Better quality of end-of-life care for persons with advanced dementia in nursing homes compared to hospitals: a Swedish national register study.

Background: Hospitalisation of patients with advanced dementia is generally regarded as less preferable compared to care at home or in a nursing home. For patients with other diagnoses, young age has been associated with better end-of-life care. However, studies comparing the quality of palliative care for persons with advanced dementia in hospitals and nursing homes are scarce.

Quality of end-of-life care in patients with dementia compared to patients with cancer: A population-based register study.

Introduction: Globally, dementia is one of the leading causes of death. Given the growing elderly population in the world, the yearly number of deaths by dementia is expected to increase. Patients dying from dementia are reported to suffer from a burden of symptoms similar to that of patients with cancer, but receive less medication against symptoms, have a lower probability of palliative care planning and seldom have access to specialised palliative care.

Higher cathepsin B levels in plasma in Alzheimer's disease compared to healthy controls.

Cathepsin B is suggested to be involved in amyloid-β (Aβ) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls.

Cystatin C levels are positively correlated with both Abeta42 and tau levels in cerebrospinal fluid in persons with Alzheimer's disease, mild cognitive impairment, and healthy controls.

Cystatin C is suggested to be involved in neurodegeneration and the development of Alzheimer's disease (AD) by binding to soluble amyloid-beta (Abeta) peptides. Studies of cystatin C levels in cerebrospinal fluid (CSF) in relation to risk of AD are conflicting and relations between cystatin C, Abeta42, and tau levels in CSF in AD, mild cognitive impairment (MCI), and healthy controls are unknown. The objective of this study was to investigate cystatin C, Abeta42, and tau levels in CSF in AD, MCI, and controls.

Cognitive function and risk of stroke in elderly men.

Objective: Vascular risk factors are associated with ischemic changes in the cerebral white matter. We studied the predictive value of cognitive test performance especially related to subcortico-frontal pathways, together with a cognitive screening test, for later incidence of fatal or nonfatal stroke or TIAs and stroke subtypes.

Methods: A sample of 930 70-year-old men without previous stroke/TIA from the community-based Uppsala Longitudinal Study of Adult Men was investigated at baseline using Trail Making Tests (TMT) A and B and the Mini-Mental State Examination (MMSE).

Systemic tocopherols and F2-isoprostanes and the risk of Alzheimer's disease and dementia: a prospective population-based study.

Oxidative stress in the brain is suggested to be involved in the pathophysiology of Alzheimer's disease (AD). In this study, serum alpha- and gamma-tocopherol, the two major systemic antioxidants, were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 616 and age 77, n = 761). In addition, urinary F2-isoprostane levels, as markers of systemic oxidative stress, were analyzed at the age of 77 in this cohort (n = 679).

Systemic inflammation and the risk of Alzheimer's disease and dementia: a prospective population-based study.

Inflammation is suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Serum interleukin-6 (IL-6) and high sensitivity serum reactive protein C (hsCRP) as markers of systemic inflammation were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 1062 and age 77, n = 749). In addition, serum amyloid protein A (SAA) and urinary prostaglandin F2alpha (PGF2alpha) metabolite levels were analyzed at age 77 in this cohort.

Glucose metabolism and the risk of Alzheimer's disease and dementia: a population-based 12 year follow-up study in 71-year-old men.

Aims/hypothesis: Accumulating evidence suggests that diabetes increases the risk of dementia, but few studies have addressed possible mechanisms underlying this relationship. The aim of our study was to investigate the longitudinal association of glucose metabolism, insulin secretion and insulin action with the development of Alzheimer's disease and vascular dementia.

Methods: The Uppsala Longitudinal Study of Adult Men is an ongoing observational study in Sweden in which 1,125 men aged 71 years and free from dementia underwent an OGTT and a euglycaemic insulin clamp between 1990 and 1995.

Genetic analysis of Alzheimer's disease in the Uppsala Longitudinal Study of Adult Men.

Background/aims: Genetic factors influencing common complex conditions have proven difficult to identify, and data from numerous investigations have provided incomplete conclusions as to the identity of these genes. Here we aimed to identify susceptibility genes for late-onset Alzheimer's disease (AD).

Methods: The case-control analysis included samples from 86 AD patients and 404 cognitively healthy controls selected from the Uppsala Longitudinal Study of Adult Men (ULSAM).

Serum cystatin C and the risk of Alzheimer disease in elderly men.

Background: Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD).

Methods: Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD.

Impaired insulin secretion increases the risk of Alzheimer disease.

Objective: Subjects with diabetes are reported to have an increased risk of dementia and cognitive impairment. However, the underlying causes remain unknown. We investigated the longitudinal associations between midlife insulin secretion, glucose metabolism, and the subsequent development of Alzheimer disease (AD) and dementia.

