Extrapyramidal symptoms related to adjunctive nizatidine therapy in an adolescent receiving quetiapine and paroxetine

Weight gain is a serious problem with recently introduced atypical antipsychotic agents. Nizatidine, a histamine2 (H2)-receptor antagonist, may help reduce this weight gain. To our knowledge, no adverse effects have been reported when nizatidine is given at recommended doses with atypical antipyschotic agents. We describe, however, an adolescent who was receiving quetiapine and paroxetine for schizophrenia and depression, and developed extrapyramidal symptoms (EPS; parkinsonism and akathisia) after taking nizatidine for weight loss. Based on a report of another patient who developed EPS after taking higher-than-recommended doses of nizatidine, we reviewed the literature on treatment with H2-receptor antagonists for weight gain and on central nervous system adverse effects of nizatidine. Nizatidine may be effective for reducing weight gain associated with both medical and psychiatric conditions. Its safety profile is usually benign, although some patients may develop serious adverse effects, such as EPS and delirium. Therefore, the drug is recommended for short-term management of weight gain associated with atypical antipsychotic agents. Patients receiving nizatidine therapy should be monitored closely for development of EPS, particularly when high doses are prescribed.     

Breast cancer metastatic to abdomen and pelvis: role of surgical resection

OBJECTIVE: The purpose of this study was to describe the characteristics and outcome of women with metastatic breast cancer to the abdomen and pelvis, and to assess the role of surgical resection of abdominal and pelvic metastasis in this disease. METHODS: We retrospectively reviewed the medical records of 59 women with documented metastatic breast cancer to the abdomen or pelvis who had exploratory surgery by the Gynecology Service between 1986 and 2001. RESULTS: Exploratory surgery was performed a median of 5 years (range, 0-25 years) after initial diagnosis of breast cancer. Median survival from diagnosis of abdominal disease was 23 months, and 5-year survival was 24%. Survival was 36 months for optimally debulked patients (<2 cm of residual disease) and 20 months for suboptimally debulked patients (P = 0.07). Patients diagnosed 5 or more years after initial breast cancer diagnosis had a median survival of 36 months versus 17 months if diagnosed earlier (P < 0.01). On multivariate analysis the time to recurrence of breast cancer in the abdomen and optimal debulking were both significant variables. Hazard ratio for dying of disease if recurring before 5 years was 2.7 (CI 1.45-5.03) [P < 0.01]. Hazard ratio for dying of disease if suboptimal debulking was achieved was 2.14 (CI 1.13-4.02) [P = 0.02]. CONCLUSIONS: The disease pattern of metastatic breast carcinoma to the abdomen and pelvis does not appear to effect survival. Survival in patients where optimal debulking is achieved and in those recurring late is improved. Surgical resection of metachronous metastatic breast cancer to the abdomen and pelvis may be an important component of the management of this disease and should be considered in candidate patients.     

Major hepatectomy at interval debulking for stage IV ovarian carcinoma: a case report

BACKGROUND: Previous studies have reported the results of hepatic resection for metastatic ovarian cancer at the time of primary cytoreductive surgery and at the time of recurrence. CASE: We present the first case of major hepatic resection performed at the time of interval cytoreduction for metastatic ovarian carcinoma. CONCLUSION: Interval debulking with hepatic resection may be a promising approach for patients left with bulky parenchymal liver metastasis after primary cytoreductive surgery.     

The effect of aspirin on the periodontal parameter bleeding on probing

BACKGROUND: The absence or presence of bleeding on probing (BOP) is a sign of periodontal health or disease, but the presence of BOP is not an accurate predictor of disease progression. Aspirin is increasingly used in the prevention of cerebrovascular and cardiovascular diseases and is a non-disease factor that may modify bleeding indices given its antithrombolytic activity. The purpose of this double-blind placebo-controlled randomized clinical trial was to study the effect of short-term daily aspirin ingestion on the clinical parameter BOP. METHODS: A total of 46 periodontally healthy subjects were included in this study: 16 received placebo, 15 low-dose aspirin (81 mg), and 15 regular dose (325 mg) aspirin. Clinical parameters assessed included plaque index, periodontal probing depth, and BOP using an automated pressure-sensitive probe. Measurements were recorded before and after 7-day exposure to placebo and aspirin regimens. RESULTS: A statistically significant difference in BOP was found in patients with > or = 20% of bleeding sites during the visit prior to placebo or aspirin exposure (n = 11). The group treated with 325 mg aspirin exhibited a moderate yet statistically significant increase in BOP (12.4%) compared to the placebo group (there was no significant difference between the 81 mg aspirin group and placebo). The tendency to bleed was not statistically significant in the group which exhibited <20% (n = 35) of bleeding sites during the visit prior to exposure. CONCLUSION: Aspirin intake of 325 mg daily for 7 days moderately increased the appearance of bleeding on probing in a population that had > or = 20% BOP sites.     

