Long-term evaluation of extended thymectomy with anterior mediastinal dissection for myasthenia gravis.

BACKGROUND: Thymectomy for the treatment of myasthenia gravis (MG) is well established. The extent of resection, however, remains a source for debate. Outcomes for newer surgical techniques need to be compared to more extensive procedures. METHODS: A retrospective review was done of 64 consecutive patients who underwent transsternal thymectomy with extended anterior mediastinal dissection for MG between 1979 and 2000 and who were operated on by a single surgeon. RESULTS: Fifty-six patient charts were available, providing 58 operative procedures. Three patients had died of unrelated causes. The mean age of symptom onset was 36.0 +/- 2.5 years, with a mean duration of 3.3 +/- 0.5 years until surgery was undertaken. The mean length of follow-up was 6.8 +/- 0.8 years. Operative procedures were associated with a 10.3% major morbidity rate and no mortality. Drug-free remission was achieved in 50.0% of the patients, and symptoms were absent or improved in 76.8% of the patients. Patients followed up long-term (>10 years) achieved the greatest remission rate (71.4%) and symptomatic improvement (85.7%). After thymectomy, the mean dosages of prednisone and Mestinon decreased by 69.3% and 58.8%, respectively. CONCLUSIONS: Extended thymectomy provides excellent overall symptom improvement, which is enhanced over time. This review provides a basis for long-term comparison with other less invasive and perhaps less extensive procedures.

Epithelial permeability is not increased in rats following small bowel resection.

BACKGROUND: Increased intestinal permeability and translocation of bacteria and/or bacterial products may cause infection and liver dysfunction in patients with the short bowel syndrome. In previous studies, serum from mice undergoing small bowel resection (SBR) enhanced growth of cultured rat intestinal epithelial cells (RIEC-6), implicating a role for a serum factor(s) in the enterocyte response to SBR. These experiments tested the hypothesis that epithelial cell permeability is increased following SBR. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent a 75% SBR or sham operation. Intestinal permeability in the remnant ileum was determined by Ussing chambers on Postoperative Day (POD) 3. Additionally, serum was collected on POD 1, 3, and 7 and mesenteric lymph was harvested on POD 3. Once confluent, RIEC-6 cells were incubated for 3 days in media supplemented with 10% fetal bovine serum (FBS; control), 1% FBS, 1% FBS plus 9% Sham serum, or 1% FBS plus 9% SBR serum or exposed to media with varied concentrations of SBR or Sham lymph. Monolayer permeability was determined by measuring the passage of dextran-rhodamine. RESULTS: Intestinal permeability was reduced in rats undergoing SBR. Sham serum-treated monolayers demonstrated the greatest permeability. Incubation with SBR serum reduced permeability to near control media. There were no permeability differences between SBR and Sham lymph-treated monolayers. CONCLUSION: The early adaptive response of the remnant intestine after SBR is associated with reduced permeability. These results suggest an alternative mechanism for the increased bacterial translocation that has been described following SBR.

Serum from mice after small bowel resection enhances intestinal epithelial cell growth.

BACKGROUND/PURPOSE: The adaptive response of the intestine to massive small bowel resection (SBR) is remarkably complex. An in vitro model of adaptation may facilitate the elucidation of signaling pathways involved in this process. In an effort to establish such a model, the effects of serum from resected mice on cultured intestinal epithelial cells were studied. METHODS: Serum was collected and pooled from male ICR mice 3 days after either 50% SBR or sham operation. Rat intestinal epithelial cells (RIEC-6) were plated at equal density and grown in the presence of 1% fetal bovine serum (FBS), 10% FBS, 1% FBS plus 9% sham serum, or 1% FBS plus 9% SBR serum. Cell number, proliferation, and caspase-3 activity were determined. RESULTS: RIEC-6 cell growth was reduced significantly in 1% FBS or sham serum. SBR serum markedly accelerated cell growth and proliferation when compared with all other groups and significantly suppressed caspase-3 activity. CONCLUSIONS: Massive intestinal resection in mice results in a serum factor that induces intestinal cell growth in vitro. This in vitro model of trophic signaling will permit further detailed investigations into the mechanisms of intestinal adaptation.

cDNA microarray analysis of adapting bowel after intestinal resection.

