy because desmoids may arise through surgical intervention.

Palmitate oxidation rate and action on glycogen synthase in myoblasts from insulin-resistant subjects.

Elevated plasma lipid and nonesterified fatty acid concentrations reduce insulin-mediated glucose disposal in skeletal muscle. Cultured myoblasts from 21 subjects were studied for rates of palmitate oxidation and the effect of palmitate on glycogen synthase activity at the end of an 18-h incubation in serum- and glucose-free media. Oxidation rates of 40 microM palmitate in cultured myoblasts correlated with the fasting glucose (r = 0.71, P = 0.001), log fasting insulin (r = 0.52, P = 0.03), and insulin-mediated glucose storage rate (r = -0.50, P = 0.04) of the muscle donors. Myoblast glycogen synthase activity can be regulated by 240 microM palmitate, but the changes are associated with the basal respiratory quotient and not with the insulin resistance of the muscle donor. These results indicate that myoblasts producing elevated palmitate oxidation rates in vitro can be used to identify skeletal muscle abnormalities which are primary contributors to insulin resistance in vivo. Effects of 240 microM palmitate on myoblast glycogen synthase activity appear to be mechanistically different from the relationship between myoblast palmitate oxidation rates and insulin resistance of the muscle donor.

Mapping of a gene for nonspecific X-linked mental retardation (MRX 75) to Xq24-q26.

Nonspecific X-linked mental retardation is a heterogeneous condition consisting of nonsyndromal mental retardation in males. It is caused by mutation in one of several genes on the X chromosome (MRX genes). Here we report on the localization of a presumptive MRX gene to chromosomal region Xq24-q26 in a German family with nonspecific X-linked mental retardation (MRX 75, HUGO Human Gene Nomenclature Committee). Two point linkage analysis with 23 informative markers gave a lod score of 2.53 at theta = 0 for markers DXS425, DXS1254, DXS1114, and HPRT.

Multiregional, not multiple origins.

Multiregional evolution is a model to account for the pattern of human evolution in the Pleistocene. The underlying hypothesis is that a worldwide network of genic exchanges, between evolving human populations that continually divide and reticulate, provides a frame of population interconnections that allows both species-wide evolutionary change and local distinctions and differentiation. "Multiregional" does not mean independent multiple origins, ancient divergence of modern populations, simultaneous appearance of adaptive characters in different regions, or parallel evolution. A valid understanding of multiregional evolution would go a long way toward reducing the modern human origins controversy.

Microsatellite instability-a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer.

BACKGROUND: Clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the clinical criteria may be missed. AIMS: To examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype relation in families with verified mutations. METHODS: Systematic search for germline mutations (hMSH2 and hMLH1 genes) was performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) and 12 the looser HNPCC criteria (group 2). Seventeen patients showed familial clustering of cancers (group 3) and 10 patients under 50 years had sporadic cancer (group 4), the latter of whom all exhibited MSI+ tumours. RESULTS: A similar proportion of germline mutations was found in patients who fulfilled the clinical criteria of HNPCC and had MSI+ tumours (groups 1 and 2; 15/39) compared with patients who did not meet these clinical criteria but who had MSI+ tumours (groups 3 and 4; 8/27 patients). Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations. CONCLUSIONS: MSI in tumour tissue is a useful criterion for selecting patients who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hMSH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.

Arthroscopic transglenoid multiple suture repair: 2 to 8 year results in 150 shoulders.

One hundred fifty-six arthroscopic transglenoid multiple suture repairs were performed for chronic anterior shoulder instability. In 150 shoulders (96% follow-up), the outcome with respect to recurrence of instability and the Bankart Score was determined a minimum of 2 years and a mean of 4.1 years after surgery (range, 2 to 8.2 years). During the follow-up interval, 11 shoulders (7.3%) redislocated. Fourteen other shoulders (9.3%) had at least one episode that we interpreted as recurrent subluxation. Shoulders with a Bankart lesion and younger patients had a higher probability of recurrent instability (P < .05). We concluded that this method is most effective in shoulders without a Bankart lesion and in patients older than 25 years of age (regardless of pathology).

The arthroscopic treatment of multidirectional shoulder instability: two-year results of a multiple suture technique.

Nineteen consecutive shoulders in 19 patients were treated for multidirectional shoulder instability with an arthroscopic capsular shift. Indications for the procedure included complaints of pain, instability, or both that was unresponsive to a prescribed exercise program that stressed rotator cuff and scapular stabilizer strengthening. All patients had evidence of increased joint laxity on physical examination; 17 had a 2+ or greater sulcus test and 2 had 3+ laxity both anteriorly and posteriorly. Fourteen of the 19 patients were injured during athletic activity. All surgeries were performed in an outpatient setting. All the patients were evaluated at an average of 34 months postoperatively with a minimum follow-up of 25 months. Based on the outcome scale described by Tibone and Bradley, the average postoperative score was 91 out of a possible 100 with 13 excellent, 5 good, and 1 fair result. All but 1 of the athletes returned to their previous level of performance but none were elite throwers. One patient had recurrent anterior subluxations treated with a repeat arthroscopic capsular shift and was rated as good. The patient rated as fair had no improvement in her pain after surgery. One patient complained of a painful supraclavicular suture that resolved spontaneously. There were no neurovascular complications or infections. Visualization of intra-articular pathology was enhanced with the arthroscope and aided in the diagnosis of multidirectional instability. The described technique proved safe and effective in treating multidirectional instability and enabling athletes to return to their previous level of function.

