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Biomedical subjects

J C Langer

Publications and source records attributed to J C Langer.

At least 73 records · Page 4Linked to original sources
PubMed1996

Analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumors. Correlation with histological subtype and clinical outcome.

Neuroendocrine tumors of lung, including typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC) constitute a spectrum of malignancies in which the pathologist at times has difficulty in discerning tumor subtype and aggressiveness in a reproducible fashion. Therefore, 59 primary neuroendocrine lung tumors including 10 TCs, 26 ACs, 15 LCNECs, and 8 SCLCs were selected from cases collected from 1976 to 1988 and immunostained for p53 protein. All of these tumors were also genotyped for specific point mutational damage affecting p53 (exons 5, 7, and 8; with ACs additionally sequenced for p53 exon 6); 13 tumors for K-ras-2 (exon 1); and 31 tumors for c-raf-1 (exon 15) growth-regulatory genes. Genotyping was performed on topographically selected, minute tumor samples removed from unstained formalin-fixed, paraffin-embedded tissue sections (topographic genotyping) using polymerase chain reaction and direct sequencing. The distribution of p53 immunohistochemical staining had four patterns: negative in TCs, one-half of ACs, 3 of 15 LCNECs, and 1 of 8 SCLCs; less than 10% but more than five tumor cells per 10 high power fields (focal) in a subset (7 of 26) of aggressive ACs; 10 to 49% of tumor cells (patchy) in a subset (6 of 26) of ACs with a higher grade of aggressiveness; and 50 to 100% of tumor cells (diffuse), exclusively seen in LCNECs (12 of 15) and SCLCs (7 of 8). Three patterns of immunohistochemical staining intensity of p53 protein were seen: negative, weak or mild, and moderate to marked. SCLCs and LCNECs accounted for cases of moderate to marked staining and were the only ones to have mutations in p53 exons 5, 7, or 8. No mutations were found in AC and TC, showing absent to weak staining and no staining, respectively. The difference in distribution and staining intensities between LCNEC and SCLC compared with AC and TC was statistically significant (P < 0.001). Patients having AC with patchy p53 immunostaining usually had survival limited to 3 years, whereas those having AC with focal p53 immunostaining subsequently developed metastatic or recurrence of AC disease (P < 0.05). The absence of point mutations in cases with patchy or focal immunostaining suggests increased expression of wild-type p53 tumor suppressor protein likely in response to growth deregulation in a more aggressive subtype of AC. A novel hypothesis is presented in regard to these findings. K-ras-2 and c-raf-1 gene sequence analysis showed no evidence of point mutational change in any of the tumors studied. The TC and AC categories are therefore genetically distinct from the higher grade neuroendocrine SCLC and LCNEC. Immunohistochemistry for p53 on AC lung tumors may be helpful to delineate cases at higher risk for aggressive behavior. Additionally, although LCNEC is categorized as a non-small-cell carcinoma, it is more akin genetically and immunohistochemically to SCLC.

Carcinoid Tumor↗
PubMed1996

Gastroschisis and omphalocele.

Infants with omphalocele and gastroschisis represent a challenging group of patients. Antenatal diagnosis may affect management by stimulating a search for associated anomalies, and by changing the site, mode, or timing of delivery. During the neonatal period, great care must be taken to minimize fluid and heat loss, and to prevent bowel distension. Although the goal of the surgeon is to accomplish abdominal wall closure in a single stage, a number of options exist where this is not possible. Other considerations include prevention and control of sepsis, nutritional support, respiratory status, and dysfunction of the liver, kidneys, and intestine because of increased abdominal pressure. Long-term outcome, in the absence of major chromosomal and structural anomalies, is excellent.

Abdominal Muscles↗
PubMed1995

Mast cell mediators and peritoneal adhesion formation in the rat.