BACKGROUND/PURPOSE: Studies of the genetic regulation of various physiologic processes have been hampered by methodologies that are limited to the analysis of individual genes. The advent of cDNA microarray technology has permitted the simultaneous screening of numerous genes for alterations in expression. In this study, cDNA microarrays were used to evaluate gene expression changes during the intestinal adaptive response to massive small bowel resection (SBR). METHODS: Male ICR mice (n = 20) underwent either a 50% SBR or sham operation and then were given either orogastric epidermal growth factor (EGF, 50 microg/kg/d) or saline. After 3 days, cDNA microarray analysis was performed on mRNA extracted from the remnant ileum. RESULTS: From over 8,700 different genes, the array identified 27 genes that were altered 2-fold or greater after SBR. Small proline-rich protein 2 (sprr2), the gene with the greatest expression change (4.9-fold), was further upregulated by EGF. This gene has never been characterized in the intestine or described in intestinal adaptation. CONCLUSIONS: cDNA microarray analysis showed enhanced expression of sprr2, a gene not previously known to be involved in the physiology of adaptation after SBR. This technology provides a more rapid and efficient means of dissecting the complex genetic regulation of gut adaptation.

Renal cell carcinoma as a secondary malignancy after treatment of acute promyelocytic leukemia.

Numerous children have been treated successfully for cancer and are surviving into adulthood. As this population has aged, an increasing number of secondary malignancies has emerged. Renal cell carcinoma (RCC) is a rare tumor in childhood and has not been documented previously to occur after treatment of acute promyelocytic leukemia (APL). This report describes the clinical course of APL treated in a child in whom RCC subsequently developed during adolescence approximately 5 years after therapy.

Analysis of intestinal adaptation gene expression by cDNA expression arrays.

BACKGROUND: As a tool for determining gene expression on a genomic scale, cDNA microarrays are a promising new technology that can be applied to the study of complex physiologic processes. The objective of this study was to characterize the expression of individual genes and patterns of gene expression that might provide insight into the mechanism of intestinal adaptation after massive small bowel resection. METHODS: Male ICR mice underwent a 50% proximal small bowel resection (SBR) or sham operation. After 3 days, the remnant ileum was harvested, weighed, and RNA extracted. Changes in gene expression were detected utilizing Clontech Atlas mouse cDNA expression arrays. Some of these changes were confirmed by reverse transcriptase-polymerase chain reactions (RT-PCR) and Northern blots. RESULTS: Analysis of these cDNA arrays revealed changes in the expression of multiple genes, including those involved in cell cycle regulation, apoptosis, DNA synthesis, and transcriptional regulation. The patterns of expression were consistent with the increased cell proliferation and apoptosis observed during intestinal adaptation. A large number of genes not previously associated with intestinal adaptation were identified. CONCLUSIONS: This technology may facilitate the elucidation of the intricate cellular mechanisms underlying intestinal adaptation.

Epidermal growth factor is critical for intestinal adaptation following small bowel resection.

The loss of small intestinal mucosal surface area is a relatively common clinical situation seen in both the pediatric and adult population. The most frequent causes include mesenteric ischemia, trauma, inflammatory bowel disease, necrotizing enterocolitis, and volvulus. Following surgical resection, the remnant intestine compensates or adapts to the loss of native bowel by increasing its absorptive surface area and functional capacity. Unfortunately, many patients fail to adapt adequately, and are relegated to lifelong intravenous nutrition. Research into intestinal adaptation following small bowel resection (SBR) has evolved only recently from the gross and microscopic level to the biochemical and genetic level. As understanding of this process has increased, numerous therapeutic strategies to augment adaptation have been proposed. Epidermal growth factor (EGF) is an endogenous peptide that is secreted into the gastrointestinal tract and able to influence gut ontogeny, as well as mucosal healing. Early studies have demonstrated its ability to augment the adaptive process. Focusing on a murine model of massive intestinal loss, the morphological, structural, biochemical, and genetic changes that occur during the intestinal adaptive process will be reviewed. The role of EGF and its receptor as critical mediators of the adaptive process will be discussed. Additionally, the ability of EGF to augment intestinal proliferation and diminish programmed cell death (apoptosis) following SBR will be examined. Enhancing adaptation in a controlled manner may allow patients to transition off parenteral nutrition to enteral feeding and, thereby, normalize their lifestyle.

Gastrointestinal duplications.