Enteral nutritional supplementation prevents mesenteric lymph node T-cell suppression in burn injury

OBJECTIVE: To determine the effects of an immune-enhancing diet supplemented with glutamine, arginine, fish oil, and dietary nucleotides on mesenteric lymph node T-cell functional disturbances encountered after burn injury in rats. DESIGN: A prospective animal study. SETTING: University medical center research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Rats received a 30%, total body surface, full-thickness burn. Burn-injury rats received the IMPACT diet supplemented with glutamine, arginine, fish oil, and nucleotides or arginine, fish oil, and nucleotides, or an isocaloric/isonitrogenous diet without supplementation with glutamine, arginine, fish oil, or nucleotides. MEASUREMENTS AND MAIN RESULTS: Two days after injury, we found a significant decrease in the proliferation and interleukin-2 production by mesenteric lymph node T cells derived from rats fed on conventional chow compared with sham rats. The burn-related suppression of mesenteric lymph node T-cell proliferation and interleukin-2 production was prevented when the rats were fed on a high-protein diet rich in glutamine, arginine, fish oil, and nucleotides. We found that the immunostimulatory effects of the enriched diet are dependent on the presence of glutamine, arginine, fish oil, and nucleotides as feeding of rats on the isocaloric/isonitrogenous diet deficient in glutamine, arginine, fish oil, and nucleotides did not prevent the burn-related suppression of mesenteric lymph node T-cell dysfunction. Finally, our studies suggested that immunostimulatory effects of the diet are mediated by prostaglandin E(2) regulation of T-cell activation signaling molecule P59fyn. CONCLUSION: These results suggest that a diet rich in arginine, fish oil, and nucleotides, with and without glutamine, can effectively prevent T-cell dysfunction encountered after burn injury.     

Differential requirements for CTL generation by novel immunostimulants: APC tropism,use of the TAP-independent processing pathway,and dependency on CD80/CD86 costimulation

A major drawback of subunit vaccines is their inability to generate cytolytic T lymphocytes (CTL), a deficit attributed to segregation of the class I and class II antigen-processing pathways. We sought to understand processes involved in CTL induction by three proprietary adjuvants: Tomatine, PROVAX, and a synthesized glycolipid (Glc-N-(8/16), Glycolipid). We used in vivo models to investigate antigen uptake, macrophage involvement, TAP-independent processing, and costimulatory molecule dependencies. Glycolipid required splenic and lymph node macrophages, whereas Tomatine generated CTL independently of either macrophage population. In contrast, PROVAX showed partial macrophage requirements. Immunized TAP knockout mice revealed that ovalbumin (OVA)-Tomatine and OVA-PROVAX, but not OVA-Glycolipid, generate class I-peptide complexes. All three immunostimulants also elicited CD86-dependent TH1 cytokine responses.     

Sulfonylureas rapidly cross phospholipid bilayer membranes by a free-diffusion mechanism