We have previously shown that mast cell stabilization attenuates peritoneal adhesion formation in the rat. The present study investigated the mechanism of this protection. Adhesions were created in weanling rats using cecal scraping and application of 95% ethanol. Rats received specific blockers for the mast cell products histamine, serotonin (5HT), leukotriene D4, and platelet activating factor intraperitoneally 30 min before laparotomy and at the time of abdominal closure. Control animals received saline. Adhesions were assessed blindly 1 week later using a standardized scale. Adhesion formation was not affected by histamine blockade using combined mepyramine and ranitidine, 5-HT1 blockade using methysergide, 5-HT3 blockade using ondansetron, leukotriene D4 blockade using MK-571, or platelet activating factor blockade using WEB-2086. However, blockade of the 5-HT2 receptor using ketanserin resulted in significant dose-dependent attenuation of adhesions compared to saline. These data suggest that mast cells mediate peritoneal adhesion formation in the rat through release of serotonin acting on 5HT2 receptors. Further understanding of this process may lead to new strategies for the prevention of postoperative adhesions.

Animals↗
PubMed1995

Effects of intraamniotic helium, carbon dioxide, and water on fetal lambs.

The hysteroscopic approach to the correction of congenital anomalies in utero may be helped by the temporary introduction of clear, electrically neutral fluids (liquids or gases) into the amniotic cavity. Accordingly, the authors determined the effects of three candidate fluids (helium, carbon dioxide, and water) on the oxygenation, acid-base balance, electrolyte concentrations, and hemodynamic function of nine sheep fetuses at 120 days' gestation (full term 145 days). Each fetus was exposed, in random order, to each of the three fluids, at an intraamniotic pressure of 15 mm Hg. The authors found that helium produced no changes in any of the measurements and was well tolerated by the fetus and the mother. Carbon dioxide decreased fetal arterial pH, and increased both arterial PCO2 and PO2. Although the decrease in pH was explained entirely by the increase in PCO2, the increase in arterial PO2 may have resulted from vasodilatation of the placental circulation or vasoconstriction of the fetal circulation with a redistribution of blood flow to the placenta. Water caused mild fetal hyponatremia and hypochloremia, without significant changes in acid-base balance or oxygenation. The results suggest that both helium and water may represent viable alternatives for amniotic fluid replacement during hysteroscopic surgery.

Acid-Base Equilibrium↗
PubMed1995

Etiology of intestinal damage in gastroschisis. III: Morphometric analysis of the smooth muscle and submucosa.

The response of intestinal smooth muscle to injury may explain some of the motility derangement observed in infants with gastroschisis. An experimental model of gastroschisis was created and a detailed analysis of the intestinal muscle layer was undertaken to study this response. An abdominal wall defect and evisceration of the bowel were carried out in fetal lambs at 80 days' gestation (full term, 145 days), with delivery at 100 days or 135 days. Smooth muscle cell size and number were determined by detailed morphometric analysis, proliferative rate was determined using proliferating cell nuclear antigen staining, and collagen content was determined by morphometry after Verhoeff van Gieson staining. Compared with controls, there was a significant increase in cell number (hyperplasia) in the gastroschisis animals at 100 days and an increase in size (hypertrophy) at 135 days. The proliferation rate of smooth muscle was significantly lower and the submucosal collagen thickness was significantly greater in the gastroschisis animals during both periods. These data suggest that gastroschisis is characterised by initial hyperplasia, with subsequent diminution in smooth muscle proliferation. The hypertrophy may reflect a response to injury in which cell growth instead of proliferation occurs. The persistent elevation in collagen throughout gestation in animals with gastroschisis may be a reflection of this hyperplastic response in the smooth muscle cells and an important factor in the bowel-wall thickening. This deranged pattern of growth may lead to the clinical problems observed in human infants with this disease.

Abdominal Muscles↗
PubMed1995

Mucosal permeability after subclinical intestinal ischemia-reperfusion injury: an exploration of possible mechanisms.

