Adherence to dietary guidelines and risk of dementia: a prospective cohort study of 94 184 individuals.

AIMS: Recent estimates suggest that 40% of dementia cases could be avoided by treating recognised cardiovascular risk factors such as hypertension, diabetes, smoking and physical inactivity. Whether diet is associated with dementia remains largely unknown. We tested if low adherence to established dietary guidelines is associated with elevated lipids and lipoproteins and with increased risk of Alzheimer's disease and non-Alzheimer's dementia ­ a dementia subtype with a high frequency of cardiovascular risk factors. METHODS: We used the prospective Copenhagen General Population Study including 94 184 individuals with dietary information and free of dementia at baseline. Mean age at study entry was 58 years, and 55% (N = 51 720) were women and 45% (N = 42 464) were men. Adherence to dietary guidelines was grouped into low, intermediate and high adherence based on food frequency questionnaires. Main outcomes were non-Alzheimer's dementia and Alzheimer's disease. RESULTS: Low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and plasma triglyceride levels were higher in individuals with intermediate and low adherence to dietary guidelines compared with individuals with high adherence (all p for trends <0.001). Age and sex-adjusted hazard ratios (HRs) for non-Alzheimer's dementia v. individuals with high adherence were 1.19 (95% confidence interval 0.97­1.46) for intermediate adherence, and 1.54 (1.18­2.00) for low adherence. Corresponding HRs in multivariable-adjusted models including APOE genotype were 1.14 (0.92­1.40) and 1.35 (1.03­1.79). These relationships were not observed in individuals on lipid-lowering therapy. CONCLUSIONS: Low adherence to national dietary guidelines is associated with an atherogenic lipid profile and with increased risk of non-Alzheimer's dementia ­ the subtype of dementia with a high frequency of vascular risk factors. This study suggests that implementation of dietary guidelines associated with an anti-atherogenic lipid profile could be important for prevention of non-Alzheimer's dementia.

The effect of TGF-ß1 polymorphisms on pulmonary disease progression in patients with cystic fibrosis.

BACKGROUND: Transforming Growth Factor-ß1 (TGF-ß1) is a genetic modifier in patients with cystic fibrosis (CF). Several single nucleotide polymorphisms (SNPs) of TGF-ß1 are associated with neutrophilic inflammation, lung fibrosis and loss of pulmonary function. AIM: The aim of this study was to assess the relationship between genetic TGF-ß1 polymorphisms and pulmonary disease progression in CF patients. Furthermore, the effect of TGF-ß1 polymorphisms on inflammatory cytokines in sputum was investigated. METHODS: 56 CF-patients and 62 controls were genotyped for three relevant SNPs in their TGF-ß1 sequence using the SNaPshot® technique. Individual "slopes" in forced expiratory volume in 1 s (FEV1) for all patients were calculated by using documented lung function values of the previous five years. The status of Pseudomonas aeruginosa (Pa) infection was determined. Sputum concentrations of the protease elastase, the serine protease inhibitor elafin and the cytokines IL-1ß, IL-8, IL-6, TNF-α were measured after a standardized sputum induction and processing. RESULTS: The homozygous TT genotype at codon 10 was associated with a lower rate of chronic Pa infection (p < 0.05). The heterozygous GC genotype at codon 25 was associated with lower lung function decline (p < 0.05). Patients with homozygous TT genotype at the promotor SNP showed higher levels of TNF-α (p < 0,05). Higher levels of TGF-ß1 in plasma were associated with a more rapid FEV1 decline over five years (p < 0.05). CONCLUSIONS: Our results suggest that polymorphisms in the TGF-ß1 gene have an effect on lung function decline, Pa infection as well as levels of inflammatory cytokines. Genotyping these polymorphisms could potentially be used to identify CF patients with higher risk of disease progression. TGF-ß1 inhibition could potentially be developed as a new therapeutic option to modulate CF lung disease.

Extracellular 20S proteasome in BAL and serum of patients with alveolar proteinosis.

BACKGROUND AND OBJECTIVES: Pulmonary alveolar proteinosis (PAP) is characterized by alveolar accumulation of surfactant lipoproteins. Proteasomes are involved in the nonlysosomal protein degradation. We hypothesize that enzymatically active proteasome is increased in the alveolar space of PAP. PATIENTS AND METHODS: 31 PAP patients (29 with primary, 2 with secondary form), 14 disease controls (10 with COPD and 4 with emphysema) and 18 healthy controls were studied. 20S Proteasome was measured by ELISA in bronchoalveolar lavage fluid (BALF) and in serum. Enzyme activity of extracellular proteasome (pkat/mg) was measured through fluorogenic substrate cleavage. RESULTS: Proteasome concentration in BAL was higher in PAP patients than in disease controls or healthy subjects (566±420 vs 53±27 vs 60±42ng/ml, respectively, p<0.0001 for both). Serum proteasome levels were higher in PAP patients than in healthy controls (825±712 vs 405±176ng/ml, p=0.018). PAP patients with active disease had higher serum levels than those who achieved remission (1317±1176 vs 439±422ng/ml, p=0.008). Proteasomal enzyme activity was increased in BAL of PAP patients (p<0.05). CONCLUSIONS: The 20S proteasome is increased and active in BAL of patients with PAP. Extracellular proteasome may contribute to the alveolar degradation of accumulated proteins in PAP.

