The beers criteria--an instrument to optimise the pharmacotherapy of geriatric patients

Geriatric patients represent an important population group in counselling and care of pharmacists. Despite this high need, there are only few investigations in this special patient population and derived aids for competent and practice-oriented pharmaceutical care. The Beers criteria developed in the US represent an instrument to detect potentially inappropriate medication in older adults. In order to propagate in Germany a translation and adaptation to the German drug market was performed. Systematic consensus building by an expert panel will be necessary for wide acceptability. Applying the Beers criteria presents an opportunity of pharmacist to optimise the pharmacotherapy of geriatric patients.     

Postmarketing evaluation of the safety and effectiveness of varicella vaccine

BACKGROUND: The Oka strain of live attenuated varicella virus was licensed for use in healthy children in the United States in March, 1995. We report a postmarketing evaluation of the short term safety of this vaccine within Kaiser Permanente. METHODS: After licensure varicella vaccination was introduced into the preventive care program of the Northern California Kaiser Permanente Medical Care Program. Potential adverse events after vaccination with varicella vaccine were identified from automated clinical databases of hospitalizations, emergency room visits and clinic visits. Deaths were identified from automated clinical databases at Kaiser as well as from the State death records for California. To evaluate safety, rates of diagnosis-specific events in the risk periods were compared with the rates of such diagnosis-specific events in two self control and one historical control period. RESULTS: During the study period of April 1, 1995, to December 31, 1996, a total of 89753 adults and children received varicella vaccine. A total of 3200 relative risks were calculated, and of these 5 hospital diagnostic categories, 9 emergency visit diagnostic categories and 30 outpatient diagnostic categories demonstrated at least 1 relative risk with a P value of <0.05 in 1 or more age groups and in comparisons with 1 control period or more. The p value for these tests was not adjusted for multiple comparisons. Of these categories 14 demonstrated an increased risk either in more than 1 age group or against more than 1 comparison group. These categories included elective procedures, febrile seizure, febrile illness, well child, acute gastroenteritis, varicella, congenital anomaly, "rule out sepsis," trauma, viral syndrome, apnea, back pain, congenital valvular heart disease and vision evaluation for glasses. Of these the outcomes of elective procedure, congenital anomaly, congenital valvular heart disease, well child and vision evaluation for glasses were judged not to have a biologically plausible association with vaccination. A second diagnostic grouping included febrile illness, viral illness, febrile seizure and "rule out sepsis." In an analysis of these events which adjusted for the concomitant administration of M-M-R(II) vaccine, none of the associations was statistically associated with receipt of varicella vaccine. The diagnostic category of "rule out sepsis" still had a relative risk of 1.95 with P = 0.02. None of the children in the "rule out sepsis" category had positive bacteriologic cultures from any other normally sterile site. Because of the large number of gastroenteritis cases, we reviewed a random sample of 100 exposed and 100 unexposed cases. From this review no consistent time association or clustering of any of these events was seen in the exposed follow-up time interval. Only gastroenteritis and negative evaluations for sepsis were thought to be possibly associated with receipt of varicella vaccine. Although there was a statistically significant increased risk over the entire 30 day-period, there was no clustering of these events within the 30-day window. CONCLUSION: In this study population of 89753 children and adults, the varicella vaccine (Oka strain, Merck) appeared to have a favorable safety profile. In addition rates of varicella-like rash and of breakthrough cases were both low and consistent with the rates observed in prelicensure studies.     

Urea as an endogenous surrogate in human microdialysis to determine relative recovery of drugs: analytics and applications

During in vivo microdialysis studies time-consuming and laborious bedside calibration methods, e.g. retrodialysis, have to be performed. To reduce the burden on the patient it would be desirable to establish a reliable, time-saving calibration technique to obtain the in vivo recovery describing the relative drug transfer across the membrane of the microdialysis probe. The performed study aimed to evaluate and validate the use of urea as an endogenous reference compound to determine relative in vivo recovery of anti-infectives, e.g. linezolid used herein as model drug. In order to meet the special requirements imposed by microdialysis to measure urea concentrations in very small sample volumes ( approximately 10 microL) a photometric assay in 96-well microtiter plates was established based on the method of Berthelot. Subsequently, concentration- and flow rate-dependence were evaluated in vitro to determine the relative recovery (RR) of urea. Finally, urea and linezolid concentrations in human microdialysis samples were measured. The developed assay was validated according to international guidelines and met all requirements. Relative in vitro recovery was found to be independent from concentration and dependent on flow rate. Subsequently, relative in vivo recovery of urea was correlated with relative in vivo recovery of linezolid obtained by the traditional retrodialysis method. In healthy volunteers, the mean ratio of the relative recovery of linezolid to the relative recovery of urea was 0.6 for the subcutaneous (s.c.: CV 33.4%, n = 48) and 0.7 for the intramuscular probe (i.m.: CV 18.8%, n = 40), respectively. In critically ill patients this ratio was 0.7 for both tissues (s.c.: CV 32.8%, n = 18; i.m.: CV 22.1%, n = 17). Successful calibration of the urea reference technique without the need to use in vitro data will further promote the application of microdialysis in clinical studies especially in critically ill patients, as it reduces the imposed burden to a minimum.     