Changes in mucosal permeability may be important in the etiology of necrotizing enterocolitis. The authors have previously shown that subclinical ischemia-reperfusion injury results in increased permeability in the rat intestine, and have partially characterized this phenomenon. In the present study the authors attempt to determine the mechanism by which these changes occur. Six-week-old rats underwent 10-minute superior mesenteric artery occlusion (SMAO) or sham, and mucosal permeability to 51CrEDTA was measured after 30 minutes. Rats were pretreated with saline, inhibitors of oxygen free radicals (superoxide dismutase+catalase, vitamin E, allopurinol, alpha-phenyl-N-tert butyl-nitrone), inhibitors of eicosanoids (indomethacin, quinacrine, diethylcarbamazine, 13-azaprostanoic acid), the putative cytoprotective agent prostaglandin E2, or the inhibitor of neutrophil free radical production fructose 1-6 diphosphate. None of the agents significantly attenuated the increase in mucosal permeability caused by SMAO, although indomethacin and prostaglandin E2 significantly exacerbated the permeability changes. To further explore the role of neutrophils, tissue myeloperoxidase was measured 30 minutes after SMAO. There was no significant difference in myeloperoxidase levels between sham and SMAO animals. These data suggest that the early increase in mucosal permeability after subclinical ischemia-reperfusion injury is not mediated by oxygen free radicals, eicosanoids, or neutrophils. The deleterious effect of indomethacin and prostaglandin E2 suggests a possible protective role for the cyclooxygenase system, but further studies are necessary to elucidate this possibility.

Animals↗
PubMed1995

Hypertrophic pyloric stenosis: ultrastructural abnormalities of enteric nerves and the interstitial cells of Cajal.

Dysfunction of pyloric inhibition has been implicated in the pathophysiology of hypertrophic pyloric stenosis. Normal inhibition likely is mediated by peptidergic enteric nerves and also may involve interstitial cells of Cajal (ICC). The authors used electron microscopy to qualitatively assess these structures in infants with pyloric stenosis and in normal controls. Pyloric muscle strips from five infants with hypertrophic pyloric stenosis, from three normal pediatric organ donors, and from three adults were examined. The following observations were made. (1) Muscle cells were primarily in a proliferative phase in pyloric stenosis and exhibited very few gap junctions between smooth muscle cells or ICC compared with the control specimens. (2) The circular muscle layer in pyloric stenosis was characterized by near absence of large granular vesicle-containing nerve fibers compared with the control specimens. (3) There were fewer nerve cell bodies in the myenteric plexus in pyloric stenosis, and the total number of ganglia was lower than that in control samples. (4) Interstitial cells of Cajal were almost completely absent in patients with hypertrophic pyloric stenosis, but there was a group of cells resembling ICC that was termed ICC-like cells. These cells may represent a failure or delay in the maturation process of the ICC. These findings show that there are significant structural abnormalities of the inhibitory nervous system in hypertrophic pyloric stenosis. The ontogenic origins and functional significance of these results require further investigation.

Case-Control Studies↗
PubMed1994

Smooth muscle from aganglionic bowel in Hirschsprung's disease impairs neuronal development in vitro.

Hirschsprung's disease results from the congenital absence of enteric neurons in human distal colon. The reason for aganglionosis is unknown but may reflect an unfavourable microenvironment for neuronal development. We asked if smooth muscle cells from the anganglionic region could affect neuronal development in vitro. Neurons from neonatal mouse superior cervical ganglia were added to cultures of smooth muscle obtained from normal or aganglionic regions of five patients with Hirschsprung's disease. Although neurons initially showed more rapid attachment to aganglionic smooth muscle, this was equal by 60 min and thereafter. Progressive increase in the diameter of the nerve cell body was characteristic of normal maturation in vitro. This was consistently inhibited by 15-22% in neurons grown on aganglionic muscle compared with normal controls over the 6-day test period (P < 0.05). This phenomenon was preserved when the smooth muscle cells were lysed by brief exposure to distilled water before initiation of co-culture (16-18% inhibition; P < 0.05). These data imply that smooth muscle of the aganglionic colon is less favourable for neuronal development than the normally innervated region and suggest a membrane-linked factor. Clearly, this persists in postnatal life and in vitro and may reflect an abnormality of cellular interaction causing Hirschsprung's disease.

