Pneumonia in the very old

Pneumonia is a major medical problem in the very old. The increased frequency and severity of pneumonia in the elderly is largely explained by the ageing of organ systems (in particular the respiratory tract, immune system, and digestive tract) and the presence of comorbidities due to age-associated diseases. The most striking characteristic of pneumonia in the very old is its clinical presentation: falls and confusion are frequently encountered, while classic symptoms of pneumonia are often absent. Community-acquired pneumonia (CAP) and nursing-home acquired pneumonia (NHAP) have to be distinguished. Although there are no fundamental differences in pathophysiology and microbiology of the two entities, NHAP tends to be much more severe, because milder cases are not referred to the hospital, and residents of nursing homes often suffer from dementia, multiple comorbidities, and decreased functional status. The immune response decays with age, yet pneumococcal and influenza vaccines have their place for the prevention of pneumonia in the very old. Pneumonia in older individuals without terminal disease has to be distinguished from end-of-life pneumonia. In the latter setting, the attributable mortality of pneumonia is low and antibiotics have little effect on life expectancy and should be used only if they provide the best means to alleviate suffering. In this review, we focus on recent publications relative to CAP and NHAP in the very old, and discuss predisposing factors, microorganisms, diagnostic procedures, specific aspects of treatment, prevention, and ethical issues concerning end-of-life pneumonia.     

Single-cell analysis of mtDNA deletion levels in sporadic amyotrophic lateral sclerosis

One possible cause for the neuronal loss in sporadic amyotrophic lateral sclerosis (S-ALS) is an increase of free radicals, which may produce oxidative damage to susceptible biomolecules, which, in turn, can damage the mitochondrial DNA (mtDNA). Following laser microdissection of single motor neurons from paraffin-embedded autopsy tissue, we analyzed the presence of a common mtDNA deletion, the 5 kb common deletion (CD). Spinal cord neurons showed slightly higher CD detection rate in patients than controls (94% vs 75%). No significant differences were found between patients and controls for neurons derived from other motor or non-motor regions. A PCR assay of serial DNA dilutions (10-fold) showed no CD level differences between motor neurons in S-ALS and controls. These data suggest that neuronal death in S-ALS is not associated with significant accumulation of mtDNA deletions.     

Physical workload, ergonomic problems, and incidence of low back injury: a 7.5-year prospective study of San Francisco transit operators

BACKGROUND: The etiologic role of biomechanical factors for low back injury (LBI) needs to be confirmed in prospective studies that control for psychosocial factors. METHODS: Complete baseline information on 1,233 vehicle operators was gathered during medical examinations and by questionnaire. First LBI during 7.5 years of follow-up was ascertained from insurance records. Hazard ratios and etiologic fractions were analyzed with Cox regression models stratified by injury severity and controlling for age, sex, height, weight, ethnicity, and biomechanical and psychosocial job factors. Severe LBI was defined as medically diagnosed postlaminectomy syndrome, spinal stenosis, herniated lumbar disc, sciatica, or spinal instability. RESULTS: An exponential dose-response relationship was found between weekly driving hours and incidence of first LBI. Indicators of physical workload were more strongly associated with more severe low back injuries compared to less severe injuries. Rates of severe LBI increased 39% for every 10-hr increase in weekly driving (hazard ratio 1.39, 95% confidence interval 1.15-1.68). Higher risks of severe LBI were also found among operators performing heavy physical labor on cable cars (hazard ratio 2.76, 95% confidence intervals 1.24-6.14) or reporting more ergonomic problems at baseline (HR for upper quartile 1.65 (95% confidence interval 1.08-2.50). Estimates of etiologic fractions suggest that reduction of ergonomic problems to the low level currently experienced by 25% of drivers would result in a 19% reduction of severe LBI among all drivers. A change from full- (more than 30 hr) to part-time driving (20-30 hr) could reduce the number of severe LBI by 59%, although this gain would be reduced to 28% at the company level if injuries expected among additional employees, hired to maintain full service are included. CONCLUSIONS: Duration of professional driving and ergonomic problems are independent and preventable risk factors for LBI even after adjustment for psychosocial factors.     

Nephrologists' view on exercise training in chronic kidney disease (results of the questionnaire at the WCN 2003)

During the WCN 2003 in Berlin a questionnaire on the opinion of nephrologists about physical activity was provided. A total of 47 participants completed the questionnaire (Germany 6, other European countries 15, non-European countries 15, unknown country 12). 37% of the individuals stated that they exercise on a regular basis, whereas 41% exercise infrequently. 95% agreed on the fact that the sedentary lifestyle is an important risk factor in CKD patients; 78% thought that it is the responsibility of the nephrologist to advice the patients about physical activity. 33% offer in-centre training programs. 15% of the patients participate in out-centre groups. This occurs most frequently in Germany where the health care system provides the largest financial support. 74% were in need of written material about exercising. Thus, it is an important goal to include instructions concerning training instruction and infrastructure into the routine treatment regimen of CKD patients, dialysis patients and kidney transplant recipients.     

