Richard A. Hodin

A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit.

A cDNA encoding a novel member of the thyroid/steroid hormone receptor superfamily, called Rev-ErbA alpha, has been isolated from a rat GH3 cell library. Rev-ErbA alpha is an approximately 56-kilodalton protein most similar in structure to the thyroid hormone receptor (c-erbA) and the retinoic acid receptor, but it does not bind either thyroid hormone or retinoic acid. The mRNA encoding Rev-ErbA alpha is present in many tissues and is particularly abundant in skeletal muscle and brown fat. A genomic DNA fragment containing the entire Rev-ErbA alpha cDNA sequence was isolated and characterized. Remarkably, this DNA fragment also contained a portion of the c-erbA alpha gene. r-erbA alpha-1 and r-erbA alpha-2 are alternative splice products of the c-erbA alpha gene and are members of the receptor superfamily. The genes encoding Rev-ErbA alpha and r-erbA alpha-2 overlap, with their coding strands oriented opposite one another. A 269-base-pair segment of the bidirectionally transcribed region is exonic in both the Rev-ErbA alpha and r-erbA alpha-2 genes, resulting in complementary mRNAs. Thus, through alternative splicing and opposite-strand transcription, a single genomic locus codes for three different members of the thyroid/steroid hormone receptor superfamily. Potential implications of this unusual genomic arrangement are discussed.

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition.

Under conditions of starvation and disease, the gut barrier becomes impaired, and trophic feeding to prevent gut mucosal atrophy has become a standard treatment of critically ill patients. However, the mechanisms responsible for the beneficial effects of enteral nutrition have remained a mystery. Using in vitro and in vivo models, we demonstrate that the brush–border enzyme, intestinal alkaline phosphatase (IAP), has the ability to detoxify lipopolysaccharide and prevent bacterial invasion across the gut mucosal barrier. IAP expression and function are lost with starvation and maintained by enteral feeding. It is likely that the IAP silencing that occurs during starvation is a key component of the gut mucosal barrier dysfunction seen in critically ill patients.

Differential and tissue-specific regulation of the multiple rat c-erbA messenger RNA species by thyroid hormone.

Thyroid hormone (T3) has been shown to regulate the level of its receptor in a number of tissues and cell lines. Recently, proteins encoded by the protooncogene c-erbA have been identified as T3 receptors. In the rat, four c-erbA gene products have been isolated, three of which, r-erbA alpha-1, r-erbA beta-1, and r-erbA beta-2, encode biologically active T3 receptors; the fourth, r-erbA alpha-2, may play an inhibitory role in T3 action. The present work examines the molecular nature of T3 receptor autoregulation using probes specific for each c-erbA mRNA. Rats were rendered hypothyroid with propylthiouracil and then treated with either saline or T3. Northern blot analyses reveal marked tissue-specific and differential regulation of the multiple c-erbA mRNAs by T3. In the pituitary the levels of r-erbA beta-1 mRNA increase, whereas the levels of the pituitary-specific r-erbA beta-2 mRNA decrease with T3 treatment. In heart, kidney, liver, and brain the levels of r-erbA beta-1 are unaffected by thyroidal status. The levels of both r-erbA alpha mRNAs decrease with T3 treatment in all tissues examined except for the brain, where there is no change. In addition, we find that changes in the mRNAs encoding specific subpopulations of T3 receptors do not always parallel changes in total nuclear T3 binding. Differential regulation of the specific c-erbA mRNA species could have important consequences for T3 action.

Impact of Hospital Volume on Postoperative Morbidity and Mortality Following a Colectomy for Ulcerative Colitis