Axons↗
PubMed1994

Pneumatic reduction of intussusception using carbon dioxide.

Pneumatic reduction using air has recently become popular for the initial non-surgical management of intussusception. Since carbon dioxide (CO2) is rapidly absorbed from body surfaces, it should theoretically result in less cramping and distension following reduction. We reviewed our recent experience with the pneumatic reduction of intussusception using CO2 in 26 children. In 22 of these the intussusception was reduced (85%). There was one performation with CO2; the patient did not suffer any postoperative complications. Five additional children who had been treated unsuccessfully with barium had intussusception subsequently reduced with CO2. Following CO2 reduction, most children were fed within hours, and there were no instances of significant abdominal distension or cramping. We conclude that pneumatic reduction of intussusception using CO2 is safe and effective, and has the theoretical advantage of more rapid absorption from the gastrointestinal tract than air.

Carbon Dioxide↗
PubMed1994

Fryns syndrome: a rare familial cause of congenital diaphragmatic hernia.

Fryns syndrome is a rare autosomal recessive disorder characterized by diaphragmatic hernia and multiple anomalies. Almost all infants have died at birth, and survivors have had severe mental retardation. The authors report on a family in which three children had diaphragmatic hernia diagnosed prenatally. The first child died of severe pulmonary hypoplasia in the neonatal period. The second survived after diaphragmatic hernia repair, and was found to have Fryns syndrome based on the spectrum of associated anomalies and the family history. He has done well except for significant gastroesophageal reflux, mild developmental delay, and mild hypotonia. The third child's diaphragmatic hernia was diagnosed early during fetal life, and the parents chose to terminate the pregnancy. These cases illustrate the spectrum of Fryns syndrome and the importance of a family history in patients with congenital diaphragmatic hernia. This is the first report of survival of a patient with Fryns syndrome without severe mental retardation.

Abnormalities, Multiple↗
PubMed1993

Histamine does not mediate mucosal permeability changes after subclinical intestinal ischemia-reperfusion injury.

UNLABELLED: Subclinical intestinal ischemia-reperfusion injury (IRI) increases mucosal permeability, and may be an important mechanism in the etiology of necrotizing enterocolitis. The current study was designed to assess the role of histamine in mediating this phenomenon. Six-week-old rats underwent 10-minute superior mesenteric artery occlusion (SMAO) or sham operation, and ileal mucosal permeability to 51Cr EDTA was measured 30 minutes after reperfusion. Rats were pretreated with intravenous saline, mepyramine (6 mg/kg), or ranitidine (5 mg/kg). SMAO resulted in a significant increase in permeability compared to sham, which was not attenuated by either of the histamine antagonists. In a second experiment, mucosal permeability to 51Cr EDTA was measured in 6-week-old rats during aortic infusion of saline or histamine (0.5 mg/kg/min). There was no significant increase in permeability as a result of histamine infusion. In a third experiment, 6-week-old and 10-day-old rats underwent sham or 10-minute SMAO, and both portal vein and ileal tissue histamine levels were measured 30 minutes after reperfusion. There was no significant difference between sham and SMAO with respect to portal vein histamine or tissue histamine at either age. IN CONCLUSION: (1) increased permeability was not blocked by either H1 or H2 blockers; (2) histamine infusion did not increase permeability; and (3) SMAO did not increase portal vein or tissue histamine levels. These data suggest that histamine does not play a role in mediating the increase in permeability after subclinical IRI in this model.

Animals↗
PubMed1993

Optimal management of patent ductus arteriosus in the neonate weighing less than 800 g.

