Increased microvascular blood content is an early event in colon carcinogenesis.

BACKGROUND: Increased premalignant epithelial microvascular blood content is a common theme in neoplastic transformation; however, demonstration of this phenomenon in colon carcinogenesis has been stymied by methodological limitations. Our group has recently developed a novel optics technology, four dimensional elastic light scattering fingerprinting (4D-ELF), which allows examination of the colonic mucosal architecture with unprecedented accuracy. In this study, we utilised 4D-ELF to probe the preneoplastic colonic microvasculature. METHODS: Colonic mucosal blood content was assessed by 4D-ELF at serial preneoplastic time points from azoxymethane (AOM) treated Fisher 344 rats and age matched control animals. We also examined the pretumorigenic intestinal mucosa of the MIN mouse, and compared with wild-type mice. Finally, in a pilot study, we examined superficial blood content from the endoscopically normal mid transverse colon in 37 patients undergoing screening colonoscopy. RESULTS: In the AOM treated rat model, augmentation of superficial mucosal and total mucosal/superficial submucosal blood supply preceded the appearance of aberrant crypt foci (ACF) and temporally and spatially correlated with future ACF occurrence. These findings were replicated in MIN mice. The 4D-ELF based results were corroborated with immunoblot analysis for haemoglobin on mucosal scrapings from AOM treated rats. Moreover, 4D-ELF analysis of normal human colonic mucosa indicated that there was a threefold increase in superficial blood in patients who harboured advanced adenomas. CONCLUSION: We report, for the first time, that blood content is increased in the colonic microvasculature at the earliest stages of colon carcinogenesis. These findings may provide novel insights into early biological events in colorectal carcinogenesis and have potential applicability for screening.

Pigtail stents: an alternative in the treatment of difficult bile duct stones.

BACKGROUND: When bile duct stones cannot be removed after sphincterotomy by balloon or basket extraction, stent placement can serve as a bridge to additional procedures. Biliary stents may also fragment large stones, allowing them to pass spontaneously or making them easier to extract at a later time. METHODS: Twenty patients with difficult to extract bile duct stones were prospectively studied. The patients underwent ERCP and placement of a 7F double-pigtail stent in the bile duct for 6 months. RESULTS: In seven patients (35%), repeat ERCP revealed no stones in the duct. Four patients (20%) had small stone fragments that were easily extracted with a balloon. Six patients (30%) continued to have large stones at repeat ERCP; two of these patients eventually underwent surgery, the duct was cleared in three with mechanical lithotripsy, and one had long-term stenting. Three patients (15%) did not undergo repeat ERCP and were therefore treated with long-term stent placement. CONCLUSIONS: This study suggests that placement of a pigtail biliary stent is a safe and effective alternative in the management of bile duct stones that resist extraction if lithotripsy is not available. After 6 months of stent placement, stones may pass or become easier to remove in a significant proportion of patients.

Functional health status of adults with achondroplasia.

Little is known regarding the functional health status of individuals with achondroplasia. This cross-sectional survey of adults with achondroplasia was undertaken to assess the functional health status of this population and its determinants. The study sample consisted of members of the Little People of America (LPA) who completed a mailed questionnaire consisting of a demographics component, a general and disease-specific comorbidities component, and the Short Form 36 (SF-36) health status questionnaire. Univariate analyses and multivariate linear regression models were used for data analysis. Four hundred thirty-seven individuals with a mean age of 38 years completed the survey. The age- and gender-adjusted Mental Component Summary (MCS) scores did not significantly differ from those of the general population. In contrast, the age- and gender-adjusted Physical Component Summary (PCS) scores were significantly lower than the general population starting in the fourth decade of life. Musculoskeletal diseases were most prevalent and had the greatest impact on the PCS scores. Two-thirds of this cohort had undergone at least one operation. Only musculoskeletal procedures were significantly associated with PCS and MCS scores. The functional health status of adults with achondroplasia, as measured by the SF-36, is not drastically reduced in comparison with that of the general U.S. population.

Regulation of proliferation and platelet-derived growth factor expression in palmar fibromatosis (Dupuytren contracture) by mechanical strain.