BACKGROUND & AIMS Postoperative morbidity and mortality following a colectomy for ulcerative colitis (UC) has been primarily reported from tertiary care referral centers that perform a high volume of operations; however, the postoperative outcomes among nonselected hospitals are not known. We set out to evaluate postoperative morbidity and mortality using a nationally representative database and to determine the factors that influenced outcomes. METHODS We analyzed the 1995-2005 Nationwide Inpatient Sample to identify 7108 discharges for UC patients who underwent a total abdominal colectomy. The effects of hospital volume on postoperative morbidity and mortality were evaluated in logistic regression models adjusting for demographic and clinical factors. RESULTS Postoperative mortality and morbidity rates were 2.3% and 30.8%, respectively. Most operations were performed in low-volume hospitals that had an increased risk of death (adjusted odds ratio [aOR], 2.42; 95% confidence interval [CI]: 1.26-4.63). In-hospital mortality was increased in patients who were admitted emergently (aOR, 5.40; 95% CI: 3.48-8.40), aged 60-80 years (aOR, 8.70; 95% CI: 3.30-22.92), and those with Medicaid (aOR, 4.29; 95% CI: 2.13-8.66). Emergently admitted UC patients whose surgery was performed 6 days after their admission had significantly increased likelihood of in-hospital death (aOR, 2.12; 95% CI: 1.13-3.97). CONCLUSIONS Postoperative mortality was lowest in hospitals that performed the highest volume of operations. Increasing the proportion of total colectomies performed in high-volume hospitals may improve clinical outcomes for patients with UC.

Tissue-Engineered Small Intestine Improves Recovery After Massive Small Bowel Resection

Objective:Rescue with tissue-engineered small intestine (TESI) after massive small bowel resection (MSBR). Summary Background Data:Short bowel syndrome is a morbid product of massive small bowel resection. We report the first replacement of a vital organ by tissue engineering with TESI after MSBR. Methods:Ten male Lewis rats underwent TESI implantation with green fluorescent protein (GFP)-marked cells (TESI+, n = 5) or sham laparotomy (TESI−, n = 5) followed by MSBR. Side-to-side anastomosis of TESI to proximal small intestine was performed or omitted. TESIØ animals underwent implantation of engineered intestine with no further surgery. Weights were measured QOD until day 40. Transit times were measured. DNA assay was performed with computer morphometry. Northern blots of RNA were probed for intestinal alkaline phosphatase (IAP) and villin. Hematoxylin and eosin, S100, and smooth muscle actin immunohistochemistry were performed. Blood was collected at sacrifice. Results:All 10 rats initially lost then regained weight. The initial rate of weight loss was higher in TESI+ versus TESI−, but the nadir was reached a week earlier with more rapid weight gain subsequently to 98% preoperative weight on day 40 in animals with engineered intestine versus 76% (P < 0.03). Serum B12 was higher at 439 pg/mL versus 195.4 pg/mL. IAP mRNA appeared greater in TESI+ than TESIØ, with constant villin levels. Histology revealed appropriate architecture including nerve. GFP labeling persisted. Conclusions:Anastomosis of TESI significantly improved postoperative weight and B12 absorption after MSBR. IAP, a marker of differentiation in intestinal epithelium, is present in TESI, and GFP labeling was accomplished.

Cytokine-induced intestinal epithelial hyperpermeability: role of nitric oxide.

OBJECTIVE Incubation of enterocytic monolayers with interferon (IFN)-gamma increases nitric oxide (NO) production and permeability, but NO synthesis inhibitors ameliorate the development of IFN-gamma-induced hyperpermeability. Induction of inducible nitric oxide synthase (iNOS), an isoform of the enzyme responsible for NO biosynthesis, is often enhanced by the synergistic effects of multiple cytokines. Moreover, many of the cytopathic effects of NO are mediated by peroxynitrite, which is produced by the reaction of NO with superoxide radical anion. In the present study, we sought to determine whether combinations of several proinflammatory cytokines, including IFN-gamma, interleukin-1beta, and tumor necrosis factor-alpha, have synergistic effects on the induction of iNOS expression and/or hyperpermeability to hydrophilic solutes in cultured enterocytic monolayers. We also assessed the effects of aminoguanidine (a relatively selective iNOS inhibitor), L-N(G)-monomethyl arginine (an isoform-nonselective NO synthase inhibitor), and Tiron (a superoxide radical anion scavenger) on the development of cytokine-induced hyperpermeability. DESIGN Caco-2 monolayers were incubated under control conditions or with IFN-gamma, interleukin-1beta, or tumor necrosis factor-alpha alone, pairwise combinations of these cytokines, or all three cytokines together (cytomix; CM). iNOS messenger RNA (mRNA) expression was assessed using Northern blot analysis. The permeability of Caco-2 monolayers growing on permeable supports in bicameral chambers was assessed by measuring the apical-to-basolateral flux of fluorescein disulfonic acid. The concentration of nitrate plus nitrite in culture supernatants, an indirect measure of NO production, was determined using the Griess reaction. RESULTS After 24 hrs of incubation, up-regulation of iNOS mRNA expression was evident only in cells exposed to IFN-gamma-containing formulations. Expression of iNOS mRNA was far greater in cells incubated with CM than in cells treated with IFN-gamma alone or either of the two-component IFN-gamma-containing cytokine combinations. Compared with IFN-gamma, CM resulted in a higher rate of NO production over 48 hrs of incubation. The permeability of Caco-2 monolayers increased by approximately six-fold and approximately 20-fold after incubation for 48 hrs with IFN-gamma alone and CM, respectively. The increase in permeability induced by incubation with CM was significantly ameliorated by the addition of aminoguanidine, L-N(G)-monomethyl arginine, or Tiron. CONCLUSIONS IFN-gamma-containing combinations of cytokines are potent inducers of iNOS in cultured enterocytic monolayers. Peroxynitrite may be an important mediator of cytokine-induced gut epithelial hyperpermeability.

