Alternative end joining during switch recombination in patients with ataxia-telangiectasia.

Ataxia-Telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic diseases with similar cellular phenotypes that are caused by mutations in the recently described ATM (encoding ATM) and NBS1 (encoding p95) genes, respectively. Both disorders are accompanied by immunodeficiency in a majority of patients, but the mechanism involved has as yet not been established. We demonstrate that in cells from A-T patients, the switch (S) recombination junctions are aberrant and characterized by a strong dependence on short sequence homologies and devoid of normally occurring mutations around the breakpoint.

Effect of the (C825T) Gbeta(3) polymorphism on adrenoceptor-mediated lipolysis in human fat cells.

A common Gbeta(3) gene polymorphism (C825T) influences G protein receptor-mediated signal transduction. We investigated whether this polymorphism influences lipolysis in isolated subcutaneous fat cells from 114 healthy obese subjects. The Gbeta(3) protein content was markedly decreased in adipocytes of TT carriers, but the alternatively spliced short form of Gbeta(3) previously shown in platelets of 825T carriers was not detected.

Combined endothelin receptor blockade evokes enhanced vasodilatation in patients with atherosclerosis.

Endothelin (ET)-1 causes vasoconstriction via ET(A) and ET(B) receptors located on vascular smooth muscle cells and vasodilatation via ET(B) receptors on endothelial cells. Studies in vitro indicate an upregulation of ET(B) receptors in atherosclerosis. The present study investigated the vascular effects evoked by endogenous ET-1 in atherosclerotic patients.

Effects of tiagabine and diazepam on operant ethanol self-administration in the rat.

Objective: Benzodiazepines (BDZ) are widely used in the treatment of anxiety and ethanol withdrawal. It has been suggested that this class of compounds may increase the reinforcing value of ethanol; however, the literature is scarce. Tiagabine has recently been introduced into clinical use as an anti-epileptic drug.

Insulin resistance in type 2 diabetes: role of fatty acids.

Insulin resistance is one of the key factors responsible for hyperglycaemia in type 2 diabetes and can result in a number of metabolic abnormalities associated with cardiovascular disease (insulin resistance syndrome), even in the absence of overt diabetes. The mechanisms involved in the development of insulin resistance are multifactorial and are only partly understood, but increased availability of free fatty acids (FFAs) is of particular importance for the liver and skeletal muscle. The role of FFAs in type 2 diabetes is most evident in obese patients who have several abnormalities in FFA metabolism.

Human cytomegalovirus (HCMV)-infected endothelial cells and macrophages are less susceptible to natural killer lysis independent of the downregulation of classical HLA class I molecules or expression of the HCMV class I homologue, UL18.

A number of reports have suggested that human cytomegalovirus (HCMV)-infected fibroblasts are resistant to natural killer (NK) lysis, and that the HCMV-encoded human leucocyte antigen (HLA) class I homologue UL18 may be responsible for this effect. While fibroblasts are easy to infect in vitro, their role in HCMV pathogenesis in vivo is unclear. Here, we have established systems to address NK recognition of infected endothelial cells and macrophages, two important HCMV cellular reservoirs in vivo.

Prospective 7-year monitoring of MAC bacteremia in HIV-positive Swedish patients.

OBJECTIVE: To record the cumulative incidence of Mycobacterium avium complex (MAC) bacteremia among HIV-infected patients and to study colonization in relation to symptoms of infection. METHODS: In a prospective study, 61 patients with a CD4 count less-than-or-eq, slant200x106/L were followed by cultures from sputum, feces and blood every 3--6 months and for development of MAC bacteremia and clinical symptoms. The main end-points were MAC bacteremia and death.

Frequencies of lipopolysaccharide-defined epitopes in Haemophilus influenzae type b and non-typable isolates determined with monoclonal antibodies.

OBJECTIVE: To investigate the frequency of expression and stability of saccharide epitopes in 178 Haemophilus influenzae (39 type b and 138 non-typable) isolates from blood, cerebrospinal fluid, nasopharynx, pharynx, middle ear, conjunctiva, and pleural and bronchial fluid from symptomatic and asymptomatic children using five murine monoclonal antibodies (MAbs, MAHI 3, 4, 6, 8, 10) specific for the oligosaccharide moiety of the lipopolysaccharide (LPS) of H. influenzae, which recognize defined saccharide structures. METHODS: A whole bacteria enzyme immunoassay (EIA) and colony dot immunoblotting were used to determine the frequency of expression and stability of saccharide epitopes in the 178 H.

The antidepressant and antiinflammatory effects of rolipram in the central nervous system.

Rolipram is a selective inhibitor of phosphodiesterases (PDE) IV, especially of the subtype PDE IVB. These phosphodiesterases are responsible for hydrolysis of the cyclic nucleotides cAMP and cGMP, particularly in nerve and immune cells. Consequences of rolipram-induced elevation of intracellular cAMP are increased synthesis and release of norepinephrine, which enhance central noradrenergic transmission, and suppress expression of proinflammatory cytokines and other mediators of inflammation.

Effects of alpha-MSH on kainic acid induced changes in core temperature in rats.

The effects of intraperitoneal (i.p.) administration of kainic acid (KA) and alpha-melanocyte-stimulating hormone (alpha-MSH) alone or in combination, on core temperature of freely moving rats were examined.

The Middle Molecule Hypothesis Revisited. Should Short, Three Times Weekly Hemodialysis Be Abandoned?

