Mechanisms of acute and chronic intestinal inflammation induced by indomethacin

The objective of this study was to characterize the mechanisms of acute and chronic intestinal mucosal injury and inflammation induced by subcutaneously injected indomethacin (Indo). One injection of Indo (7.5 mg/kg) produced acute injury and inflammation in the distal jejunum and proximal ileum that were maximal at three days and completely resolved within one week. Two daily subcutaneous injections of Indo produced a more extensive and chronic inflammation that lasted in an active form in more than 75% of the rats for at least two weeks. Epithelial injury, as measured by enhanced mucosal permeability, was significantly elevated only at one day in the acute model (one injection) but was persistently elevated in the chronic model (two injections). Bile duct ligation completely attenuated increased mucosal permeability in the acute model, however, depletion of circulating neutrophils had no effect. Neither Indo (0–0.1 mg/ml) nor normal bile was cytotoxic to cultured rat intestinal epithelial cells; however, they synergistically promoted significant cytotoxicity. Bile collected from rats treated with Indo was cytotoxic towards the epithelial cells in a dose-dependent manner. Sulfasalazine and metronidazole (100 mg/kg/day, both) attenuated enhanced mucosal permeability in the chronic model. Massive bacterial translocation into the mesenteric lymph nodes, liver, and spleen following two injections of Indo was significantly attenuated by metronidazole. We conclude that: (1) a single injection of Indo produces acute intestinal mucosal injury and inflammation that resolve completely within three to seven days, whereas two daily injections of Indo produce both acute and chronic injury and inflammation, (2) enterohepatic circulation of Indo is important in promoting the acute phases of injury and inflammation, (3) circulating neutrophils do not play a role in the pathogenesis of this model, and (4) endogenous bacteria play an important role in exacerbating and/or perpetuating the chronic phases of injury and inflammation.This work was supported by DK 43785 (to M.B.G., Project 6), DK 33720 (to R.D.S.), and DK 40249 (to R.B.S.).     

Dorsal fracture dislocations of the proximal interphalangeal joint: surgical complications and long-term results.

This retrospective study assessed the short-term complications and long-term subjective and objective results of operative treatment of acute unstable dorsal proximal interphalangeal joint dislocations treated by 2 methods: open reduction internal fixation and volar plate arthroplasty. Fifty-six patients were included in this study. Twenty-three (41%) were treated by volar plate arthroplasty and 33 (59%) were treated by open reduction internal fixation. Postoperative complications occurred in 10 patients (18%). The most frequent complication was redislocation, which occurred in 6 patients (volar plate arthroplasty, 3 patients; open reduction internal fixation, 3 patients) and necessitated salvage surgery in 4 of these 6 cases. In all 6 cases, the fracture of the base of the middle phalanx involved more than 50% of the articular surface. Twenty-four patients (43%) returned for long-term evaluation at an average follow-up period of 46 months (range, 13-125 months). Twenty of these 24 patients (83%) reported little or no pain despite a high incidence (96%) of posttraumatic degenerative changes. Eighteen (75%) reported no difficulty with work activities; 92% continued leisure activities with little or no modification. Proximal interphalangeal joint flexion contractures and extension lag at the distal interphalangeal joint were common. These data indicate that if reduction is maintained, patients may expect few functional deficits despite radiographic degenerative changes and loss of mobility.     

Why insurers should reimburse for compression stockings in patients with chronic venous stasis

BACKGROUND: Chronic venous stasis ulcers produce substantial morbidity rates and result in a significant expense to society. Fortunately, compression stockings (CS) have been found to reduce the rate of recurrence in patients with previous ulceration. Surprisingly, Medicare and other insurers do not reimburse the expense associated with CS or with patient education (Ed), which is essential to ensure compliance. METHODS: A Markov decision analysis model was used for analysis of the cost-effectiveness of a strategy of reimbursement for CS and Ed (prophylaxis) versus one that does not supply these resources in a 55-year-old patient with prior venous stasis ulceration. The mean time to ulcer recurrence (53 months with CS+Ed; 18.7 months without prophylaxis), the mean time for ulcer healing (4.6 months), the probabilities of hospitalization (12%) and amputation (0.4%) after the development of an ulcer, and quality-adjustment factors (0.80 during ulcer treatment) were derived from the literature. The cost of CS ($300/year) and Ed ($93 for initial evaluation; $58/year; $40/recurrence) and the medical cost of ulcer treatment (average cost, $1621/recurrence) were calculated from our hospital cost accounting system. RESULTS: A strategy of CS and Ed was cost saving, with 0.37 quality-adjusted life years and $5904 saved, compared with a strategy that does not provide these resources. The inclusion of loss of revenue related to absence from work in the analysis increased cost savings to $17,080 during the patient's lifetime. With sensitivity analysis, CS and Ed remained cost-effective (lifetime cost per quality-adjusted life year saved, <$60,000) if amputations and the cost of ulcer treatment were eliminated or if the cost of prophylaxis was increased to 600% of the base-case. The mean time to recurrence in patients with CS and Ed needed to be reduced from 53 months to 21.1 months before this strategy was no longer cost-effective. CONCLUSION: Prophylactic CS and Ed in patients with prior venous stasis ulceration are cost saving, even with the most conservative of assumptions. Insurers should routinely reimburse for these interventions.     