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods.

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods.

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.

Autologous graft-versus-host disease induction in advanced breast cancer: role of peripheral blood progenitor cells.

The purpose of the present study was to investigate the impact of the use of peripheral blood progenitor cells (PBPCs) on the induction of autologous graft-versus-host disease (GVHD) in patients with advanced breast cancer. 14 women with stage IIIB and 36 women with stage IV breast cancer received cyclosporine (CsA) 2.5 mg kg-1 i.v. daily, d 0-28, and interferon-gamma (IFNg) 0.025 mg/m2 s.c. qod, d7-28, following PBPC-T +/- bone marrow transplantation (BMT). Preceding high-dose chemotherapy consisted of cyclophosphamide 6 g/m2 and thiotepa 800 mg/m2. Histologically proven > or = grade II cutaneous GVHD was induced in18/50 (36%) of patients and was independent of the source of haematopoietic support. In vitro studies showed that post-transplant, 76% of patients had developed auto-cytotoxicity against their own pre-transplant PHA-lymphoblasts. A significant correlation between the occurrence of GVHD > or = grade II and cytolysis was observed in the NK cell-line K562 and the T47D breast cancer cell-line. With a median follow-up of 2(1/2) years, the overall survival (OS) is 58%, the disease-free survival (DFS) 26%, both independent of the development of GVHD and similar to what has been observed in other studies on high-dose chemotherapy in advanced breast cancer. It therefore remains unclear whether the induction of autologous GVHD with the occurrence of auto-cytotoxic lymphocytes can result in an anti-tumour effect in this group of patients.

A behavioral treatment for sitting and standing intolerance in a patient with chronic low back pain.

This study reports on the effectiveness of an individualized shaping treatment program for sitting and standing intolerance in a patient with chronic low back pain following a laminectomy for removal of an intradural tumor. Functional assessment of sitting and standing tolerance, observation of pain behaviors, and a self-report measure regarding the pain experience were carried out during baseline, treatment, posttreatment, and at a 6-month follow-up. By the end of the 6-week inpatient treatment, the patient was able to stand still for 25 min and to sit for 15 min. The overall pain behavior diminished significantly. These findings underscore the importance of relatively simple and cost-effective individualized behavioral programs for chronic pain patients.

Some properties of isolated mitochondrial ATPase from salmon heart.

A soluble Mg-dependent ATPase, similar to the mitochondrial ATPase from beef heart, has been isolated from heart mitochondria of salmon (Salmo salar). The salmon heart ATPase has 5 subunits with molecular weights similar to the beef heart enzyme, but the Stoke's radius of the intact salmon enzyme is larger. The salmon heart ATPase is less temperature labile than the beef heart enzyme. The salmon heart ATPase is strongly inhibited by ADP, and the inhibition is highly temperature dependent. The ITPase activity is also inhibited by IDP (Ki = 180 micron). 2,4-Dinitrophenol in small concentrations stimulates the ITPase activity as well as the ATPase activity of the "washed" salmon heart enzyme. However, in an enzyme preparation which had been freed of most of the bound nucleotides by dialysis in the presence of glycerol (Roveri et al., 1980) the ITPase activity is not stimulated by 2,4-dinitrophenol.

ATPase of bovine heart mitochondria. Modulation of ITPase activity by ATP, ADP, acetyl ATP and acetyl AMP.

(1) Mitochondrial ATPase (F1) is influenced by specific nucleotides in its kinetic behavior towards its substrates. In this work, initial hydrolysis rates, as well as continuous reaction progress, were measured by recording proton production (equivalent to triphosphate hydrolysis). (2) After preincubation with ATP, F1 hydrolyzes MgITP partly as if it were MgATP, with respect to temperature dependence and 2,4-dinitrophenol inhibition/stimulation. (3) Acetyl ATP is a competitive inhibitor versus ATP on the F1-ATPase. With F1 which has been freed of ambient ATP by repeated precipitations with ammonium sulfate the Ki of acetyl ATP is 400 nM. (4) F1-ATPase which was depleted of bound nucleotides in the presence of glycerol (Garret, N.E. and Penefsky, H.S. (1975) J. Biol. Chem. 250, 6640-6647) was preincubated with ADP and acetyl ATP. These preparations were assayed for hydrolytic activity with MgITP as substrate. Compared to a nonpreincubated control enzyme, the hydrolysis with these preparations was first stimulated, then inhibited. This stimulation/inhibition effect is most pronounced at 10 degrees C, but is also observed at 20 degrees C. (5) When nucleotide-depleted enzyme is preincubated with acetyl AMP, its ability to hydrolyze MgITP slowly decreases to approx. 50% after 60 min. This effect is reversed by further preincubation with acetyl ATP. It is speculated that under appropriate conditions AMP may exist or arise in a buried position on F1-ATPase, and act there as an inhibitor of MgITP hydrolysis.