Enhanced allograft survival and modulation of T-cell alloreactivity induced by inhibition of MMP/ADAM enzymatic activity.

Recent studies have shown significantly increased expression of matrix metalloproteinases (MMP) and disintegrin-type metalloproteinases (ADAM) during allograft rejection. In this regard, our previous studies have demonstrated contrasting roles for MMP-2 and MMP-9 during allograft rejection: MMP-2-deficiency enhanced allograft survival while MMP-9-deficiency decreased allograft survival. The aim of this study was to determine the effect of broad-spectrum MMP/ADAM inhibition on the pathogenesis of allograft rejection. Toward this, heterotopic BALB/c cardiac allografts were transplanted into C57BL/6 recipients treated with MMP/ADAM inhibitors, GM6001 or doxycycline. Systemic MMP/ADAM inhibition significantly enhanced allograft survival. Functioning allografts recovered from MMP/ADAM inhibitor-treated recipients showed lower cellular infiltration and tissue remodeling than rejected allografts recovered from control recipients. In addition, decreased chemotaxis of CD4+ and CD8+ T cells, B cells and macrophages was observed in vitro in the presence of MMP/ADAM inhibitors. Enhanced T-cell alloreactivity was also observed ex vivo in MMP/ADAM inhibitor-treated recipients and in vitro in the presence of MMP/ADAM inhibitors. These observations were associated with enhanced cytokine, chemokine and growth factor production. These results indicate that MMPs and ADAMs play a critical role in the pathogenesis of allograft rejection and may represent novel therapeutic targets for the treatment and/or prevention of this disease.

Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms.

Fibrosing alveolitis (FA) is characterized by persistent inflammation and elevated production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and interleukin-1 receptor antagonist (IL-1ra) in the lung. Single base variations at position +2018 in the IL-1ra gene (IL-1RN) and position -308 in the TNF-alpha gene (TNF-A) are overrepresented in other chronic inflammatory disease populations. We have tested the hypothesis that predisposition to FA may also be influenced by these polymorphisms by genotyping 88 cases and matched controls from England and 61 cases and 103 unmatched controls from Italy. The rarer allele for IL-1RN and TNF-A was designated allele 2 in each case. For IL-1RN allele 2, in the English group, the relative odds of FA were increased in homozygous subjects by an odds ratio (OR) of 10.2 (95% confidence intervals [CI], 1.26 to 81.4; p = 0.03) and for carriers by an OR of 1.85 (95% CI, 0.94 to 3.63; p = 0.075). In the Italian population, the risk of FA was increased, in IL-1RN allele 2 homozygotes (OR, 2.54; 95% CI, 0.68 to 9.50; p = 0.2) and in carriers (OR 2.40; 95% CI, 1.26 to 4.60; p = 0.008). Carriage of TNF-A allele 2 was also associated with increased risk of FA in the English (OR, 1.85; 95% CI, 0.94 to 3.63; p = 0.075) and Italian (OR, 2.50; 95% CI, 1.14 to 5.47; p = 0.022) populations. These data suggest IL-1RN (+2018) allele 2 and TNF-A (-308) allele 2 confer increased risk of developing FA and, therefore, that unopposed IL-1beta and/or excessive TNF-alpha may play a pathophysiologic role in this condition.

Inflammatory neutrophils retain susceptibility to apoptosis mediated via the Fas death receptor.

Apoptosis and clearance of neutrophils is essential for successful resolution of inflammation. Altered signaling via the Fas receptor could explain the observed prolongation of neutrophil lifespan and associated tissue injury at inflammatory sites. We therefore compared inflammatory neutrophils extracted from joints of rheumatoid arthritis patients, with peripheral blood neutrophils. Inflammatory neutrophils underwent constitutive apoptosis in culture more rapidly than peripheral blood neutrophils; this was not explained by changes in surface expression of Fas or by induction of Fas ligand. Inflammatory neutrophils remained sensitive to Fas-induced death, at levels comparable to those seen in peripheral blood neutrophils. Similarly, granulocyte-macrophage colony-stimulating factor reduced apoptosis but did not abolish signaling via Fas. These data provide evidence for the rate of apoptosis in inflammatory neutrophils being continually modulated by death and survival signals in the inflammatory milieu. This allows for rapid resolution of inflammation as levels of survival factors fall, and suggests new strategies for inducing resolution of inflammation.