Application of a yeast assay to detect functional p53 mutations in archival prostate cancer tissue

Detection and functional evaluation of mutant p53 alleles using a yeast assay could yield significant information for predicting the prognosis of patients with prostate cancer (CaP). Since the current version of this yeast assay is not applicable to archival tissues, we developed a modified assay for use on formalin-fixed, paraffin-embedded tissue and have applied it to the study of patient samples. Using this modified assay, we examined archival CaP samples from 10 patients for mutations in exons 5-8 of p53 gene. Mutations were detected in four samples: three resulted in the formation of red yeast colonies indicating complete loss of function, while one gave pink yeast colonies, indicating that this mutant retained partial function. In parallel, we analyzed these samples for p53 abnormalities using a single-strand conformational polymorphism (SSCP) approach. Only three of the four yeast-positive samples gave abnormal SSCP bands. In each case where abnormal p53 was found by both methods, DNA sequencing revealed the identical base change. These results suggest that the modified yeast assay may be more sensitive than SSCP for detection of p53 mutations, and demonstrate that the modified method can be used to detect and evaluate the function of p53 mutants present in archival tissue.     

Role of bacterial translocation in necrotizing enterocolitis

The intestinal mucosa functions as a major local defense barrier preventing bacteria that colonize the gut from invading organs and tissues. Under certain circumstances, bacteria colonizing the gastrointestinal tract can cross the gut mucosal barrier to infect the mesenteric lymph node and systemic organs via a process termed bacterial translocation. Factors that promote the translocation of bacteria or endotoxin from the gut include bacterial overgrowth with gram-negative enteric bacilli, impaired host immune defenses and injury to the gut mucosa resulting in increased intestinal permeability. These same promoting factors are present in patients at increased risk of developing necrotizing enterocolitis. Consequently, this review focuses on the potential role of bacterial and endotoxin translocation from the gut in the pathogenesis of necrotizing enterocolitis.     

Methadone applicant dropouts: impact of requiring involvement of friends or family in treatment

This paper examines attrition among applicants to a methadone maintenance program before and after it began to require that applicants have a relative or close friend willing to act as a treatment sponsor. Few applicants were unable to locate sponsors. The dropout rate was greater for Blacks than for Hispanics and Anglo Whites both before and after the sponsor requirement was introduced. However, young addicts, addicts with recent drug histories, and singles were somewhat less likely to enter treatment after the requirement was introduced. Implications for drug treatment clinicians and administrators are discussed.     

Sex hormones modulate distant organ injury in both a trauma/hemorrhagic shock model and a burn model

BACKGROUND: Emerging data suggest a gender dimorphism in resistance and susceptibility to distant organ injury after mechanical and thermal trauma. The aim of this study was to determine the role that testosterone and estradiol play in modulating resistance or susceptibility to distant organ injury, and whether their effects were associated with differences in the production of nitric oxide. METHODS: Adult male, female, castrated male, and ovariectomized female Sprague-Dawley rats were given intraperitoneal pentobarbital sodium anesthesia and subjected to trauma/sham shock or trauma/hemorrhagic shock (T/HS). A second set of animals were subjected to a 40% total body surface area, third-degree burn or sham burn. At 3 hours after resuscitation, plasma levels of nitrite/nitrate were measured, and the extent of lung injury (permeability to Evans Blue dye and neutrophil sequestration by myeloperoxidase) and intestinal injury (morphology) were determined. RESULTS: Proestrus females showed resistance to lung and gut injury after both T/HS and burns, and had low levels of nitrite/nitrate production. This resistance to injury was abrogated by ovariectomy with an associated increase in nitric oxide production. Males showed increased lung and gut injury after both T/HS and burns associated with increased production of nitrite/nitrate. Castration decreased susceptibility to both lung and gut injury, and decreased production of nitrite/nitrate. A correlation was noted between intestinal and lung injury, and both intestinal and lung injury correlated with plasma nitrite/nitrate levels. CONCLUSIONS: Male sex hormones potentiate, while female hormones reduce T/HS and burn-induced lung and gut injury. Production of nitric oxide is associated with increased lung and gut injury after T/HS and burns.     

A clinical review of shotgun wounds to the chest and abdomen

Since a controversy exists over whether patients with truncal shotgun wounds should have selective or mandatory exploration, we reviewed the records of 1,222 patients with truncal missle wounds treated over a six year period at our institution. Based upon a detailed review of 42 of these patients, who had sustained shotgun wounds, we believe that not all patients with truncal shotgun wounds require mandatory surgical exploration. That, in fact, a subgroup of patients can be identified who can be safely managed nonoperatively, based upon the pattern of the injury and the clinical status of the patient at the time of arrival to the emergency room.