Palmar fibromatosis (Dupuytren contracture) causes fibrosis of specific palmar fascial bands. These bands are subjected to repetitive mechanical strain in situ. Primary cell cultures were derived from (a) palmar fibromatosis from eight patients, (b) uninvolved palmar fascia (Skoog's fibers) from four of these patients, and (c) normal palmar fascia from four additional patients. The cells were plated onto collagen-coated membranes either subjected to cyclic strain (25% maximal strain at 1 Hz) or without strain. Bromodeoxyuridine incorporation showed an increase in proliferation in all cultures subjected to strain. This increase was highest for palmar fibromatosis (10 to 40% nuclear incorporation, p = 0.02). Skoog's fibers and fascia from the normal individuals showed a trend (not significant) toward increase with strain (8 to 25%, p = 0.15 for Skoog's fibers, and 8 to 15%, p = 0.45 for normal fascia). Cyclic strain increased the expression of platelet-derived growth factor-A relative to glyceraldehyde-3-phosphate dehydrogenase in palmar fibromatosis (2.2 to 3.5, p = 0.05) and Skoog's fibers (0.8 to 2.0, p = 0.04). The expression of platelet-derived growth factor-B relative to glyceraldehyde-3-phosphate dehydrogenase was enhanced by cyclic strain only in the fibromatosis tissue (0.7 to 2.1, p = 0.04). The normal fascia did not express platelet-derived growth factor. Platelet-derived growth factor neutralizing antibody decreased bromodeoxyuridine incorporation in fibromatosis cultures subjected to cyclic strain to near levels for those grown in the absence of strain (38 to 16%, p = 0.05). Conditioned medium from fibromatosis cells grown under stain showed a trend toward increased proliferation in additional fibromatosis cultures compared with conditioned medium from fibromatosis cells grown without strain (9 to 15% nuclear incorporation, p = 0.20). The observed palmar fibromatosis contracture can be partially explained on the basis of the cell's response to cyclic strain, which may be mediated by platelet-derived growth factor.

Identification of matrix metalloproteinases and metalloproteinase inhibitors in bovine corpora lutea and their variation during the estrous cycle.

Corpora lutea (CL) were collected from cattle to study key physiologic events in angiogenesis. Our objective was to evaluate the activity of matrix metalloproteinases (MMP) and endogenous inhibitors. Corpora lutea were collected 2, 4, 6, 8, 10, 12, 14, and 16 d (n = 3/d) after estrus was first detected. In zymograms, a band of protein migrating at a relative molecular mass (M(r)) of 98 kDa was increased early in the cycle; a M(r) = 88 kDa band was detectable on all days. The molecular weights of these proteins are consistent with the MMP-9 family members. In all samples, a band of enzyme activity was detected at M(r) = 62 kDa, and another band of lesser density was detected at M(r) = 60 kDa. The molecular weights of these proteins are consistent with the MMP-2 family members. An immunoreactive band, detected in all samples with equal density, migrated between M(r) = 27 and 29 kDa, as did the tissue inhibitor of metalloproteinase (TIMP-1) standard. A second band, which was less dense in samples from d 2 through 6, migrated at M(r) = 19 kDa, as did the TIMP-2 standard. A third band was detected in all samples; it migrated at M(r) = 35 kDa, as did the cartilage-derived inhibitor (CDI) standard, and was less dense in d 8 and d 12 through 16 samples. In summary, MMP (gelatinases) and MMP inhibitors are present in developing luteal tissue, and the M(r) = 98 kDa enzyme, CDI, and TIMP-2 varied during the estrous cycle.

"Mother-baby" biliary endoscopy: the University of Chicago experience.

OBJECTIVE: The "mother-baby" technique of peroral cholangioscopy is a relatively recent development in biliary endoscopy and permits direct visualization of the biliary tree. This paper presents the experience of one institution with this new technique. METHODS: We used the Olympus mother-baby endoscopy system at the University of Chicago and at one of its affiliated hospitals to examine and treat selected lesions in the biliary tree that had eluded successful diagnosis or treatment by standard means. In addition, we used the baby endoscope alone through surgically created percutaneous tracts to treat selected patients with retained stones. RESULTS: From July 1990 to June 1993, peroral cholangioscopy was performed 18 times in 12 patients at the University of Chicago and affiliated hospitals. The baby endoscope was successfully passed into the bile duct in 15 of 18 cases (83.3%). Additionally, the baby endoscope alone was used through a T-tube or cholecystostomy tract 10 times in six patients. Complications occurred in two patients and were minor; there were no fatalities. With refinement of technique, successful passage of the baby endoscope was accomplished in 100% of patients undergoing peroral cholangioscopy. CONCLUSIONS: Direct visualization of the biliary tree with the ability to sample (brush, biopsy) or treat (basket removal, electrohydraulic or laser lithotripsy) lesions significantly aided in the care of all patients in whom the baby endoscope was successfully passed by providing the correct diagnosis and, when appropriate, by allowing definitive treatment of lesions. The eventual role of this technique in the current cost-conscious climate is unclear, but at present it should be limited to selected referral centers.

The expression of platelet-derived growth-factor gene in Dupuytren contracture.