Gastrointestinal duplications are rare congenital lesions that can develop anywhere along the alimentary tract and may present in the newborn period as an abdominal mass. They are differentiated from other intraabdominal cystic lesions by the presence of a normal gastrointestinal mucosal lining. Multiple theories have been proposed to account for these lesions; however, no single theory adequately explains all the known duplications. They are most frequently single, tubular, or cystic and located on the mesenteric side of the native alimentary tract structure. Symptoms often are related to the location of the duplication; oral and esophageal lesions can create respiratory difficulties, whereas lower gastrointestinal lesions may cause nausea, vomiting, bleeding, perforation, or obstruction. Treatment is resection with care taken to protect the common blood supply of the native structures. Occasionally, a partial resection with mucosal excision is required to preserve intestinal mucosa.

Bax is required for increased enterocyte apoptosis after massive small bowel resection.

BACKGROUND: Massive small bowel resection (SBR) increases rates of both enterocyte proliferation and apoptosis. Previous studies have demonstrated increased intestinal expression of proapoptotic bax mRNA and protein, as well as the appearance of an 18-kd bax cleavage product within 12 hours of SBR. This study tested the hypothesis that bax is required for postresection increases in enterocyte apoptosis. METHODS: Male bax-null and C57Bl/6 (control) mice underwent either a 50% proximal SBR or sham operation. After 3 days, the remnant ileum was harvested and weighed. Apoptotic indexes, proliferation indexes, villus heights, and crypt depths were determined. RESULTS: The usual adaptive increases in ileal wet weight, crypt depth, and rate of proliferation occurred in both the control and bax-null mice. Resection significantly increased the rate of apoptosis in the control mice; however, it failed to alter the apoptotic index in the bax-null mice. CONCLUSIONS: Bax is necessary for the increase in apoptosis that occurs after SBR, but its absence has no significant effect on short-term adaptation. These findings suggest that enterocyte proliferation and apoptosis are differentially regulated during intestinal adaptation.

Salivary epidermal growth factor and intestinal adaptation in male and female mice.

Salivary epidermal growth factor (sEGF) levels are increased in male mice after small bowel resection (SBR) and may be important during intestinal adaptation. Since males have greater sEGF than females, the influence of sex on postresection adaptation was tested. Females had lower sEGF; however, sEGF substantially increased in both sexes after a massive (50%) SBR. Adaptive increases in DNA and protein content, villus height, and crypt depth, as well as crypt cell proliferation rates in the remnant ileum, were not different between males and females. Although significant postresection increases in sEGF were identified, EGF mRNA and protein did not change within the submandibular gland. Glandular kallikrein-13 and ileal EGF receptor expression were greater after SBR in female mice. Intestinal adaptation is equivalent in female and male mice after SBR. Despite lower sEGF, females demonstrated increased expression of a kallikrein responsible for sEGF precursor cleavage as well as amplified ileal EGF receptor expression. These results endorse an important differential response between sexes regarding sEGF mobilization and intestinal receptor availability during adaptation.

Epidermal growth factor alters the bax:bcl-w ratio following massive small bowel resection.

BACKGROUND: Following massive small bowel resection (SBR), the expression of bax and bcl-w is associated with increased enterocyte apoptosis. Epidermal growth factor (EGF) has been shown to enhance enterocyte proliferation and retard apoptosis in the adapting bowel. This study examined the effect of EGF on the expression of these bcl-2 family members during adaptation. MATERIALS AND METHODS: Mice (C57Bl/6; n = 38) underwent a 50% SBR or sham operation and then were randomized to receive twice-daily orogastric saline or EGF (50 microg/kg/day). After 3 days, the remnant ileum was removed, apoptotic index (No. apoptotic bodies/crypt) calculated, and expression of mRNA and protein for bax and bcl-w quantified. RESULTS: EGF prevented the expected increase in the apoptotic index after SBR and altered the ratio of bax to bcl-w in favor of cell survival. CONCLUSION: Following massive small bowel resection, EGF retards rates of enterocyte apoptosis and modifies the expression of bcl-2 family members. By decreasing bax and increasing bcl-w expression, the balance between pro- and anti-apoptotic genes is shifted in favor of cell survival. Alteration of bcl-2 family member expression may be an important mechanism by which EGF reduces the increased enterocyte apoptosis that occurs after massive small bowel resection.

p21 (WAF1/CIP1) is required for the mitogenic response to intestinal resection.

