Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis

The success of agents that inhibit tumor necrosis factor (TNF), such as infliximab, adalimumab and etanercept, has led to a desire for orally available small molecules that have a better safety profile and are less costly to produce than current agents. One target for anti-TNF therapy that is currently under investigation is TNF-converting enzyme, which promotes the release of soluble TNF from its membrane-bound precursor. Inhibitors of this enzyme with drug-like properties have been made and tested in the clinic. These inhibitors include TMI-005 and BMS-561392, both of which have entered into phase II clinical trials. This article summarizes preclinical and clinical findings regarding the use of inhibitors of TNF-converting enzyme for the treatment of rheumatoid arthritis.     

Relationships Between Respiratory Symptoms and FEV<Subscript>1</Subscript> in Men and Women with Normal Lung Function: The Korean Health and Genome Study

Although the prevalence of chronic obstructive pulmonary disease (COPD) and its relationship with respiratory symptoms are well documented, few studies have focused on individuals with normal lung function, particularly in developed regions of Asia. The purpose of this report is to examine the relationship between respiratory symptoms and FEV₁ in a population-based sample of Korean men and women with normal lung function. Subjects comprised 7518 individuals aged 40–69 years without airflow obstruction based on spirometric testing and in the absence of a medical history of pulmonary disease. Respiratory symptoms included chronic cough, chronic phlegm, wheezing, and shortness of breath. In men, the age-adjusted mean FEV₁ was lower by 165 ml in smokers and 133 ml in nonsmokers in the presence versus the absence of wheezing (p < 0.05). While walking at a usual pace, FEV₁ in smoking men was 210 ml lower in the presence versus the absence of shortness of breath (p < 0.05). Among nonsmoking men, overall shortness of breath and shortness of breath while walking uphill were associated with a lower FEV₁ by 56 and 80 ml, respectively) versus those who reported having no shortness of breath (p < 0.05). Respiratory symptoms were unrelated to FEV₁ in women smokers, although only 3.5% smoked cigarettes. In nonsmoking women, FEV₁ was lower by an average of 89 ml in the presence versus the absence of wheezing (p < 0.001). Nonsmoking women also had a lower FEV₁ in the presence of shortness of breath (overall, while at rest, and while walking uphill or at a usual pace, p < 0.001). Our findings suggest that respiratory symptoms are associated with a lower FEV₁ in men and nonsmoking women with normal lung function. Whether respiratory symptoms can be used to identify individuals at risk for developing COPD needs further study.     

Variations in the Risk for Cerebrovascular Events after Kidney Transplant Compared with Experience on the Waiting List and after Graft Failure