Because sulfonylureas directly activate the exocytotic machinery, we were interested in the extent to which these compounds penetrate the beta-cell plasma membrane and the underlying molecular mechanism(s). We now provide evidence that sulfonylureas cross phospholipid bilayer membranes rapidly and effectively by a free-diffusion mechanism. Two sulfonylurea compounds investigated by 1H nuclear magnetic resonance spectroscopy, glibenclamide and tolbutamide, were found to incorporate into phospholipid bilayers, with the ionizable sulfonamide exposed to the aqueous interface and its apparent dissociation constant (pKa) increased to approximately 7.0. Diffusion of weak amphiphilic acids across membranes is associated with a measurable change in pH. Thus, by using a fluorescence-based pH assay, we could investigate the diffusion of sulfonylurea compounds across phospholipid bilayer membranes. A fluorescent pH indicator (pyranin or [2',7'-bis (2-carboxyethyl)-5(6)-carboxyfluorescein] [BCECF]) was trapped in egg phosphatidylcholine vesicles. Addition of glibenclamide decreased internal pH (pHin), and addition of albumin reversed this drop by 50%. With the same amount of tolbutamide, the decrease in pHin was much smaller, primarily because of the lower partitioning of tolbutamide into phospholipid bilayers. Using similar protocols, we also demonstrated diffusion by the same mechanism across the beta-cell plasma membrane. Thus, we now provide a molecular mechanism by which sulfonylureas can penetrate the plasma membrane and reach intracellular sites regulating exocytosis.     

Extracellular domain determinants of LET-23 (EGF) receptor tyrosine kinase activity in Caenorhabditis elegans

Negative regulation of ErbB/EGFR signalling pathways is important for normal development and the prevention of cancer. In a genetic screen to uncover mechanisms that negatively regulate ErbB signalling in Caenorhabditis elegans, we isolated a second-site mutation (sy621) that promotes the activity of a gain-of-function allele (sa62gf) of the let-23 (EGF) receptor tyrosine kinase. We show that activation by the sa62 mutation (C359Y) likely results from a break in the conserved disulphide-bonded eighth module at the junction of CR1 and L2. The sy621 mutation causes a G270E change in the third disulphide-bonded module of CR1, and causes no phenotype on its own, but cooperates with the sa62 mutation to promote receptor activity. Although both sa62 single- and double-mutant receptors can function in the absence of ligand, they can be further activated by ligand. Our results support the current model for ligand-induced dimerization based on the recent crystal structures of HER3 and the EGFR, and provide more evidence for the generation of distinctly activated ErbB family members through mutation.     

Positive surgical margins and ipsilateral breast tumor recurrence predict disease-specific survival after breast-conserving therapy

BACKGROUND: The current study identified determinants of systemic recurrence and disease-specific survival (DSS) in patients with early-stage breast carcinoma treated with breast-conserving surgery and radiation therapy (breast-conserving therapy, or BCT). METHODS: The study population consisted of 1,043 consecutive women with Stages I or II breast carcinoma who underwent BCT between 1970 and 1994. Clinical and pathologic characteristics evaluated included age, tumor size, tumor grade, estrogen and progesterone receptor status, surgical margins, axillary lymph node involvement, and use of adjuvant therapy. RESULTS: At a median follow-up time of 8.4 years, 127 patients (12%) had developed an ipsilateral breast tumor recurrence (IBTR), and 184 patients (18%) had developed a systemic recurrence. On multivariate logistic regression analysis, tumor size greater than 2 cm, positive lymph nodes, lack of adjuvant tamoxifen therapy, and positive margins (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.1-12.3; P = 0.034) were predictors of systemic recurrence. When IBTR was added into the model, adjuvant therapy and surgical margins were not independent predictors; however, IBTR was an independent predictor of systemic recurrence (IBTR vs. no IBTR; OR, 6.2; 95% CI, 3.1-12.3; P < 0.001). The 10 year DSS rate after BCT was 87%. On multivariate Cox proportional hazards model analysis, the following factors were independent predictors of poor DSS: tumor size greater than 2 cm (vs. < or = 2 cm; relative risk [RR], 2.3; 95% CI, 1.2-4.3; P = 0.010), negative progesterone receptor status (vs. positive; RR, 2.7; 95% CI, 1.4-5.1; P = 0.003), positive margins (vs. negative; RR, 3.9; 95% CI, 1.4-11.5; P = 0.011), and IBTR (vs. no IBTR; RR, 5.5; 95% CI, 2.8-11.0; P < 0.001). CONCLUSIONS: Positive surgical margins and IBTR are predictors of systemic recurrence and disease-specific survival after BCT. Aggressive local therapy is necessary to ensure adequate surgical margins and to minimize IBTR.