BACKGROUND: Increased enterocyte proliferation and apoptosis characterize the intestinal adaptive response to massive small bowel resection (SBR). Since p21 (WAF1/CIP1) has been implicated to play a role in cellular differentiation and apoptosis, this study tested the hypothesis that p21 is obligatory for adaptation to occur. MATERIALS AND METHODS: p21-null (n = 36) and wild-type (C57B1/6, n = 19) mice underwent a 50% SBR or sham operation. After 3 days, parameters of adaptation (ileal wet weight, villus/crypt morphology, and ileal protein content), an enterocyte proliferation index (PI), and an apoptotic index (AI) were determined in the residual ileum. In a separate set of experiments, p21-null (n = 11) and control (n = 20) mice underwent the aforementioned operative procedures and the remnant intestine was subjected to a reverse transcription polymerase chain reaction for p27 (KIP1). RESULTS: Both AI and PI increased after SBR in the wild-type mice. In the p21-null mice, SBR increased AI, but did not affect the PI. After SBR, adaptive parameters increased in the wild-type mice, but failed to increase in the p21-null mice. The absence of p21 caused a baseline increase in p27 mRNA, which did not change after SBR. CONCLUSION: p21 appears to be required to increase enterocyte proliferation and to augment the other parameters of intestinal adaptation. In the absence of p21, the proliferative and apoptotic responses to SBR are uncoupled. These results suggest a differential mechanism for the regulation of enterocyte proliferation and apoptosis in the adapting intestine.

Intestinal adaptation occurs independent of transforming growth factor-alpha.

BACKGROUND/PURPOSE: Signal transduction via the epidermal growth factor receptor (EGFR) is critical for intestinal adaptation after massive small bowel resection (SBR). Although it has been assumed that the major ligand for the EGFR during adaptation is EGF, the role for transforming growth factor-alpha (TGF-alpha), another major ligand for the EGFR is unknown. The purpose of this study was to test the hypothesis that TGF-alpha is an important ligand for the EGFR during intestinal adaptation. METHODS: Wild-type mice (C57BI/6) underwent a 50% proximal SBR or sham operation (bowel transection or reanastomosis) and were then assigned randomly to receive either intraperitoneal TGF-alpha or placebo. In a separate experiment, SBR or sham operations were performed in mice lacking TGF-alpha (Waved-1). After 3 days, adaptation was measured in the ileum. RESULTS: Exogenous TGF-alpha enhanced intestinal adaptation in the wild-type mice after SBR as shown by increased ileal wet weight and DNA content. Normal adaptation occurred in the mice lacking TGF-alpha as shown by increased ileal wet weight, protein and DNA content, proliferation, villus height, and crypt depth. CONCLUSIONS: Although exogenous TGF-alpha enhanced adaptation after massive SBR, adaptation was preserved in TGF-alpha-absent mice. These results refute TGF-alpha as an essential ligand for EGFR signaling during intestinal adaptation.

Effect of massive small bowel resection on the Bax/Bcl-w ratio and enterocyte apoptosis.

Following small bowel resection (SBR), the remnant intestine undergoes adaptation. Enterocyte proliferation is increased and counterbalanced by increased rates of apoptosis. To elucidate a mechanism for increased enterocyte apoptosis, this study tested the hypothesis that the ratio between pro-apoptotic Bax and pro-survival Bcl-w correlates with the apoptosis that occurs following SBR. Mice (C57Bl/6; n = 76) underwent a 50% proximal SBR or sham operation. After 12 hours and 1, 2, 3, and 7 days, the ileum was removed, the apoptotic index (apoptotic bodies/crypt) was recorded, and the messenger RNA and protein for Bax and Bcl-w were quantified. The apoptotic index was equivalent in the sham and SBR mice at 12 hours; however, it was significantly elevated following SBR at every other day measured. The ratio of Bax to Bcl-w messenger RNA relative to sham operation increased after SBR at 24 hours, decreased by day 3, and returned to baseline levels by 1 week. The protein ratio showed an increase by day 1, which remained elevated through day 7. An augmented ratio of Bax to Bcl-w messenger RNA and protein corresponded with the increase in enterocyte apoptosis. Alterations in the expression ratio of these genes may play a role in establishing a new homeostatic set point between proliferation and apoptosis during adaptation.

Differential expression of ileal Na(+)/H(+) exchanger isoforms after enterectomy.

