Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study

BACKGROUND AND OBJECTIVES: Data suggest that atorvastatin may be nephroprotective. This subanalysis of the Treating to New Targets study investigated how intensive lipid lowering with 80 mg of atorvastatin affects renal function when compared with 10 mg in patients with coronary heart disease. DESIGN, SETTING, PARTICIPANTS, ; MEASUREMENTS: A total of 10,001 patients with coronary heart disease and LDL cholesterol levels of <130 mg/dl were randomly assigned to double-blind therapy with 10 or 80 mg/d atorvastatin. Estimated GFR using the Modification of Diet in Renal Disease equation was compared at baseline and at the end of follow-up in 9656 participants with complete renal data. RESULTS: Mean estimated GFR at baseline was 65.6 +/- 11.4 ml/min per 1.73 m2 in the 10-mg group and 65.0 +/- 11.2 ml/min per 1.73 m2 in the 80-mg group. At the end of follow-up (median time to final creatinine measurement 59.5 months), mean change in estimated GFR showed an increase of 3.5 +/- 0.14 ml/min per 1.73 m2 with 10 mg and 5.2 +/- 0.14 ml/min per 1.73 m2 with 80 mg (P < 0.0001 for treatment difference). In the 80-mg arm, estimated GFR improved to > or = 60 ml/min per 1.73 m2 in significantly more patients and declined to < 60 ml/min per 1.73 m2 in significantly fewer patients than in the 10-mg arm. CONCLUSIONS: The expected 5-yr decline in renal function was not observed. Estimated GFR improved in both treatment groups but was significantly greater with 80 mg than with 10 mg, suggesting this benefit may be dosage related.

Macrocyclic chelator-coupled gastrin-based radiopharmaceuticals for targeting of gastrin receptor-expressing tumours

PURPOSE: Diethylenetriamine-pentaacetic acid (DTPA)-coupled minigastrins are unsuitable for therapeutic application with the available beta-emitting radiometals due to low complex stability. Low tumour-to-kidney ratio of the known radiopharmaceuticals is further limiting their potency. We used macrocyclic chelators for coupling to increase complex stability, modified the peptide sequence to enhance radiolytic stability and studied tumour-to-kidney ratio and metabolic stability using (111)In-labelled derivatives. METHODS: Gastrin derivatives with decreasing numbers of glutamic acids were synthesised using (111)In as surrogate for therapeutic radiometals for in vitro and in vivo studies. Gastrin receptor affinities of the (nat)In-metallated compounds were determined by receptor autoradiography using (125)I-CCK as radioligand. Internalisation was evaluated in AR4-2J cells. Enzymatic stability was determined by incubating the (111)In-labelled peptides in human serum. Biodistribution was performed in AR4-2J-bearing Lewis rats. RESULTS: IC(50) values of the (nat)In-metallated gastrin derivatives vary between 1.2 and 4.8 nmol/L for all methionine-containing derivatives. Replacement of methionine by norleucine, isoleucine, methionine-sulfoxide and methionine-sulfone resulted in significant decrease of receptor affinity (IC(50) between 9.9 and 1,195 nmol/L). All cholecystokinin receptor affinities were >100 nmol/L. All (111)In-labelled radiopeptides showed receptor-specific internalisation. Serum mean-life times varied between 2.0 and 72.6 h, positively correlating with the number of Glu residues. All (111)In-labelled macrocyclic chelator conjugates showed higher tumour-to-kidney ratios after 24 h (0.37-0.99) compared to (111)In-DTPA-minigastrin 0 (0.05). Tumour wash out between 4 and 24 h was low. Imaging studies confirmed receptor-specific blocking of the tumour uptake. CONCLUSIONS: Reducing the number of glutamates increased tumour-to-kidney ratio but resulted in lower metabolic stability. The properties of the macrocyclic chelator-bearing derivatives make them potentially suitable for clinical purposes.

The blood-central nervous system barriers actively control immune cell entry into the central nervous system

Before entering the central nervous system (CNS) immune cells have to penetrate any one of its barriers, namely either the endothelial blood-brain barrier, the epithelial blood-cerebrospinal fluid barrier or the tanycytic barrier around the circumventricular organs, all of which maintain homeostasis within the CNS. The presence of these barriers in combination with the lack of lymphatic vessels and the absence of classical MHC-positive antigen presenting cells characterizes the CNS as an immunologically privileged site. In multiple sclerosis a large number of inflammatory cells gains access to the CNS parenchyma. Studies performed in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis, have enabled us to understand some of the molecular mechanisms involved in immune cell entry into the CNS. In particular, the realization that /alpha4-integrins play a predominant role in leukocyte trafficking to the CNS has led to the development of a novel drug for the treatment of relapsing-remitting multiple sclerosis, which targets /alpha4-integrin mediated immune cell migration to the CNS. At the same time, the involvement of other adhesion and signalling molecules in this process remains to be investigated and novel molecules contributing to immune cell entry into the CNS are still being identified. The entire process of immune cell trafficking into the CNS is strictly controlled by the brain barriers not only under physiological conditions but also during neuroinflammation, when some barrier properties are lost. Thus, immune cell entry into the CNS critically depends on the unique characteristics of the brain barriers maintaining CNS homeostasis.

Overexpression of lymphotoxin in T cells induces fulminant thymic involution

Activated lymphocytes and lymphoid-tissue inducer cells express lymphotoxins (LTs), which are essential for the organogenesis and maintenance of lymphoreticular microenvironments. Here we describe that T-cell-restricted overexpression of LT induces fulminant thymic involution. This phenotype was prevented by ablation of the LT receptors tumor necrosis factor receptor (TNFR) 1 or LT beta receptor (LTbetaR), representing two non-redundant pathways. Multiple lines of transgenic Ltalphabeta and Ltalpha mice show such a phenotype, which was not observed on overexpression of LTbeta alone. Reciprocal bone marrow transfers between LT-overexpressing and receptor-ablated mice show that involution was not due to a T cell-autonomous defect but was triggered by TNFR1 and LTbetaR signaling to radioresistant stromal cells. Thymic involution was partially prevented by the removal of one allele of LTbetaR but not of TNFR1, establishing a hierarchy in these signaling events. Infection with the lymphocytic choriomeningitis virus triggered a similar thymic pathology in wt, but not in Tnfr1(-/-) mice. These mice displayed elevated TNFalpha in both thymus and plasma, as well as increased LTs on both CD8(+) and CD4(-)CD8(-) thymocytes. These findings suggest that enhanced T cell-derived LT expression helps to control the physiological size of the thymic stroma and accelerates its involution via TNFR1/LTbetaR signaling in pathological conditions and possibly also in normal aging.

Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism

Chronic ethanol consumption is a strong risk factor for the development of certain types of cancer including those of the upper aerodigestive tract, the liver, the large intestine and the female breast. Multiple mechanisms are involved in alcohol-mediated carcinogenesis. Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest. AA is toxic, mutagenic and carcinogenic in animal experiments. AA binds to DNA and forms carcinogenic adducts. Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk. Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form. This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol. When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted. In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2. In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast. These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis.