Halofuginone--an inhibitor of collagen type I synthesis--prevents postoperative formation of abdominal adhesions.

OBJECTIVE: To evaluate the effects of halofuginone, a specific inhibitor of collagen type I synthesis, on the postoperative formation of abdominal adhesions in rats. SUMMARY BACKGROUND DATA: Postoperative adhesions remain the leading cause of small bowel obstruction in the Western world. Surgical trauma causes the release of a serosanguineous exudate that forms a fibrinous bridge between two organs. This becomes ingrown with fibroblasts, and subsequent collagen deposition leads to the formation of a permanent adhesion. Most of the drugs used have been clinically ineffective, and none has been specific to a particular extracellular matrix molecule. Therefore, there are serious concerns about the toxic consequences of interfering with the biosynthesis of other collagens, other matrix proteins, or vital collagen-like molecules. METHODS: Adhesions were induced by scraping the cecum until capillary bleeding occurred. The adhesions were scored 21 days later. Halofuginone was either injected intraperitoneally (1 microg/25 g body weight) every day, starting on the day of operation, or added orally at concentrations of 5 or 10 mg/kg, starting 4 days before the operation. Collagen alpha1(I) gene expression was evaluated by in situ hybridization, total collagen was estimated by Sirius red staining, and collagen type III was detected by immunohistochemistry. RESULTS: The adhesions formed between the intestinal walls were composed of collagen and were populated with cells expressing the collagen alpha1(I) gene. Regardless of the administration procedure, halofuginone significantly reduced the number and severity of the adhesions. Halofuginone prevented the increase in collagen alpha1(I) gene expression observed in the operated rats, thus reducing collagen content to the control level. In fibroblasts derived from abdominal adhesions, halofuginone induced dose-dependent inhibition of collagen alpha1(I) gene expression and collagen synthesis. Collagen type III levels were not altered by adhesion induction or by halofuginone treatment. CONCLUSIONS: Upregulation of collagen synthesis appears to have a critical role in the pathophysiology of postoperative adhesions. Halofuginone, an inhibitor of collagen type I synthesis, could be used as an important tool in understanding the role of collagen in adhesion formation, and it may become a novel and promising antifibrotic agent for preventing postoperative adhesion formation.     

Hyperreactio luteinalis in a normal pregnancy: Sonographic and MRI findings

A case of hyperreactio luteinalis in an otherwise normal pregnancy is reported. Ascites was present, but no peritoneal implants or adenopathy were seen. Findings that would have suggested the correct diagnosis are the symmetrical and bilateral pattern of the mass, as well as the rather uniform size of the loculi, which were 1 to 3 cm in diameter.     

Panic disorder and the vestibular system

This article reviews the interrelationship between panic disorder and vestibular function. There is a possibility of both somatopsychic and psychosomatic interactions between panic and the vestibular system. Another possibility is that vestibular dysfunction could be associated with certain mental disorders, including panic disorder, as a nonspecific marker. Somatopsychic interactions are suggested by findings of high prevalence of vestibular dysfunction in selected patients with panic disorder, by the occurrence of "space and motion phobia" in patients with panic disorder, and by the report of anxiety and pseudoagoraphobia in some patients with a primary complaint of vertigo. Psychosomatic influences include symptoms of dizziness and increased sensitivity of the vestibular system due to anxiety or hyperventilation. Vestibular dysfunction as a nonspecific marker is discussed in the context of a review of studies of the vestibular system in schizophrenia. Before more definite conclusions can be drawn whether panic disorder is related to vestibular dysfunction in some cases, further research is needed to establish the specificity of vestibular dysfunction for panic disorder.     

Adequacy of "Hot Biopsy" for the Treatment of Diminutive Polyps: A Prospective Randomized Trial

Patients with diminutive polyps in the rectum or sigmoid colon were randomized to "hot biopsy" treatment for either 1) electrocautery for 2 s (fixed duration cautery) or 2) cautery until visible necrosis of the polyp base was evident (variable duration cautery). Sigmoidoscopy was performed 4 wk after treatment to determine the adequacy of polyp eradication. In the fixed duration cautery group, 11 of 21 polyps (52%) were eradicated, compared with 12 of 14 polyps (86%) in the variable duration cautery group (p = 0.04). When analyzed according to whether or not visible necrosis was achieved (some of the polyps in the fixed duration cautery group showed necrosis with 2 s cautery), 19 of 23 polyps (83%) were eradicated when necrosis was evident, compared to 5 of 12 (42%) without necrosis (p = 0.004). We conclude that hot biopsy treatment for diminutive polyps is significantly more effective when visible necrosis is achieved during cautery. Furthermore, even with visible necrosis, there is a 17% failure rate of polyp eradication.     

