The role of cyclooxygenase selective inhibitors in the gastrointestinal tract

This article reviews the gastrointestinal manifestations of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and the improved gastrointestinal safety profile of cyclooxygenase selective (COX)-2 inhibitors. By inhibiting the COX enzyme, NSAIDs provide effective analgesia and suppress inflammation in a variety of conditions. Most NSAIDs (nonselective or traditional) not only inhibit prostaglandins at sites of inflammation but also inhibit prostaglandins that have important normal functions in other parts of the body. This may be harmful when normal gastrointestinal mucosal function is impaired and mucosal damage occurs. Although such damage is often trivial and usually not symptomatic, gastrointestinal ulceration may produce pain and, more ominously, lead to bleeding, perforation, or obstruction. A new approach to the gastrointestinal complications of NSAIDs became feasible with the discovery of two isoforms of COX, COX-1 and COX-2, with COX-1 expressed mainly in the gastrointestinal tract. The development of NSAIDs that preferentially inhibit COX-2 offers the promise of relieving pain and inflammation without the side effects attendant to COX-1 blockade. In prospective studies evaluating gastrointestinal ulceration with COX-2-specific NSAIDs, rates of endoscopic ulceration have been equivalent to those with placebo and much lower than those with nonselective NSAIDs. In the recently released studies of gastrointestinal outcomes (perforated, painful, or bleeding ulcers), incidence of clinically relevant ulceration with COX-2 NSAIDs is much lower than that of traditional NSAIDs.     

Management of ectopic pregnancy at a military medical center

OBJECTIVE: Advances in laparoscopic surgical techniques and ultrasound technology along with the popularization of treatment with methotrexate have revolutionized accepted algorithms for treating ectopic pregnancy. I analyzed the management of ectopic pregnancy at a military medical center. METHODS: A retrospective chart review of ectopic pregnancies at Womack Army Medical Center between January 1997 and July 1999 was conducted. RESULTS: A total of 129 cases of ectopic pregnancy were found. Of those, 77 patients received primary surgical management, 51 patients received primary therapy with methotrexate, and 1 patient was managed expectantly. Eleven patients failed methotrexate therapy and went on to surgical therapy. Of the 88 patients ultimately treated surgically, 76 underwent laparoscopic procedures, 12 received laparotomy, and 11 more converted from laparoscopy to laparotomy. CONCLUSION: The advent of methotrexate therapy has greatly facilitated the treatment of ectopic pregnancy and altered our institutional algorithm; however, primary surgery is still used more often.     

Characteristics of indolent non-Hodgkin lymphoma in patients with type 1 human immunodeficiency virus infection

BACKGROUND: There is recent evidence that the incidence of indolent non-Hodgkin lymphoma (NHL) appears to be increased in persons with the acquired immunodeficiency syndrome (AIDS). The current study was conducted to describe the clinical, immunologic, and pathologic characteristics of indolent B-cell lymphoma in patients infected with the human immunodeficiency virus (HIV). METHODS: The current report was a retrospective study of 10 cases of indolent NHL identified from the AIDS-Lymphoma Registry at the University of Southern California School of Medicine. These patients were compared with 336 consecutive patients with systemic intermediate/high-grade AIDS-related NHL who were diagnosed and treated at a single institution. RESULTS: The pathology of the indolent cases included follicular lymphoma (five patients), small lymphocytic lymphoma (two patients), and one case each of mucosa-associated lymphoid tissue (MALT), monocytoid B-cell, and marginal zone lymphoma. When comparing the indolent lymphomas with the intermediate/high-grade AIDS-NHL cases, no differences were observed with regard to demographic characteristics or history of prior opportunistic infection. HIV patients with indolent lymphomas were found to have a significantly higher median CD4+ lymphocyte count compared with patients with intermediate/high-grade NHL (531 /mm3 vs. 90 /mm3) (P < 0.0001). Bone marrow involvement was significantly more common in indolent NHL cases (50%) versus intermediate/high-grade NHL cases (17%) (P = 0.02). The median survival for patients with indolent NHL was significantly longer compared with patients with intermediate/high-grade NHL (66.8 months vs. 7.1 months) (P = 0.007). CONCLUSIONS: Indolent lymphomas occurring in patients infected with HIV appear to differ from intermediate/high-grade lymphomas with regard to immune status and propensity for bone marrow involvement and prolonged survival. The median survival in the group of HIV-seropositive patients with indolent NHL examined in the current study was found to be comparable to that reported in HIV-negative individuals.     

Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery alone in patients with newly diagnosed brain metastases: results and implications

PURPOSE: A single-institution experience using primary stereotactic radiosurgery (SRS) alone in the management of newly diagnosed brain metastases was analyzed to identify the risk of symptomatic brain tumor recurrence (BTR) and neurologic deficit associated with such a treatment strategy. METHODS AND MATERIALS: Thirty-six patients were treated for newly diagnosed single/multiple brain metastases using SRS alone followed by planned observation. SRS minimum tumor dose ranged from 8 to 25 Gy (median: 20 Gy). Factors evaluated in analysis of treatment outcome included number of metastases, site of metastasis, primary tumor site, histology, extent of intracranial and extracranial disease, and interval to diagnosis of brain metastasis. RESULTS: Median and 1-year survival for the entire group was 9 months and 36%, respectively. BTR anywhere in the brain occurred in 47% (17/36) of patients. Forty-seven percent of BTR (8/17) recurred at the site of original metastasis; 35% (6/17) recurred at both original [corrected] and distant sites in the brain, and 18% (3/17) recurred at distant only [corrected] brain sites. Seventy-one percent (12/17) of the patients were symptomatic at the time of recurrence, and 59% (10/17) had an associated neurologic deficit. Multivariate analysis found that only the extent of disease was a predictor of BTR. Patients who had disease limited to the brain only had a BTR rate of 80% (8/10) vs. 35% (9/26) who had disease involving the brain, primary site, and/or other extracranial metastatic sites (p = 0.03). CONCLUSIONS: Use of primary SRS alone in this setting is associated with an increasingly significant risk of BTR with increasing survival time. In addition, the majority of such recurrences are symptomatic and associated with a neurologic deficit, a finding not analyzed in recently reported experiences withholding whole brain radiation therapy as part of the primary treatment of brain metastasis.     

