Higher physical fitness levels are associated with less language decline in healthy ageing.

Healthy ageing is associated with decline in cognitive abilities such as language. Aerobic fitness has been shown to ameliorate decline in some cognitive domains, but the potential benefits for language have not been examined. In a cross-sectional sample, we investigated the relationship between aerobic fitness and tip-of-the-tongue states. These are among the most frequent cognitive failures in healthy older adults and occur when a speaker knows a word but is unable to produce it. We found that healthy older adults indeed experience more tip-of-the-tongue states than young adults. Importantly, higher aerobic fitness levels decrease the probability of experiencing tip-of-the-tongue states in healthy older adults. Fitness-related differences in word finding abilities are observed over and above effects of age. This is the first demonstration of a link between aerobic fitness and language functioning in healthy older adults.

We know when we are sleepy: subjective versus objective measurements of moderate sleepiness in healthy adults.

The ability to monitor one's sleepiness has obvious implications for safety critical procedures. Laboratory findings indicate that we may be poor at doing this compared with objective measurements (e.g. reaction times (RT)). However, the respective testing situations usually differ, to favour objective measures. These typically entail longer test durations with less distractions; both factors facilitate sleepiness. Using the Karolinska Sleepiness Scale (KSS) we compared subjective responses with RTs, in 2 min epochs, over 10 min periods in identical quiet settings, early afternoon, in 21 healthy volunteers with 5h prior night's sleep restriction. Whereas the initial KSS score was unrelated to 10 min RT, the KSS subsequently showed a similar, significant increase, comparable with RT. Changes in both scores were very significantly correlated. KSS scores indicated that 5 min was an effective 'settling down' period. Participants were good at estimating their sleepiness if presented with a procedure equivalent to that of the objective measure.

Indicators of bacterial infection in patients with acute exacerbation of chronic bronchitis for application in clinical trials of antibacterial drugs.

OBJECTIVES: This study examined the accuracy of: (a) patient symptoms; (b) microscopic examination of sputum purulence (>25 WBCs and <10 epithelial cells) and (c) microscopic examination of morphological bacterial cell types, in identifying bacterial infection in patients with an acute exacerbation of chronic bronchitis (AECB) for entry to clinical trials. METHODS: Subjects had a worsening of at least two symptoms from: dyspnoea, sputum volume, and sputum purulence (Anthonisen Type 1 or 2 exacerbation). Sputum samples were collected from all subjects. RESULTS: A total of 97 sputum samples were evaluated. Overall, 58 (60%) subjects were culture-positive; 22 of 29 (76%) subjects with Type 2 exacerbation had a bacterial pathogen isolated compared with 36 of 68 (53%) Type 1 subjects. This difference was not statistically significant. Microscopically purulent samples were found to be significantly more likely to be culture-positive than non-purulent samples. However, the sensitivity (60%) and specificity (67%); and the positive predictive value (73%) and negative predictive value (53%) observed, means that this is not an ideal predictive test for clinical trials. A semi-quantitative approach to Gram staining was identified as a potential indicator of bacterial infection. Sputum specimens with one bacterial cell type present at >10 cells per field, or more than one cell type present with at least one type at a concentration of >25 cells per field, had a high proportion (91%) of culture-positive specimens. CONCLUSIONS: Symptoms alone are a poor indicator of bacterial infection. A semi-quantitative examination of a Gram-stained sputum preparation was the best indicator of bacterial infection. This finding may have relevance in the design of clinical trials of antibacterial drugs in AECB.

Antimicrobial selection for community-acquired lower respiratory tract infections in the 21st century: a review of gemifloxacin.