Factors associated with conversion to laparotomy in patients undergoing laparoscopic appendectomy.

BACKGROUND Laparoscopic appendectomy (LA) has been increasingly adopted for its advantages over the open technique, but there is a possibility of conversion to open appendectomy (OA) if complications occur or the extent of inflammation prohibits successful dissection. This study aimed to identify the preoperative predictors for conversion from laparoscopic to open appendectomy. STUDY DESIGN Medical records of 705 consecutive patients who underwent surgery for suspected appendicitis were reviewed retrospectively. LA was attempted in 595 patients by 25 different surgeons. Factors evaluated were age, gender, body mass index, previous abdominal surgery, previous appendicitis attack, pain, nausea, vomiting, fever, duration of symptoms, local or diffuse tenderness, leukocyte count and surgeons experience in LA. RESULTS Conversion to OA occurred in 58 patients (9.7%). The most common reason for conversion was dense adhesions due to inflammation, followed by localized perforation and diffuse peritonitis. Based on 261 patients evaluated by CT scan preoperatively, significant factors in the final multivariate analysis associated with conversion to OA were age > or = 65 [Odds ratio (OR) = 3.78, 95% CI:1.11-12.84], diffuse tenderness on physical examination (OR = 11.32, 95% CI: 1.32-96.62), and a surgeon with less experience in LA (< or = 10 operations, OR = 3.38, 95% CI:1.02-11.17). The presence of significant fat stranding associated with fluid accumulation, inflammatory mass or localized abscess in CT scan also significantly increased the possibility of conversion (OR = 5.60, 95% CI:2.48-12.65). CONCLUSIONS Identifying the potential factors for conversion preoperatively may assist the surgeons in making decisions concerning the management of patients with appendicitis and in the judicious use of LA.

Intestinal alkaline phosphatase prevents metabolic syndrome in mice

Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet–induced metabolic syndrome in mice. We found that both endogenous and orally supplemented IAP inhibits absorption of endotoxin (lipopolysaccharides) that occurs with dietary fat, and oral IAP supplementation prevents as well as reverses metabolic syndrome. Furthermore, IAP supplementation improves the lipid profile in mice fed a standard, low-fat chow diet. These results point to a potentially unique therapy against metabolic syndrome in at-risk humans.

Outpatient thyroid and parathyroid surgery: A prospective study of feasibility, safety, and costs

BACKGROUND The purpose of this study was to determine feasibility, safety, and cost savings of outpatient thyroid and parathyroid surgery. METHODS Consecutive unselected patients undergoing thyroid and parathyroid operations by two surgeons with a special interest in endocrine surgery were studied prospectively. RESULTS One-hundred patients underwent operation, 61 as outpatients and 39 as inpatients. Outpatients included those undergoing thyroid lobectomy (39), total thyroidectomy (10), total thyroidectomy with parathyroidectomy (1), total thyroidectomy with modified neck dissection (1), and parathyroidectomy (10). Inpatients included those undergoing thyroid lobectomy (15), total thyroidectomy (8), total thyroidectomy with neck dissection (4), removal of substernal goiter (2), and parathyroidectomy (10). The average age of inpatients was slightly higher than that of outpatients (p < 0.05). Average hospital cost for outpatients was

B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression.

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