Hyperhomocysteinemia and the risk of thromboembolic phenomenon in patients with chronic renal failure

Thromboembolic phenomena are a major cause of morbidity and mortality in patients with end-stage renal disease. Studies in patients with chronic renal failure (CRF) have demonstrated an increased relative risk of coronary artery disease (CAD) in association with hyperhomocysteinemia (HHe). However, very little data exist about the causal relationship between HHe and cerebrovascular diseases (CVA) in patients with CRF. We report the results of our observational retrospective study to determine the effect of HHe on CVA and CAD in patients with CRF (defined as creatinine clearance <50 ml/min). One hundred ten male patients were eligible for our study performed at a Veterans Affairs Medical Center. Age range was 36-86 years (median age 67 years). A fasting plasma HC level >15 micromol/l was considered as HHe. Thirty-four patients were on dialysis. Eight patients were postrenal transplantation. Our study results showed that a homocysteine (HC) level greater than 15 micromol/l was an independent predictor of CVA, after adjusting for potential confounders. Adjusted odds ratio (OR) for CVA was 10.9 (CI: 1.8-67.2, p=.01). Although our study results suggest a strong relationship between HHe and CVA, they failed to demonstrate an association between HHe and CAD. There exists a need for larger prospective randomized clinical trials to evaluate the effect of HHe on the incidence of CVA and CAD in patients with CRF.     

Neurobehavioral analysis of developmental iron deficiency in rats

Iron deficiency (ID) in early life alters the course of behavioral and cognitive development in humans, causing decreased physical activity and responsiveness to the environment. The effects of ID on behavior are similar in rats and hypothesized to be related to ID-related impairments in central dopamine pathways. The objective of this study was to examine the association between brain iron measures of dopamine function, and behavioral measures of activity and reactivity. Male and female weanling rats were fed either an iron deficient diet or control diet for 6 weeks. The iron deficient rats showed significantly decreased activity and increased anxiety-like behaviors. Iron deficient rats also showed significant decrements in brain iron content in the corpus striatum, prefrontal cortex, and midbrain and decreases in dopamine receptors and the transporter in the same areas. Multiple regression analysis showed ventral midbrain iron concentration and dopamine D(1) receptor density to be highly associated with exploration and repeated movements, respectively. In addition, the results showed anxiety-like behaviors to be related to prefrontal cortex dopamine transporter and dopamine D(1) receptor densities. We conclude from these analyses that iron concentration in dopamine containing regions and densities of dopamine receptors and the transporter, are significant predictors of measures of activity and reactivity. These observations also strengthen the argument that the Fe-dopamine link is fundamental to understanding biobehavioral difficulties seen in children with ID anemia.     

Extended Indications for Lung Volume Reduction Surgery in Advanced Emphysema

Background. Lung volume reduction surgery has shown early promise as a palliative therapy in severe emphysema. Selection of potential candidates has been based on certain functional and anatomic criteria, and a variety of operative contraindications have been proposed.

Methods. Over 15 months, we performed lung volume reduction surgery in 85 patients selected on the basis of severe hyperinflation with air trapping, diaphragmatic dysfunction, and disease heterogeneity. Patients were not excluded on the basis of severe hypercapnia, steroid dependence, profound pulmonary dysfunction, or inability to complete preoperative rehabilitation.

Results. We observed significant improvements in pulmonary function, exercise capacity, and dyspnea, with an acceptable 30-day perioperative mortality of 7% and actuarial survival of 90% and 83% at 6 and 12 months, respectively. In each “high-risk” group, perioperative mortality, actuarial survival to 1 year, and functional results were equivalent, and in some cases superior, to those in the corresponding “low-risk” patients.

Conclusions. Severe hypercapnia, steroid dependence, profound pulmonary dysfunction, and inability to complete preoperative rehabilitation do not preclude successful lung volume reduction surgery and should not be regarded as absolute exclusionary criteria.     

Regulatory substances produced by lymphocytes

A factor which suppresses DNA synthesis in rat lymph-node cells stimulated with phytohemagglutinin (PHA) and in mouse fibroblasts (L cells) was obtained from the culture supernatant of rat lymph-node cells stimulated with ovalbumin in vivo and rechallenged with the same antigen in vitro. The factor is protein in nature, as evidenced by its sensitivity to trypsin. It is relatively heat stable and its activity is lost after periodate treatment, suggesting that it is glycoprotein. On Sephadex gel filtration, it gives 2 peaks with estimated molecular weights of 80,000 and 160,000–200,000 daltons. Their isoelectric points were estimated as 2.7 and 3.0 by isoelectric focusing analysis. The factor had almost no effect on the synthesis of RNA and protein, but inhibited DNA synthesis completely. This inhibition followed multihit kinetics with a multiplicity estimated as 20–40. The suppressive effect of the factor was reversible when it was removed within 14 h after addition of PHA to cultures of rat lymph-node cells, but became completely irreversible by 30 h. Between 14 and 30 h the effect was partially reversible. These results suggest that the factor acts by inhibiting a process or processes occurring shortly before the initiation of DNA synthesis. They also imply that the factor may play a role as a short-range regulator of immune responses.