Community-acquired lower respiratory tract infections (LRTIs) are more prevalent in the elderly than in children and younger adults and form a significant proportion of all consultations and hospital admissions in this older age group. Furthermore, in a world of increasing life expectancy the trend seems unlikely to be reversed. Antimicrobial treatment of community-acquired pneumonia (CAP) must cover Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and in many circumstances should also cover the intracellular (atypical) pathogens. In contrast, acute exacerbations of chronic bronchitis (AECB) are mainly associated with H. influenzae and S. pneumoniae and not with atypical bacteria: in severe cases, other Gram-negative bacteria may be involved. Frequently in LRTIs, the aetiology of the infection cannot be identified from the laboratory specimens and treatment has to be empirical. In such situations it is important to not only to use an antibiotic that covers all likely organisms, but also one that has good activity against these organisms given the local resistance patterns. Gemifloxacin is a new quinolone antibiotic that targets pneumococcal DNA gyrase and topoisomerase IV and is highly active against S. pneumoniae including penicillin-, macrolide- and many ciprofloxacin-resistant strains, as well as H. influenzae and the atypical pathogens. In clinical trials in CAP and AECB, gemifloxacin has been shown to be as effective a range of comparators and demonstrated an adverse event profile that was in line with the comparator agents. In one long-term study in AECB significantly more patients receiving gemifloxacin than clarithromycin remained free of recurrence after 26 weeks. The improved potency, broad spectrum of activity and proven clinical and bacteriological efficacy and safety profile should make it a useful agent in the 21st century battle against community-acquired LRTIs.

A comparison of two patient-friendly ERG electrodes.

The ideal electroretinography (ERG) electrode does not exist. In deciding which electrode should be used in clinical practice the capacity to provide reproducible waveforms, maximal amplitudes and minimal irritation to the patient's eyes are the most important characteristics. This study tested two patient friendly electrodes, the gold foil (CH Electrodes, UK) and the H-K loop (Avanta, Slovenia). Seventeen normal volunteers were subjected to three standard measurements namely flash ERGs under photopic and scotopic conditions and the transient pattern ERG (PERG). Each test followed the guidelines set by the International Society for Clinical Electrophysiology of Vision (ISCEV). It was found that the mean values of the flash ERG a and b wave amplitudes and the PERG P50 and N95 amplitudes from the gold foil electrodes were approximately a factor of two larger than those from the H-K loop. In addition most of the subjects (13/17) felt less discomfort with the gold foil electrodes. We reached the conclusion that gold foil electrodes are the electrode of choice because they provide good patient comfort, reasonably high amplitudes and relatively reproducible results.

Randomized, double-blind study comparing 5- and 7-day regimens of oral levofloxacin in patients with acute exacerbation of chronic bronchitis.

A randomized, double-blind, multicentre study was conducted in adult patients with acute exacerbation of chronic bronchitis (AECB), to compare the efficacy of a 5-day course of levofloxacin 500 mg once daily, with the standard 7-day regimen at the same dose. Five hundred and thirty-two patients from 48 centres in 10 countries were randomized to receive levofloxacin: 268 and 264 received the 5- and 7-day courses, respectively. The primary efficacy analysis was the clinical response at 7-10 days post-treatment in the per-protocol (PP) population. Clinical success rates in the primary PP analysis of 482 patients were 82.8% (197/238) for the 5-day group and 84.8% (207/244) for the 7-day group. The difference in success rates was -2.1% with a 95% CI of (-9.1 to 4.9%). The bacteriological response showed eradication rates of 82.1% (92/112) and 83.2% (84/101) in the 5- and 7-day groups, respectively. Both treatments were well tolerated. These results show that for patients with AECB levofloxacin 500 mg once daily for 5 days provides equivalent clinical and bacteriological success to the same dose given for 7 days irrespective of the patient's age, the frequency of exacerbations or the presence of co-existing cardiopulmonary or chronic obstructive airways disease.

Clinical trials of antibacterial agents: a practical guide to design and analysis. Statisticians in the Pharmaceutical Industry Working Party.