When the middle molecule (MM) hypothesis was formulated in 1975, no MM had yet been identified as a uremic toxin. Meanwhile, the birth and implementation of the Kt/V concept gained wide acceptance and has remained the world standard for assessing dialysis adequacy. However, over the past 20 years, accumulating evidence has made it clear that MM's are important uremic toxins, and that the dose of dialysis based on removal of small molecular substances does not protect against excessive hemodialysis mortality, morbidity, or the presence of uremic signs and symptoms.

The Arg 389 Gly beta1-adrenergic receptor gene polymorphism and human fat cell lipolysis.

Background: The beta1-adrenoceptor is a candidate gene for obesity because of its role in catecholamine-induced energy homeostasis. A common Arg 389 Gly variant polymorphism has been shown in recombinant cells to influence its-coupling properties.

Objective: To investigate the effect of the Arg 389 Gly beta1-adrenoceptor polymorphism on catecholamine-induced lipolysis in native human fat cells obtained by subcutaneous biopsy.

Regulation of switching and production of IgA in human B cells in donors with duplicated alpha1 genes.

IgA is the predominant immunoglobulin class synthesized in humans and can be subdivided into two subclasses, IgA1 and IgA2, each encoded by a separate gene and differentially expressed depending on age and anatomical localization of the producing cells. Duplication of the alpha1 gene is frequently observed in selected populations. As this duplication may serve to enhance IgA-mediated immunity, we determined its effect on switching and production of IgA in human B cells.

Suppression of T cells results in long-term survival of mouse heart xenografts in C6-deficient rats.

The present study aimed to investigate the role of cellular immune response in the absence of membrane attack complex (MAC) formation in the concordant mouse-to-rat heart xenografting. Hearts from BALB/c mice were transplanted into the neck vessels of C6-competent (C6(+)) and C6-deficient (C6(-)) PVG rats. Liposome-encapsulated dichloro-methylene diphosphonate (Lip-Cl2MDP) was administered at a dose of 10 ml/kg 2 days before transplantation and every 5 days thereafter.

Animal models for respiratory chain disease.

Elucidation of the pathogenesis in respiratory chain diseases is of great importance for developing specific treatments. The limitations inherent to the use of patient material make studies of human tissues often difficult and the mouse has therefore emerged as a suitable model organism for studies of respiratory chain diseases. In this review, we present an overview of the field and discuss in depth a few examples of animal models reproducing pathology of human disease with primary and secondary respiratory chain involvement.

Maintaining functional and behavioral abilities in Alzheimer disease.

Limitations associated with conventional acetylcholinesterase inhibitors have led to interest in therapies with more than one mode of action. Galantamine is a novel treatment for Alzheimer disease with a dual mode of action. The mechanisms involved may result in better long-term cognitive function, and may specifically affect behavioral symptoms.

Downregulation of Tfam and mtDNA copy number during mammalian spermatogenesis.

Mitochondrial transcription factor A (Tfam) is required for mtDNA maintenance, and mitochondrial Tfam protein levels directly affect mtDNA copy number. Previous studies have shown significant reduction of Tfam protein levels in mitochondria together with the appearance of abundant testis-specific Tfam mRNA isoforms as spermatogenesis proceeds in both mouse and man. Interestingly, an abundant testis-specific nuclear Tfam protein isoform of unknown function is found in the mouse, but not in humans.

Vitamin B12 in primary health care and geriatrics--attitudes, knowledge and competence.

Objectives: The objective of the study was to test attitudes, knowledge and competence of Swedish general practitioners and geriatricians concerning B12-associated problems in 1998.

Methods: Postal questionnaires were sent to a random sample of 485 GPs and a total sample of 613 geriatricians. The response rates were 70% in the GP group and 69% in the geriatrician group.

Clinical pharmacokinetics and pharmacodynamics of insulin aspart.

Insulin aspart is a novel rapid-acting insulin analogue with improved subcutaneous absorption properties when compared with soluble human insulin. Pharmacokinetic studies show an absorption profile with a time to reach peak concentration (t(max)) about half that of human insulin, a peak plasma drug concentration (Cmax) approximately twice as high and shorter residence time. The potency and bioavailability of insulin aspart are similar to those of human insulin.

Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice.

We generated mitochondrial late-onset neurodegeneration (MILON) mice with postnatal disruption of oxidative phosphorylation in forebrain neurons. They develop normally and display no overt behavioral disturbances or histological changes during the first 5 months of life. The MILON mice display reduced levels of mitochondrial DNA and mitochondrial RNA from 2 and 4 months of age, respectively, and severely respiratory chain-deficient neurons from 4 months of age.

Increased levels of somatostatin in rat ankles with adjuvant arthritis.

Levels of somatostatin were investigated in the ankles and spinal cords of rats suffering from acute and chronic adjuvant arthritis. As measured by radioimmunoassay, somatostatin showed significantly higher concentrations only in chronic arthritic ankles. No significant difference was observed in somatostatin levels between the spinal cords of normal and arthritic groups.

A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD.

Objective: To evaluate the long-term clinical efficacy and safety of donepezil versus placebo over 1 year in patients with mild to moderate AD.

Methods: Patients (n = 286; mean age, 72.5 years) with possible or probable AD from five Northern European countries were randomized to receive either donepezil (n = 142; 5 mg/day for 28 days, followed by 10 mg/day) or placebo (n = 144) for 1 year.

Shifts in B12 opinions in primary health care of Sweden.

Aims: The diagnosis and management of vitamin B12 deficiency varies between countries and within countries. The aim of the study was to map current attitudes and values behind clinical decision-making in Swedish primary health care, which has a unique B12 tradition: two patients out of three are treated with oral high-dose cyanocobalamin. Most patients with B12-associated problems are managed in primary health care by general practitioners (GPs).