Background and objectives: This study examined the risks, predictors, and mortality implications of cerebrovascular disease events after kidney transplantation in a national cohort.Design, setting, participants, & measurements: This analysis used United States Renal Data System registry data to study retrospectively Medicare-insured kidney transplant candidates (n = 51,504), recipients (n = 29,614), and recipients with allograft failure (n = 2954) in 1995 through 2002. New-onset cerebrovascular disease events including ischemic stroke, hemorrhagic stroke, and transient ischemic attacks were ascertained from billing records, and participants were followed until Medicare-end or December 31, 2002. Multivariable survival analysis was used to compare cerebrovascular disease event incidence and risk profiles among the study samples.Results: The cumulative, 3-yr incidence of de novo cerebrovascular disease events after transplantation was 6.8% and was lower than adjusted 3-yr estimates of 11.8% on the waiting list and 11.2% after graft loss. In time-dependent regression, transplantation predicted a 34% reduction in subsequent, overall cerebrovascular disease events risk compared with remaining on the waiting list, whereas risk for cerebrovascular disease events increased >150% after graft failure. Similar relationships with transplantation and graft loss were observed for each type of cerebrovascular disease event. Smoking was a potentially preventable correlate of posttransplantation cerebrovascular disease events. Women were not protected. All forms of cerebrovascular disease event diagnoses after transplantation predicted increased mortality.Conclusions: Along with known benefits for cardiac complications, transplantation with sustained graft function seems to reduce risk for vascular disease events involving the cerebral circulation.The risk for cardiovascular disease, broadly categorized as the leading cause of morbidity and mortality among patients with renal failure (1), seems to improve with kidney transplantation. Lower rates of cardiac death (2) and specific cardiac complications including myocardial infarction (3,4), congestive heart failure (5), and atrial fibrillation (6) have been reported among transplant recipients compared with transplant candidates on the waiting list; however, less is known about the epidemiology of cerebrovascular disease events (CVE) in ESRD or the potential for modification of CVE risk with transplantation. Whereas an analysis of American dialysis patients tracked in the Dialysis Morbidity and Mortality cohort of the United States Renal Data System (USRDS) found that kidney transplantation was associated with markedly reduced risk for stroke compared with dialysis (7), lack of information on waiting list membership prevents distinction of the benefits of transplantation from selection bias as a result of characteristics conferring transplant candidacy.Single-center studies of transplant recipients have illustrated the adverse mortality implications of posttransplantation CVE (8–10), but small sample sizes and consequently few observed events limit the precision of estimated disease frequencies and the statistical power for inferences on clinical correlates. Counts of observed cases of CVE in published studies have ranged from 19 (4.7%) of 402 prevalent diagnoses in a cross-sectional study of Spanish transplant patients (8) to 48 and 54 events among variably followed cohorts of 922 and 675 American transplant recipients (9,10), respectively. With respect to CVE types, the study of prevalent CVE among Spanish recipients identified seven (37%) of 19 diagnoses as hemorrhagic, but published cohort studies after transplantation have either not included hemorrhagic events in the outcome definition (10) or not distinguished CVE types in results reporting (9). None of these studies considered risk before transplantation or after allograft failure.To advance understanding of the risks and predictors of CVE associated with kidney transplantation, we performed a retrospective study of ischemic stroke, hemorrhagic stroke, and transient ischemic attacks (TIA) among a large cohort of recent kidney transplant recipients recorded in the USRDS. We aimed to describe the incidence, clinical correlates, and mortality implications of new-onset events. We also compared variations in CVE incidence and risk profiles among transplant candidates and among recipients after allograft failure, with attention to risk predicted by time-dependent transitions from waiting list to transplantation and from transplantation to graft loss.     

Transient leukemoid proliferation of the cytogenetically unbalanced +21 cell line of a constitutional mosaic boy

A newborn without any signs of Down's syndrome was found to have an acute proliferation that remitted without drug therapy. Chromosomal analysis of blood, bone marrow, and skin cells revealed that the child was a constitutional mosaic with normal cells and a low number of cells in which one no. 21 chromosome was replaced by a probably isochromosome for the no. 21 long arm: 46,XY/46,XY,i(21q). The abnormal cell line of the mosaic appeared to be selectively involved in this proliferation.     

Hepatic covalent adduct formation with zomepirac in the CD26-deficient mouse

BACKGROUND AND AIMS: Zomepirac (ZP), a non-steroidal anti-inflammatory drug (NSAID), has been reported to cause immune-mediated liver injury. In vivo, ZP is metabolized to a chemically reactive acyl glucuronide conjugate (ZAG) which can undergo covalent adduct formation with proteins. Such acyl glucuronide-derived drug-protein adducts may be important in the development of immune and toxic responses caused by NSAID. We have shown using immunoabsorptions that the 110 kDa CD26 (dipeptidyl peptidase IV) is one of the hepatic target proteins for covalent modification by ZAG. In the present study, a CD26-deficient mouse strain was used to examine protein targets for covalent modification by ZP/metabolites in the liver. METHODS AND RESULTS: The CD26-deficient phenotype was confirmed by immunohistochemistry, flow cytometry analysis, RT-PCR, enzyme assay and immunoblotting. Moreover, by using monoclonal antibody immunoblots, CD26 was not detected in the livers of ZP-treated CD26-deficient mice. Immunoblots using a polyclonal antiserum to ZP on liver from ZP-treated mice showed three major sizes of protein bands, in the 70, 110 and 140 kDa regions. Most, but not all, of the anti-ZP immunoreactivity in the 110 kDa region was absent from ZP-treated CD26-deficient mice. CONCLUSION: These data definitively showed that CD26 was a component of ZP-modified proteins in vivo. In addition, the data suggested that at least one other protein of approximately 110 kDa was modified by covalent adduct formation with ZAG.     