Dupuytren contracture is a disease of the palmar fascia characterized by nodular fibroblastic proliferation; its etiology and pathogenesis are poorly understood. Growth factors are polypeptides that regulate cell growth and differentiation and extracellular matrix production. Platelet-derived growth factor is known to cause fibroblastic proliferation, and it may be involved in the pathogenesis of Dupuytren contracture. The purpose of this study was to determine if the gene for the B chain of platelet-derived growth factor is expressed in Dupuytren contracture. Tissue from patients who had Dupuytren disease was examined immunohistochemically with the 5B5 antibody, which is a marker for fibroblasts. Polymerase chain reaction, gel electrophoresis, Southern blotting, and in situ hybridization were also used to study gene expression in the tissue as well as in normal fascia, A172 cells, and MRC5 cells. Total cellular RNA was extracted from tissue and cells. Polymerase chain reaction was done with oligonucleotide primers complementary to a portion of the platelet-derived growth-factor-B and platelet-derived growth-factor-receptor genes. The platelet-derived growth-factor-B gene was expressed in all six specimens from the patients who had Dupuytren contracture as well as in the A172 cells, but not in the normal fascia lata or the MRC5 cells. These results were confirmed with Southern blotting of the products of the reaction with a platelet-derived growth-factor-B probe. The gene for the platelet-derived growth-factor receptor was expressed by all tissues and cells studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet-derived growth factor in fibrous musculoskeletal disorders: a study of pathologic tissue sections and in vitro primary cell cultures.

Despite the great variability in the clinical behavior of fibrous lesions of the musculoskeletal system, they are composed of cytologically similar fibrocytes. Receptors for estrogen or progesterone, or both, are present in some of these lesions and some increase their rate of growth during periods of high levels of sex steroid hormones. The platelet-derived growth factor-B (PDGF-B) proto-oncogene encodes the B chain of PDGF, a mitogen for fibrocytes. Tissue from aggressive fibromatosis, fibrous dysplasia, plantar fibromatosis, and recurrent plantar fibromatosis was analyzed with use of the polymerase chain reaction and in situ hybridization for the expression of PDGF-B and PDGF beta receptor. Cell culture was used to determine if estrogen and progesterone stimulation modulated the expression of PDGF-B. Aggressive fibromatosis, fibrous dysplasia, and recurrent plantar fibromatosis expressed PDGF-B; plantar fibromatosis, normal plantar fascia, normal fascia lata, and mature scar did not. All of the tissues expressed PDGF beta receptor. The level of expression in aggressive fibromatosis and fibrous dysplasia was four times that in the recurrent plantar fibromatosis. Estrogen and progesterone stimulation in aggressive fibromatosis resulted in an increase in the level of expression. Therefore, the detection of PDGF-B may be an adjunct in the pathologic identification of locally invasive lesions. Its production may be a common mechanism leading to a fibroproliferative response through deregulation of the control of growth by both paracrine and autocrine mechanisms.

A reassessment of spinal stabilization in severe cerebral palsy.

A homogenous population of 37 institutionalized patients with scoliosis and severe cerebral palsy was evaluated to assess the impact of spinal stabilization on comfort, function, health, and ease of nursing care. Through a prospective care-burden study, a 34-month retrospective analysis, and a healthcare worker questionnaire, 17 fused patients with a mean current scoliosis of 35 degrees were compared with 20 nonfused patients with a mean scoliosis of 76 degrees. No clinically significant differences were noted in pain or pulmonary medication utilization or therapy, decubiti, function, or time for daily care. Nevertheless, the majority of healthcare workers believed that the fused patients were more comfortable.

Diagnosis and management of skeletal dysplasias.

The prenatal diagnosis of skeletal dysplasias is a challenging task due to the varied manifestations of the disorders and the great number of possible diagnoses. This difficulty will likely remain until DNA mutations are identified that will permit a specific diagnosis. Until then, the use of a multidisciplinary team is suggested for clinical diagnosis and management. Use of a systematic approach to diagnosis such as our "10-step" system is a valuable tool to decrease the complexity of the diagnostic process. Even if it does not lead to a specific diagnosis, it allows one to predict the likelihood of a severe or lethal disorder. A cautious approach to prenatal diagnosis of skeletal dysplasias is warranted due to the uncertainties inherent in clinical diagnosis of these disorders. Until specific DNA testing or rapid collagen analysis are available for the more common defects, errors in diagnosis and counseling that follow may result in termination of normal fetuses and, conversely, in continuation of pregnancies with lethal anomalies or severely affected fetuses.

Developmental dysplasia of the hip.