Guidelines on the conduct of clinical trials of antibacterial agents produced by the US Food and Drug Administration, the British Society for Antimicrobial Chemotherapy, the Infectious Diseases Society of America and a European Working Party have been reviewed. Although very informative, these guidelines provide limited practical guidance on the design and statistical aspects of phase III studies of antimicrobial agents. This paper describes the differences between antibacterial trials and clinical studies in other therapeutic areas with regard to subjective endpoints, dual clinical and bacteriological endpoints, frequent protocol violations and difficulty of using placebo controls. The importance of a detailed protocol and planned analysis strategy is emphasized. The choice of comparator agents, practical issues with the blinding of trial materials and the documentation of patients excluded from study entry are discussed. The use of different patient groups and different endpoints in analyses are described. The principles of equivalence and their application to trials of antibacterial agents are discussed, together with an approach to calculating sample size. A variety of statistical analyses of results are compared for different situations indicating some of the problems that can arise. Different methods of presentation of study data are included with emphasis on regulatory submissions rather than scientific publications. Some graphical presentations are recommended and issues regarding data across different studies are discussed.

Stimulation of 16-dehydroprogesterone and progesterone reductases of Eubacterium sp. strain 144 by hemin and hydrogen or pyruvate.

Suspensions of Eubacterium sp. strain 144, prepared from cells grown with 16-dehydroprogesterone, catalyzed the reduction of this steroid to 17-isoprogesterone at a very low rate. Modifications of the assay to optimize the pH (5.5) and increase the steroid solubility (10% [vol/vol] methanol) did not significantly enhance the reaction. However, growth of strain 144 in the presence of hemin was found to stimulate 16-dehydroprogesterone reductase during the initial 30 min of incubation, giving a biphasic time course. These biphasic kinetics could be eliminated by providing the cells with an exogenous electron donor. Strain 144 used either H2 or pyruvate for this purpose, and 17-isoprogesterone formation was nearly complete after 20 to 30 min of incubation. However, under these conditions, strain 144 further converted 17-isoprogesterone to products which lacked UV absorbance (254 nm). When progesterone was used as a substrate, it was found that strain 144 could reduce the C4-C5 double bond of this steroid by a progesterone reductase to give mostly 5 beta-pregnadione and some 5 alpha-pregnadione. Furthermore, the 3-keto group of 5 beta-pregnadione steroid was also reduced to a hydroxy function. The maximum activities of both 16-dehydroprogesterone and progesterone reductases in cell suspensions required the growth of strain 144 with hemin and 16-dehydroprogesterone and the presence of H2 or pyruvate.

Biotransformation of 16-dehydroprogesterone by the intestinal anaerobic bacterium, Eubacterium sp. 144.

Eubacterium sp. 144 biotransformed 16-dehydroprogesterone by initially hydrating approx 50% to 16 alpha-hydroxyprogesterone. The detection of this reaction was dependent, in part, on the solubility state of 16-dehydroprogesterone and was less extensive when the concentration of methanol was insufficient to solubilize the steroid. Cultures containing a mixture of 16-dehydroprogesterone and 16 alpha-hydroxyprogesterone formed isoprogesterone as a final steroid end product. However, the extent of the reductive reaction was influenced by culture age at the time of 16-dehydroprogesterone addition and decreased in older cultures. Moreover, both mid- and late-log phase cells also formed progesterone as a reduced steroid end product. The enzyme(s) responsible for isoprogesterone formation (16-dehydroprogesterone reductase) appeared to be inducible because activity was not evident until 3-6 h after the addition of 16-dehydroprogesterone to early log-phase cultures. Growth inhibitory concentrations of chloramphenicol or rifampin prevented isoprogesterone formation, but not the production of progesterone. At lower concentrations, chloramphenicol delayed both growth and isoprogesterone formation by strain 144. Interestingly, rifampin partially inhibited the 16 alpha-hydroxyprogesterone dehydratase (hydration reaction) in cultures of strain 144, but did not affect the enzyme's activity in cell extracts.