The scintigraphic characteristics of ventricular pre-excitation through Mahaim fibers with the use of phase analysis

The phase image pattern of blood pool scintigrams was blindly assessed in 11 patients exhibiting conduction through Mahaim pathways, including 6 nodoventricular and 5 fasciculoventricular. These patterns were compared with the phase image findings in normal subjects, patients with left and right bundle branch block in the absence of pre-excitation and patients with pre-excitation through atrioventricular (AV) connections. In all patients with a Mahaim pathway, the site of earliest phase angle was septal or paraseptal. Phase progression was asymmetric and the pre-excited ventricle demonstrated the earliest mean ventricular phase angle in 10 of 11 patients. This pattern, and the associated ventricular phase difference, appeared to vary from that in normal subjects and in those with a septal AV connection, in whom phase progression is generally symmetric. Scintigraphic phase analysis provided localizing information and presented patterns consistent with Mahaim pathways. Although not able to differentiate among Mahaim pathway subtypes, these phase patterns differed from those in normal subjects, those with right and left lateral free wall pathways and most patients with a septal AV pathway. However, the phase pattern of patients with a Mahaim pathway may not differ from that of patients with a septal AV connection displaying an asymmetric pattern of phase progression, or those with left and right bundle branch block in the absence of pre-excitation. Objective, yet imperfect phase measurements supported these differences. Such image findings may complement the often complex electrophysiologic evaluation of patients presenting with pre-excitation.     

Spontaneous coronary artery dissection in a woman receiving 5-fluorouracil--a case report

A 39-year-old woman with cervical cancer treated with pelvic radiation therapy and 5-fluorouracil (5-FU) was hospitalized for dehydration and intractable vomiting. She developed an acute ST-elevation myocardial infarction (MI) that extended electrocardiographically after thrombolytic therapy. Coronary angiography demonstrated a completely occluded left anterior descending (LAD) artery with extensive coronary dissection that was treated successfully with stenting. The authors discuss several factors that may have contributed to the spontaneous coronary artery dissection (SCAD) including chemotherapy-induced vasospasm, hemodynamic stress of vomiting, and hormonal changes associated with pelvic radiation.     

Dietary magnesium intake and the future risk of coronary heart disease (the Honolulu Heart Program)

Magnesium (Mg) deficiency is believed to have adverse cardiovascular consequences that are broad and complex, although an association between dietary Mg intake and the risk of coronary heart disease (CHD) has not been clearly identified. The purpose of this study is to examine the relation between dietary Mg intake and future risk of CHD. Reported findings are based on dietary Mg intake in 7,172 men in the Honolulu Heart Program. Intake of Mg was recorded at baseline examinations that took place from 1965 to 1968 when the men were aged 45 to 68 years. In 30 years of follow-up, 1,431 incident cases of CHD were identified. Within 15 years after dietary assessment, the age-adjusted incidence decreased significantly from 7.3 to 4.0 per 1,000 person-years in the lowest (50.3 to 186 mg/day) versus highest (340 to 1,183 mg/day) quintiles of Mg intake (p <0.001). When adjustments were made for age and other nutrients (singly or combined), there was a 1.7- to 2.1-fold excess in the risk of CHD in the lowest versus highest quintiles (p <0.001). The excess risk ranged from 1.5- to 1.8-fold after further adjustment for other cardiovascular risk factors (p <0.05). Associations between dietary Mg and coronary events occurring after 15 years of follow-up were modest. We conclude that the intake of dietary Mg is associated with a reduced risk of CHD. Whether increases in dietary Mg intake can alter the future risk of disease warrants further study.