Between January 1988 and December 1990, 132 neonates weighing < 800 g were admitted to our neonatal intensive care unit. Of the 76 who survived initial resuscitation, 42 had developed a hemodynamically significant patent ductus arteriosus (PDA) (mean +/- SD): gestational age 25.3 +/- 1.9 weeks, birth weight 650 +/- 93 g. Two infants were referred for primary surgical ligation because of contraindications to indomethacin. Forty infants were initially treated with indomethacin. Seventeen of 40 (43%) were subsequently referred for surgical ligation because of indomethacin failure. Infants requiring surgical duct closure were a lower gestational age (24.6 +/- 1.3 v 25.7 +/- 2.0 weeks, P = 0.49) and had a greater left atrial-aortic (LA/Ao) ratio on echocardiography (1.71 +/- 0.28 v 1.46 +/- 0.26, P = .04) compared with those treated successfully with indomethacin. There were 6 deaths (15%), all of which occurred in infants receiving indomethacin (5 indomethacin alone, 1 indomethacin+ligation). Indomethacin was directly associated with intestinal perforation in 3 patients, and acute renal failure in 1; all 4 died. Surgery was associated with minimal morbidity (intraoperative transfusion in 1, postoperative pneumothorax requiring chest tube in 1). These data suggest that in the extremely premature neonate with a hemodynamically significant PDA: (1) indomethacin therapy is associated with a high failure rate and significant complications; (2) PDA associated with a large LA/Ao ratio is unlikely to close with indomethacin therapy; and (3) surgical duct closure is associated with minimal morbidity. We conclude that primary surgical ligation may provide the optimal management for PDA in carefully selected patients.

Ductus Arteriosus, Patent↗
PubMed1993

Mucosal permeability to 51Cr EDTA following subclinical intestinal ischemia-reperfusion injury in the weanling rat.

The etiology of necrotizing enterocolitis (NEC) is uncertain. We have hypothesized that subclinical intestinal ischemia might result in increased mucosal permeability to intraluminal toxins or bacteria, resulting in inflammation and NEC. In order to pursue this hypothesis, we designed a series of studies to investigate whether the first assumption is correct, ie whether a subclinical ischemia-reperfusion injury (IRI) results in increased mucosal permeability. Using a model of superior mesenteric artery occlusion (SMAO) in weanling rats, we initially defined 10-minute SMAO as "subclinical" IRI (ie, 100% survival, no histological changes, and no hemodynamic instability). Mucosal permeability to a standard probe molecule (51Cr EDTA) was then measured after sham operation, or 2-minute or 10-minute SMAO. There was an early increase in permeability 30 minutes after reperfusion in the 10-minute SMAO group, which was completely reversed by 2 hours. Further studies suggested that having passed through the mucosa, the probe entered the systemic circulation via both portal venous and intestinal lymphatic routes. Subclinical intestinal IRI results in an early, reversible increase in mucosal permeability to 51Cr EDTA, which may be important in the pathogenesis of NEC. Further studies are required to fully characterize this phenomenon, and to determine the mechanisms by which it occurs.

Animals↗
PubMed1993

Role of mast cells in peritoneal adhesion formation.

Postoperative adhesions are a major cause of bowel obstruction and infertility. Since mast cells in the intestinal wall have been shown to degranulate after bowel manipulation, we investigated a possible role for these cells in peritoneal adhesion formation. Adhesions were created in weanling rats using cecal scraping and the application of 95% ethanol. The rats were treated with saline or one of two mast cell stabilizers, disodium cromoglycate (DSCG) or nedocromil sodium (NED), intraperitoneally 30 minutes before laparotomy and at the time of abdominal closure. The adhesions were assessed blindly 1 week later using a standardized scale. When the results in rats treated with DSCG were compared with those in rats treated with saline, the DSCG rats had significant attenuation of adhesion formation at 2 mg/kg (1.05 +/- 1.0 versus 2.15 +/- 0.8) and 10 mg/kg (1.2 +/- 0.9 versus 2.71 +/- 0.5). The application of NED decreased adhesions at a dose of 100 mg/kg (1.33 +/- 1.2 versus 2.4 +/- 0.8) but not at 10 mg/kg (2.4 +/- 0.8 versus 2.4 +/- 0.8). Histologic analysis using toluidine blue staining was done to assess the effect of DSCG on mast cell degranulation in the same adhesion model. DSCG significantly decreased the number of degranulated mast cells in the bowel wall when compared with saline (7.16 +/- 0.6 mast cells/high-power field [hpf] versus 12.4 +/- 1.9 mast cells/hpf). These data suggest that mast cells play an important role in the initial stages of peritoneal adhesion formation. In the future, pharmacologic inhibition of mast cell degranulation may be a useful adjunct for the prevention of postoperative adhesions.