Comparison of an age adjusted warfarin loading protocol with empirical dosing and Fennerty's protocol.

AIM: A warfarin loading protocol adjusting doses for age was compared to both Fennerty's protocol (Fenn) and empirical dosing (Emp). METHODS: Patients beginning warfarin were randomised to receive doses according to either the age adjusted (Age) protocol or Fenn. Data were retrospectively collected for patients who had begun warfarin in the previous six months to represent empirical dosing. The study was performed on inpatients being commenced on warfarin for the first time at two teaching hospitals. MAIN OUTCOME MEASURES: Endpoints were time to reach a stable, therapeutic International Normalised Ratio (INR) between 2-3, the number of patients experiencing an INR > or =4 in the first week and the number of patients who had a dose held in the first week. RESULTS: Thirty-five patients were assessed in the Age group, 28 in the Fenn group, and 123 patients for the Emp group. Patients using the Age protocol achieved a stable, therapeutic INR more rapidly than either the Fenn (p=0.003, log rank test) or Emp (p<0.001) group. The Age group had a lower proportion of patients experiencing an INR > or =4 in the first week (p<0.05) as well as a lower proportion having doses held in the first week (p<0.01). There were no differences between Emp and Fenn for any of the endpoints. CONCLUSION: Adjustment of warfarin loading doses for age exhibits clear superiority over the use of Fenn or Emp. This becomes increasingly important as the average age of patients being warfarinised increases, with the recognition that atrial fibrillation requires anticoagulation. Fenn consistently overdosed elderly patients, especially those aged 80 years and older.

Ifosfamide-induced neurotoxicity: a case report and review of the literature.

OBJECTIVE: To review published abstracts, journal articles, and case reports for evidence of ifosfamide-induced neurotoxicity in both adult and pediatric populations. DATA SOURCES: Peer-reviewed journal articles (October 1985 through August 1990) obtained through a computer literature search, with subsequent bibliography scanning. STUDY SELECTION: We identified 34 reports that specifically addressed neurotoxicity related to ifosfamide therapy. By consensus of the authors, 8 of these reports were excluded due to a small study population, duplication of age of data. DATA EXTRACTION: Studies were assessed by the first author and verified by the second author. Several colleagues also contributed to the analysis. DATA ANALYSIS: Risk factors and mechanisms behind this potentially fatal neurotoxic reaction remain speculative and, in some cases, contradictory. The predictive capability of a published nomogram is restricted by differences in dosage regimens and encephalopathic classifications. Currently, the best prevention against neurotoxicity is little or no use of concurrent medications that have central nervous system effects. CONCLUSIONS: Further studies should address the influence of other nephrotoxic agents (e.g., cisplatin, aminoglycosides) on the incidence of ifosfamide-induced neurotoxicity.

Current and investigational therapies for AIDS-associated Mycobacterium avium complex disease.

The epidemiology, pathogenesis, clinical manifestations, and treatment of Mycobacterium avium complex (MAC) infection are reviewed. MAC infection is one of the most common infections in AIDS patients. Its pathogenesis is poorly understood, but it is believed to develop by gastrointestinal colonization followed by systemic invasion. The relatively poor response to treatment may be partly accounted for by the tremendous mycobacterial load present by the time patients develop systemic symptoms. Clinically, MAC infection is difficult to differentiate from the signs and symptoms of AIDS or from other opportunistic infections. Signs and symptoms include fever, malaise, anorexia, night sweats, and weight loss; diarrhea and abdominal pain may also be present. There is no established therapy for MAC infection, although combinations of three to five antimicrobial agents are typically used. There has been consistently poor correlation between in vitro results and in vivo outcomes in the treatment of MAC infection. Currently, the role of treatment is mainly to suppress the progression of infection and to relieve symptoms. Recent in vitro studies and animal studies have revealed possible alternative agents and combinations of agents (e.g., macrolide antibiotics, quinolones, amikacin, cytokines) that may influence therapy of MAC infection. No known therapy for MAC has been shown to prolong survival in AIDS patients, possibly because of the high organism load that exists once patients become symptomatic. Research is needed to find improved methods for earlier detection of MAC infection, determine optimal dosage regimens of current antimycobacterial agents, develop better antimycobacterial drug-delivery systems (e.g., liposomes), and discover new antimicrobials with better activity against MAC and methods of immune modulation that will overcome immune system defects.