Plasma beta amyloid and the risk of Alzheimer disease and dementia in elderly men: a prospective, population-based cohort study.

Background: Beta amyloid (Abeta) protein accumulates in the brains of individuals with Alzheimer disease (AD) and is detectable in cerebrospinal fluid and plasma.

Objective: To examine plasma levels of Abeta peptides Abeta(40) and Abeta(42) as predictors of incident AD and other types of dementia.

Design: Prospective, population-based cohort study.

The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease.

Amyloid-beta (Abeta) with 40 (Abeta40) and 42 (Abeta42) amino acids, the main components of amyloid plaques in the Alzheimer's disease (AD) brain, can be measured in human cerebrospinal fluid (CSF) and plasma. Whereas CSF Abeta42 is decreased in AD, some studies have reported changed plasma Abeta levels in AD and in subjects with mild cognitive impairment (MCI). To this date it is unclear if and how CSF and plasma levels of Abeta correlate with each other in healthy individuals, albeit earlier studies on AD patients found no correlation between CSF and plasma Abeta.

Dicationic 2-fluorenonylcarbapenems: potent anti-MRS agents with improved solubility and pharmacokinetic properties.

The synthesis and biological evaluation of a series of dicationic-substituted 2-fluorenonylcarbapenems is described. This class of compounds showed enhanced water solubility while maintaining potent activity against MRS. Introduction of a 1-beta-methyl substituent was found to improve pharmacokinetics.

The synthesis and anti-MRSA activity of amidinium-substituted 2-dibenzofuranylcarbapenems.

A series of amidinium-substituted 2-dibenzofuranylcarbapenems with potent activity against MRSA has been synthesized via a Stille cross-coupling reaction. These new carbapenems show reduced serum protein binding and improved in vivo efficacy as a consequence of the positively charged amidinium substituent.

Synthesis and properties of 2-(naphthosultamyl)methyl-carbapenems with potent anti-MRSA activity: discovery of L-786,392.

A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.

Reduced immunotoxicity and preservation of antibacterial activity in a releasable side-chain carbapenem antibiotic.

A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.

In vivo activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L-749,345).

MK-826 (formerly L-749,345), is a potent 1-beta-methyl carbapenem with a long half-life and broad spectrum of activity. This compound is presently in phase-II clinical trials. Its activity against a number of gram-positive and gram-negative organisms was compared to those of imipenem (IPM) and eight other beta-lactam agents in two in vivo murine infection models.

Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase.

Background: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems.

Results: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure.

Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872).

MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance.

Pharmacokinetics of L-749,345, a long-acting carbapenem antibiotic, in primates.

L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation.

Aerosolization of imipenem/cilastatin prevents pseudomonas-induced acute lung injury.

Aerosolization of imipenem/cilastatin was compared with continuous intravenous infusions of the antibiotic for pharmacokinetic/pharmacodynamic analysis. The concentrations of imipenim/cilastatin in bronchoalveolar lavage fluids (BAL) obtained from rats exposed to the aerosolized antibiotic were significantly greater than the concentrations in BAL in the rats that had received intravenous infusions of imipenem/cilastatin. The two methods of antibiotic delivery were compared for their effects on bacterial-induced lung injury in rats that had Pseudomonas aeruginosa instilled into their airspaces.

Pharmacokinetics in nonhuman primates of a prototype carbapenem active against methicillin-resistant Staphylococcus aureus.

Pharmacokinetic parameters were determined for imipenem-cilastatin and a carbapenem antibiotic, L-695,256, active against methicillin-resistant Staphylococcus aureus in rhesus monkeys and a chimpanzee. L-695,256 had larger areas under the concentration-time curve than imipenem-cilastatin (30 +/- 5 versus 24 +/- 1 micrograms.h/ml in the rhesus monkeys and 77 versus 60 micrograms.

Pharmacokinetics of L-671,329 in rhesus monkeys and DBA/2 mice.

The time course of plasma drug levels and urinary recovery for two lipopeptide antifungal antibiotics, L-671,329 and cilofungin, were measured in male rhesus monkeys (Macaca mulatta) and in female DBA/2 mice. The antibiotics were administered intravenously at 10 mg/kg of body weight in phosphate-buffered saline-26% polyethylene glycol for the rhesus monkeys and in 5% dimethyl sulfoxide for the mice. Plasma and urine drug concentrations were determined by high-pressure liquid chromatography and/or a microbiological assay versus Aspergillus niger, and pharmacokinetic parameters were determined for both species.

A new class of potent, slowly reversible dehydropeptidase inhibitors.

Dehydrodipeptide analogs whose scissile carboxamide has been replaced with a PO(OH)CH2 group have been found to be potent inhibitors of the zinc protease dehydrodipeptidase 1 (DHP-1, renal dipeptidase, EC 3.4.13.