BACKGROUND: Na(+)/H(+) exchangers (NHE) are transporters involved in the absorption of NaCl along the gastrointestinal tract. The aim of this study was to determine the expression pattern of the intestinal brush border NHE isoforms 2 and 3 following massive small bowel resection (SBR). Additionally, the effect of epidermal growth factor (EGF) and salivarectomy (removal of the primary source of EGF) on the expression pattern was studied. MATERIALS AND METHODS: ICR mice underwent a proximal SBR or sham surgery and then received either orogastric saline or EGF (50 microg/kg/day). In separate experiments mice underwent salivarectomy followed by SBR or sham. Postoperatively the remaining ileum was isolated and levels of NHE-2 and NHE-3 mRNA and protein were resolved. RESULTS: Following SBR, the expression of both mRNA and protein for NHE-3 increased by approximately 2.5-fold. Treatment with EGF enhanced NHE-3 mRNA in sham animals with further elevation following SBR. The expression of NHE-2 mRNA demonstrated minimal change while protein marginally increased (40%) following SBR. EGF did not affect the expression of NHE-2 mRNA. Salivarectomy did not influence NHE-2 protein expression and inhibited the increased NHE-3 protein expression following SBR. CONCLUSIONS: Following SBR, the expression pattern for brush border NHE isoforms is distinctive. Increased expression of NHE-3 secondary to SBR and/or EGF treatment with loss of this increase following salivarectomy implies a common mechanism to enhance enterocyte proliferation and luminal absorption of NaCl and water. These results suggest that NHE-3 is an important ileal exchanger following SBR.

Intestinal overexpression of EGF in transgenic mice enhances adaptation after small bowel resection.

The effect of direct intestinal overexpression of epidermal growth factor (EGF) on postresection adaptation has been investigated by the production of transgenic mouse lines. A murine pro-EGF cDNA construct was produced, and expression of the EGF construct was targeted to the small intestine with the use of the rat intestinal fatty acid-binding protein promoter. An approximately twofold increase in intestinal EGF mRNA and protein was detected in heterozygous mice. No changes in serum EGF levels were noted. Except for a slightly shortened small intestine, no other abnormal phenotype was observed. Intestinal adaptation (increases in body weight, DNA, protein content, villus height, and crypt depth) was markedly enhanced after a 50% proximal small bowel resection in transgenic mice compared with nontransgenic littermates. This transgenic mouse model permits the study of intestinal adaptation and other effects of EGF in the small intestine in a more physiological and directed manner than has been previously possible. These results endorse a direct autocrine/paracrine mechanism for EGF on enterocytes as a means to enhance adaptation.

Rhinocerebral mucormycosis in patients with burns: case report and review of the literature.

Mucormycosis is an opportunistic infection most commonly occurring in patients with impaired host defenses or diabetes mellitus. In patients with burns the rhinocerebral form is rare, and mucormycotic infections more commonly involve the cutaneous burn wound. Both forms are associated with a high mortality rate that increases with delays in treatment. The initial management of these types of infections includes vigorous glucose control, correction of acidosis, and the administration of systemic antifungal agents such as amphotericin B. The rhinocerebral form of mucormycosis is extremely virulent and may warrant the use of interstitial and intraventricular antifungal therapy. Despite these measures, the mainstay of treatment for both forms of mucormycosis is the extensive surgical débridement of all infected and necrotic tissue.

Apoptosis and the pattern of DNase I expression following massive small bowel resection.

INTRODUCTION: Following massive small bowel resection (SBR), histologic evidence of increased enterocyte apoptosis has been demonstrated in several animal models. Deoxyribonuclease I (DNase I) is requisite for intranuclear cleavage of DNA during apoptosis; we therefore hypothesized that the expression of this gene would be increased following SBR. METHODS: Male ICR mice underwent either 50% proximal SBR or sham surgery (bowel transection/reanastomosis). After 12 h and 1, 3, and 7 days, rates of enterocyte proliferation and apoptosis were recorded as well as DNase I mRNA expression and activity. RESULTS: Adaptation after SBR was confirmed at each time point by increased proliferation. Enterocyte proliferation was increased by 12 h and apoptosis was increased by 24 h and remained elevated through Day 7. When compared with sham-operated mice, SBR resulted in a twofold increase in both DNase I expression and activity at 24 h postoperatively, which returned to baseline by Postoperative Day 3. CONCLUSIONS: DNase I expression and activity are increased early following massive SBR but return to baseline despite persistent increased rates of enterocyte apoptosis and proliferation. This enzyme may be important in the early induction of apoptosis following massive SBR, but not once a new set point has been established in the balance between the rate of enterocyte production and enterocyte loss.