Animals↗
PubMed1993

Mucosal permeability in the immature rat intestine: effects of ischemia-reperfusion, cold stress, hypoxia, and drugs.

Increased mucosal permeability may represent an important factor in the etiology of necrotizing enterocolitis (NEC). In the present study we used an immature rat model to assess the permeability effects of a number of stresses commonly seen in infants with NEC. In 10-day-old rats, mucosal permeability to 51Cr EDTA was measured after subjecting the animals to 10-minute ischemia-reperfusion injury, 30 minutes of hypoxia (14% oxygen), cold stress (4 degree C for 4 minutes), and intraperitoneal indomethacin (0.2 or 2.0 mg/kg) or theophylline (40 or 200 mg/kg). When compared with appropriate controls, mucosal permeability was found to be significantly increased by ischemia-reperfusion injury, hypoxia, and high-dose indomethacin, but not by cold, theophylline, or low-dose indomethacin. Renal clearance studies confirmed that elevated blood levels of 51Cr EDTA were due to increased permeability rather than decreased renal excretion of the probe. These studies confirm that mucosal permeability in the immature rat is increased by a variety of insults, and may represent a "common pathway" in the etiology of NEC.

Animals↗
PubMed1993

Home esophageal self-dilatation in children.

Home esophageal self-dilatation permits greater independence and more frequent treatments than intermittent hospital procedures for patients with esophageal strictures. The article describes an innovative program for teaching esophageal self-dilatation to preadolescent children, using a form of creative visualization. The child focuses on a 2-minute mental image (e.g., video game, a popular song, or swimming a race) from his/her own experience while passing a Maloney bougie. A nasal breathing technique is used, and active encouragement is provided. Topical lidocaine and oral diazepam can be used initially to assist relaxation and are stopped when the child gains confidence with the technique. The authors taught esophageal self-dilatation to three children aged 12 to 13 years with esophageal strictures. All three learned the technique within 1 week and continued it at home for between 4 and 6 months. Two of the children were taught in hospital by a nurse, and the third was taught as an outpatient by a peer who had already mastered the technique. Home esophageal self-dilatation can be successfully taught to children in the preadolescent age group. The teaching program is simple and effective and can be easily applied to other tasks such as pain control, nasogastric tube feeding, and self-injection.

Adolescent↗
PubMed1993

The single-subject randomized trial. A useful clinical tool for assessing therapeutic efficacy in pediatric practice.

The purpose of a single-subject randomized trial is to assess objectively the efficacy of a specific therapeutic intervention in an individual patient. Treatment is randomly alternated with placebo over a number of study periods. Specific outcome measures are recorded blindly and later compared via paired statistical analysis. Single-subject trials have long been successfully performed in adults, but rarely in children. We present single-subject trials of two pediatric patients done to assess the effect of cisapride on symptoms arising from gastroesophageal reflux. In the first patient, the drug affected neither vomiting nor gagging, although stool frequency increased. Since the symptoms of concern were unaffected, cisapride was discontinued. In the second patient, use of cisapride led to a significant decrease in vomiting and wheezing; the drug was therefore incorporated into the therapeutic regimen. Single-subject randomized trials are inexpensive and simple and can be used by the family physician, pediatrician, or pediatric surgeon in daily practice. They permit the rational use of effective therapy and the abandonment of ineffective measures.

Adult↗