Play interview therapy: Its history,theory and practice — A fifty year retrospective account

The method of the play interview offers the fearful child an opportunity to express himself by speaking for a series of dolls representing siblings, parents, teachers or himself. It is not the child who is aggressive, fearful, jealous or desires the parent's affection, but the doll. In this manner, the child learns to make connections between his fears and his unacceptable bad thoughts, feelings or wishes. Improvement occurs after several play interviews.This article is dedicated to Dr. Leo Kanner (1894–1981), former Director of the Children's Psychiatric Service of the Johns Hopkins HospitalLecture given to the Division of Child Psychiatry, Department of Psychiatry and Behavioral Sciences The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Md, 21205, on September 6, 1988.     

Major histocompatibility complex class I peptide presentation after Salmonella enterica serovar typhimurium infection assessed via stable isotope tagging of the B27-presented peptide repertoire

Reactive arthritis (ReA) induced by infection with several gram-negative bacteria is strongly associated with expression of the major histocompatibility complex class I molecule HLA-B27. It is thought that due to the intracellular lifestyle of ReA-inducing bacteria, bacterial fragments can be presented by HLA-B27. Cytotoxic T cells recognizing such bacterial peptides or other induced host peptides could cross-react with self peptides presented in the joints, giving rise to disease. Studies to analyze the B27 peptide repertoire in relation to infection were severely hampered, as complex peptide profiles obtained from separate infected and noninfected cell preparations had to be compared. For this study, we applied a new approach to examine the effect of Salmonella enterica serovar Typhimurium infection on the B27 peptide repertoire presented by the HLA-B*2704 subtype associated with disease. Firstly, we showed that both host cell and S. enterica serovar Typhimurium proteins can be tagged metabolically with stable-isotope-labeled arginine. We then designed experiments so that either the tagged endogenous or tagged bacterial B*2704-presented peptide repertoires from infected cells could be analyzed by mass spectrometry from single peptide preparations that included uninfected controls. Using this new approach, we found no evidence for significant changes in endogenous B*2704 peptide presentation after infection or for any S. enterica serovar Typhimurium-derived B27-bound peptide. In conclusion, the hypothesis that S. enterica serovar Typhimurium induces changes in B27 peptide presentation could not be supported.     

Incomplete effector/memory differentiation of antigen-primed CD8+ T cells in gene gun DNA-vaccinated mice

DNA vaccination is an efficient way to induce CD8+ T cell memory, but it is still unclear to what extent such memory responses afford protection in vivo. To study this, we induced CD8+ memory responses directed towards defined viral epitopes, using DNA vaccines encoding immunodominant MHC class I-restricted epitopes of lymphocytic choriomeningitis virus covalently linked to beta2-microglobulin. This vaccine construct primed for a stronger recall response than did a more conventional minigene construct. Despite this, vaccinated mice were only protected against systemic infection whereas protection against the consequences of peripheral challenge was limited. Phenotypic analysis revealed that DNA vaccine-primed CD8+ T cells in uninfected mice differed from virus-primed CD8+ T cells particularly regarding expression of very-late antigen (VLA)-4, an adhesion molecule important for targeting T cells to inflammatory sites. Thus, our DNA vaccine induces a long-lived memory CD8+ T cell population that provides efficient protection against high-dose systemic infection. However, viral replication in solid non-lymphoid organs is not curtailed sufficiently fast to prevent significant virus-induced inflammation. Our results suggest that this is due to qualitative limitations of the primed CD8+ T cells.     

Macrophage Accumulation, Division, Maturation and Digestive and Microbicidal Capacities in Tuberculous Lesions: I. Studies Involving their Incorporation of Tritiated Thymidine and their Content of Lysosomal Enzymes and Bacilli

Dermal and pulmonary tuberculous lesions were produced in rabbits with BCG, biopsied, incubated in vitro with tritiated thymidine (³HT) under hyperbaric oxygen, quickly frozen, sectioned in a cryostat, stained for the lysosomal enzyme β-galactosidase, autoradiographed, stained for acid-fast bacilli and counterstained with hematoxylin. As macrophages developed into epithelioid cells, they could still divide—ie, incorporate ³HT. However, once they became fully mature epithelioid cells that were 4-plus in β-galactosidase, they could not do so. Tuberclebacilli did not stimulate macrophage division. On the contrary, macrophages containing bacilli did not divide, except when the lesions began. During the development of tuberculous lesions, macrophages (including those rich in enzymes and those containing bacilli) died, forming caseous centers. Therefore, local cell division did not seem to be the main mechanism by which macrophages reduced their bacillary load. Such division seemed mainly to occur in young macrophages that had recently immigrated into the lesions from the bloodstream and had not yet ingested bacilli.