Combination therapy improves survival after acute myocardial infarction in the elderly with chronic kidney disease

BACKGROUND: Individuals with chronic kidney disease have a high mortality rate after acute myocardial infarction. It is not known how frequently these individuals are prescribed combination cardioprotective therapy and if survival is affected by such therapy after acute myocardial infarction. METHODS: A retrospective cohort study of 1,342 Medicare recipients with acute myocardial infarction. Data were collected by medical chart abstraction as part of the Cooperative Cardiovascular Project in 60 hospitals in North Carolina during 5/30/1996-12/28/1997. We categorized cardioprotective medication use as aspirin alone, aspirin with beta-blockers, and aspirin with beta-blockers and ace-inhibitors. Chronic kidney disease was defined as a derived glomerular filtration rate (GFR) ranging from 15-89 mL/min/1.73 m2. Cox proportional hazards regression analyses were performed to determine the effect of cardioprotective medication use on survival while controlling for potential explanatory variables. RESULTS: The prevalence of cardioprotective medication use differed among levels of chronic kidney disease. Those with severe kidney disease (GFR 15-29 mL/min/1.73 m2) were less frequently prescribed aspirin with beta-blockers, 27.1%, and only 8.6% were prescribed aspirin with beta-blockers and ace-inhibitors. Survival was improved with prescribed cardioprotective medication use. In severe kidney disease (GFR 15-29 mL/min/1.73 m2), the hazards risk for death was 0.21 (0.08, 0.53) for aspirin alone, 0.17 (0.06, 0.51) for aspirin with beta-blockers, and 0.35 (0.09, 1.42) for aspirin with beta-blockers and ace-inhibitors. CONCLUSIONS: Individuals with chronic kidney disease benefit from combination cardioprotective therapy, but are less likely to be prescribed them after acute myocardial infarction. Further investigation is warranted to identify possible reasons for these observed treatment disparities.     

Comparative in vitro and in vivo studies on the permeation and penetration of ketoprofen and ibuprofen in human skin

The aim of the present in vitro and in vivo studies was to compare the permeation and penetration of a 2.5% ketoprofen (CAS 22071-15-4) gel [Phardol Schmerz-Gel (Test-D)] with the permeation and penetration of two other ketoprofen gels (Ref-I, Ref-E) and an ibuprofen (CAS 15687-27-1) gel (Ref-D) on excised human skin. Furthermore, in vivo studies were performed. The permeation studies utilizing static Franz diffusion cells allow the determination of the transdermal (systemic) transport, whereas the penetration studies in vitro (according to the Saarbrücker model) and in vivo permit setting up a concentration-depth profile. For this purpose the permeation kinetics of ketoprofen from three different gels (each containing 2.5% ketoprofen) over a period of two days were determined at heat-separated human skin of different donors. The in vitro permeability coefficients for Test-D (6.50 x 10(-7) cm x s(-1)) and Ref-I (5.72 x 10(-7) cm x s(-1)) were comparable and the transport occurred for both by a factor of 8-9 faster than with Ref-E (0.78 x 10(-7) cm x s(-1)). In parallel to the permeation studies with ketoprofen, the permeability coefficient of caffeine from an ointment was assessed using the skin biopsies of the same donors as a quality assurance. In a second part of the studies, the in vitro penetration of ketoprofen from Test-D was determined over a period of 3 h at three different skin biopsies in comparison to a commercially available 5% ibuprofen gel (Ref-D). As a main result a concentration-depth profile for ketoprofen and ibuprofen could be issued. The ketoprofen (37.7 +/- 12.1 microg/cm2) and the ibuprofen (30.1 +/- 6.0 microg/cm2) penetrate to the same order of magnitude into the upper part of the Stratum corneum, whereas ibuprofen stronger accumulates in the deeper layers (ketoprofen: 27.3 +/- 8.5 microg/cm2; ibuprofen: 73.7 +/- 31.1 microg/cm2). An additional in vivo penetration study was performed with Test-D to set up an in vitro-in vivo (IVIV) correlation. Over a period of 3 h, the amount of ketoprofen in the Stratum corneum in vivo was 78.4 +/- 19.1 microg/cm2 being comparable to the in vitro data.     

Hydrophobic vancomycin derivatives with improved ADME properties: discovery of telavancin (TD-6424)

Novel derivatives of N-decylaminoethylvancomycin (2), containing appended hydrophilic groups were synthesized and their antibacterial activity and ADME properties were evaluated. The compounds were prepared by reacting amines with the C-terminus (C-) of 2 using PyBOP mediated amide formation, or with the resorcinol-like (R-) position of 2 using a Mannich aminomethylation reaction. These analogs retained the antibacterial activity of 2 against methicillin-resistant staphylococci and vancomycin-resistant enterococci. Compounds with a negatively charged auxiliary group also exhibited improved ADME properties relative to 2. In particular, R-phosphonomethylaminomethyl derivative 21 displayed good in vitro antibacterial activity, high urinary recovery and low distribution to liver and kidney tissues. Based on these results, 21 was advanced into development as TD-6424, and is currently in human clinical trials. The generic name telavancin has recently been approved for compound 21.