The arthroscopic treatment of posterior shoulder instability: two-year results of a multiple suture technique.

This study was undertaken to review the results of an arthroscopic posterior capsular shift procedure. Twenty consecutive shoulders in 19 patients were treated with an arthroscopic posterior capsular shift for symptomatic posterior shoulder instability. Patients underwent the procedure if they exhibited a posterior Bankart lesion or had complaints of posterior instability and evidence of increased posterior joint laxity on physical examination and examination under anesthesia. Twelve of the 20 patients were injured during athletic activity. All surgeries were performed in an outpatient setting. Twelve of the 20 patients had posterior Bankart lesions and 10 had anterior Hill-Sachs lesions. The procedure entails releasing the posterior labroligamentous structures from the posterior glenoid and freshening the glenoid neck with a bur. A suture punch is used to place multiple absorbable monofilament stitches in the ligament complex. The stitches are brought through a supraclavicular portal and tied over the clavicle or scapular spine. All 20 shoulders were evaluated at an average of 31 months postoperatively with a minimum follow-up of 24 months. Based on the outcome scale described by Tibone and Bradley, the average postoperative score was 83 out of a possible 100, with 15 excellent, 2 good, 1 fair, and 3 poor results. There were two recurrent dislocations and three subluxations for an overall recurrence rate of 25%. All the recurrences occurred in patients with posterior Bankart lesions and four of the five had a voluntary component to their instability. There were no neurovascular complications or infections. Arthroscopic evaluation facilitated the diagnosis of posterior instability with the visualization of intra-articular pathology that is difficult to identify during open procedures. Although the majority of patients were able to return to vigorous activities, a recurrence rate of 25% is disturbing and consistent with recurrence rates for open procedures.

The role of phenylalanine at position 6 in glucagon's mechanism of biological action: multiple replacement analogues of glucagon.

Extensive evidence gathered from structure-activity relationship analysis has identified and confirmed specific positions in the glucagon sequence that are important either for binding to its receptor or for signal transduction. Fifteen glucagon analogues have been designed and synthesized by incorporating structural changes in the N-terminal region of glucagon, in particular histidine-1, phenylalanine-6, and aspartic acid-9. This investigation was conducted to study the role of phenylalanine at position 6 on the glucagon mechanism of action. These glucagon analogues have been made by either deleting or substituting hydrophobic groups, hydrophilic groups, aromatic amino acids, or a D-phenylalanine residue at this position. The structures of the new analogues are as follows: [des-His1, des-Phe6, Glu9]glucagon-NH2 (1); [des-His1,Ala6,Glu9]glucagon-NH2 (2); [des-His1,Tyr6,Glu9]glucagon-NH2 (3); [des-His1,Trp6,Glu9]-glucagon-NH2 (4); [des-His1,D-Phe6,Glu9]glucagon-NH2 (5); [des-His1,Nle6,Glu9]glucagon-NH2 (6); [des-His1,Asp6,Glu9]glucagon-NH2 (7); [des-His1,des-Gly4,Glu9]glucagon-NH2 (8); [desPhe6,-Glu9]glucagon-NH2 (9); [des-Phe6]glucagon-NH2 (10); [des-His1, des-Phe6]glucagon-NH2 (11); [des-His1, des-Phe6,Glu9]glucagon (12); [des-Phe6,Glu9]glucagon (13); [des-Phe6]glucagon (14); and [des-His1, des-Phe6]glucagon (15). The receptor binding potencies IC50 values are 48 (1), 126 (2), 40 (3), 19 (4), 100 (5), 48 (6), 2000 (7), 52 (8), 113 (9), 512 (10), 128 (11), 1000 (12), 2000 (13), 500 (14), and 200 nM (15). All analogues were found to be antagonists unable to activate the adenylate cyclase system even at concentrations as high as 10(-5) M except for analogues 6 and 8, which were found to be weak partial agonists/partial antagonists with maximum stimulation between 6-12%. In competitive inhibition experiments, all the analogues caused a right shift of the glucagon-stimulated adenylate cyclase dose-response curve. The pA2 values were 8.20 (1), 6.40 (2), 6.20 (3), 6.25 (4), 6.30 (5), 6.30 (7), 6.05 (8), 6.20 (9), 6.30 (10), 6.25 (11), 6.10 (12), 6.20 (13), 6.20 (14), and 6.35 (15).

Brief communication: evidence of pathology on the frontal bone from Gongwangling.

The hominid fossil from Gongwangling (Lantian) is well known and described (Woo, [1965] Scientia Sinca 14:1032-1036; Woo [1966] Curr. Anthropol. 7:83-86; Wu and Dong [1985] in R Wu and JW Olsen (eds.): Palaeoanthropology and Paleolithic Archaeology in the People's Republic of China [New York: Academic Press, pp. 79-89]; Wu and Poirier [1995] Human Evolution in China: A Metric Description of the Fossils and a Review of the Sites [Oxford: Oxford University Press]). However, evidence of pathology on the frontal bone has been previously unreported. Two lesions occur on the right supraorbital region that can be distinguished from marks of erosion prevalent on this specimen. These are discrete and irregularly shaped, with evidence of secondary bone formation surrounding them. The cause of the condition is unclear. Possibilities include trauma or abscess from an unspecified infection.