OBJECTIVE: The definition and early treatment of congenital dysplasia of the hip are controversial. The purpose of this study was to discuss the reasons for changing the acronym to developmental dysplasia of the hip (DDH) and to address its early detection and treatment. DESIGN: This multicenter study was designed to provide an updated assessment of the definition, pathologic anatomy, prevalence, etiology, natural history, early detection, and treatment of DDH. RESULTS: DDH more accurately describes the condition previously termed congenital dysplasia of the hip. The disorder is not always present at birth (congenital) and an infant may have a normal neonatal hip screening examination and subsequently develop a dysplastic or dislocated hip. Developmental dysplasia encompasses the wide spectrum of hip problems seen in infants and children. Physicians should understand that a normal neonatal screening examination does not assure normal hip development. The diagnosis of developmental dysplasia is made by physical examination. The Ortolani and Barlow maneuvers were designed to detect a subluxatable, dislocatable, or dislocated hip in the neonatal period. In the older child, limited abduction becomes a more reliable sign. The examination is variable depending on the type of dysplasia and changes with growth. The ultrasound is proving to be a sensitive tool in confirming the diagnosis in newborns and infants from birth to 4 months of age. The ultrasound is also valuable in older infants in terms of documenting that the dysplasia is responding to treatment. However, the ultrasound depends on an experienced sonographer and, in some cases, may be too sensitive, resulting in overtreatment. After 3 to 4 months of age, an anteroposterior pelvis radiograph can confirm the diagnosis. CONCLUSIONS: All newborns should have a neonatal hip screening physical examination. After screening, the hips should be re-examined during health examination visits at 2 weeks, 2 months, 4 months, 6 months, 9 months, and 1 year of age. If any question arises during these visits or if there are associated risk factors, we recommend an ultrasound if the infant is < 4 months of age or an anteroposterior pelvis radiograph if > 4 months of age.

Escherichia vulneris osteomyelitis of the tibia caused by a wooden foreign body.

A new species in the family Enterobacteriaceae, Escherichia vulneris, was characterized by the Centers for Disease Control and Prevention in 1982. It has been shown to have a predilection for human wounds, and several case reports have described superficial wound infections with this rare organism. Until now, however, there have been no reports of osteomyelitis occurring secondary to E vulneris infection. The authors present the case of a 13-year-old boy who fell on a stick and sustained a penetrating injury to his right knee. Radiographs and magnetic resonance imaging revealed a lytic lesion with a foreign body in the tibial epiphysis. On culture, only E vulneris was found, and histologic examination showed the foreign body to be surrounded by acute and chronic inflammation, abscess formation, and foreign-body giant-cell reaction. Although a recent study questioned the pathogenicity of this organism after reviewing the cases of 12 patients in whom there was concurrent heavy growth of Staphylococcus aureus, the present case supports the finding that E vulneris is a human pathogen that should be treated when obtained from human wound cultures.

Effect of zatosetron on ipecac-induced emesis in dogs and healthy men.

Serotonin receptor (5-HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5-HT3 receptor antagonists also have antiemetic activity in ipecac-induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5-HT3 receptor antagonist, on ipecac-induced emesis in dogs and healthy men. They also evaluated the effect of ipecac administration on serotonin release and metabolism by measuring urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion in healthy men. In separate randomized, placebo-controlled trials, 20 dogs received zatosetron intravenously and eight healthy men received zatosetron (50 mg) orally, followed by ipecac syrup. In both trials, emetic response to ipecac was recorded, including the number and time of vomits and retches. Zatosetron treatment inhibited and delayed ipecac-induced emesis in both groups. In dogs, zatosetron inhibited ipecac-induced emesis in a dose-dependent manner with a 100-micrograms/kg dose producing complete inhibition. In men, zatosetron administration resulted in fewer emetic episodes after ipecac than had occurred with placebo administration (P = .03); vomiting was completely inhibited by zatosetron. In men, ipecac administration did not affect the urinary 5-HIAA/creatinine ratio (mg/g) or 5-HIAA excretion rate (microgram/hour). Our study demonstrates that zatosetron has similar efficacy on ipecac-induced emesis in healthy men, as has been shown previously with other 5-HT3 receptor antagonists in chemotherapy-induced emesis in cancer patients. We did not observe the increase of urinary 5-HIAA in our study with ipecac-induced emesis, however, as has been described previously in cisplatin-induced emesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Hip disease in adults with Down syndrome.

The life expectancy of patients with Down syndrome has increased significantly in recent years. Hip abnormalities occur in children with this syndrome but little is known about their natural history in later life. In 65 adults with Down syndrome we found hip abnormalities in 28%, and this was statistically correlated with walking ability. A subgroup of 18 patients was followed by serial examination; this showed that hip instability occurred in adulthood and became worse with time. In some patients, hip instability started after skeletal maturity.