Health in south-eastern Europe: a troubled past, an uncertain future

The political and economic turmoil that occurred in south-eastern Europe in the last decade of the twentieth century left a legacy of physical damage. This aspect of the conflict has received considerable coverage in the media. However, surprisingly less has been reported about the effects of that turmoil on the health of the people living in the region. In an attempt to identify and synthesize data on these effects, we carried out a systematic review and used the results to put together a searchable online database of documents, reports, and published material, the majority of which have not previously been easily accessible (http:// www.lshtm.ac.uk/ecohost/see/index.php). The database covers the period from the early 1990s to 2003 and will be of considerable interest to policy-makers. It contains 762 items, many of them annotated and available for downloading. This paper synthesizes the main findings obtained from the material in the database and emphasizes the need for concerted action to improve the health of people in south-eastern Europe. Furthermore, we also recommend that agencies working in post-conflict situations should invest in developing and maintaining online databases that would be useful to others working in the area.     

Solution NMR spectroscopy of [alpha -15N]lysine-labeled rhodopsin: The single peak observed in both conventional and TROSY-type HSQC spectra is ascribed to Lys-339 in the carboxyl-terminal peptide sequence

[alpha-(15)N]Lysine-labeled rhodopsin, prepared by expression of a synthetic gene in HEK293 cells, was investigated both by conventional and transverse relaxation optimized spectroscopy-type heteronuclear single quantum correlation spectroscopy. Whereas rhodopsin contains 11 lysines, 8 in cytoplasmic loops and 1 each in the C-terminal peptide sequence and the intradiscal and transmembrane domains, only a single sharp peak was observed in dodecyl maltoside micelles. This result did not change when dodecyl maltoside was replaced by octyl glucoside or octyl glucoside-phospholipid-mixed micelles. Additional signals of much lower and variable intensity appeared at temperatures above 20 degrees C and under denaturing conditions. Application of the transverse relaxation optimized spectroscopy sequence resulted in sharpening of resonances but also losses of signal intensity. The single peak observed has been assigned to the C-terminal Lys-339 from the following lines of evidence. First, the signal is observed in HNCO spectra of rhodopsin, containing the labeled [(13)C]Ser-338/[(15)N]Lys-339 dipeptide. Second, addition of a monoclonal anti-rhodopsin antibody that binds to the C-terminal 8 aa of rhodopsin caused disappearance of the peak. Third, truncated rhodopsin lacking the C-terminal sequence Asp-330-Ala-348 showed no signal, whereas the enzymatically produced peptide fragment containing the above sequence showed the single peak. The results indicate motion in the backbone amide groups of rhodopsin at time scales depending on their location in the sequence. At the C terminus, conformational averaging occurs at the nanosecond time scale but varies from microsecond to millisecond in other parts of the primary sequence. The motions reflecting conformational exchange may be general for membrane proteins containing transmembrane helical bundles.     

Species-specific profiles of mycotoxins produced in cultures and associated with conidia of airborne fungi derived from biowaste

The potential to produce mycotoxins and non-volatile secondary metabolites was investigated for approximately 250 freshly isolated fungal strains. Among the eleven most relevant species, viz. Aspergillus flavus, A. fumigatus, A. niger, A. parasiticus, A. versicolor, Emericella nidulans, Paecilomyces variotii, Penicillium brevicompactum, P. clavigerum, P. crustosum, and P. polonicum, a wide range of metabolites partly of toxicological relevance was identified. Several unknown metabolites were found for the less frequent species, which were primarily investigated for chemotaxonomic delimitation from closely related species. The spectra of metabolites in conidial extracts and culture extracts (containing also mycelium and medium) were compared for a limited number of relevant fungi. Some mycotoxins, such as sterigmatocystin in Emericella nidulans, were not present in the conidial extracts, though produced by most strains. Fumigaclavine C, tryptoquivaline, and trypacidin, characteristic for A. fumigatus, were found in conidial extracts, but highly toxic compounds such as gliotoxin and fumitremorgens were not present. Finally, compounds such as cyclopenol, cyclopenin, and penitrem A being characteristic for certain penicillia, were found in conidial extracts and are therefore assumed to occur in native bioaerosols.     

Patho-anatomical features of so-called Ph1− chronic myeloid leukemia

Summary Chronic myeloid leukemia without the Philadelphia chromosome (Ph^1– CML) is described and distinguished from chronic myeloid leukemia with the Philadelphia chromosome (Ph¹⁺ CML) on the basis of clinical and autopsy findings of four cases. Ph^1– CML showed clinical, hematological, and patho-anatomical features which could be regarded as typical.Patho-anatomically Ph^1– CML differed from Ph¹⁺ CML in the variable maturation of the leukemic proliferation in the bone marrow and extramedullary infiltrates. Up to the terminal phase Ph^1– CML can be of an extremely mature cell type. However, it can also show myeloblastic transformation after an initially mature cell stage. Ph^1– CML infiltrates are found in tissues and organs which Ph¹⁺ CML usually does not infiltrate or only to a low degree until a blastie crisis.On the basis of its course and clinical and patho-anatomical features Ph^1– CML looks like an atypical chronic myeloid leukemia. However, it is better called an acute myeloid leukemia of the mature cell type.The authors are grateful to Mr. K.-H. Tedsen for his excellent technical assistance and to Mrs. M. Soehring for translation and secretarial help.     

Histopathology of N-methyl-N-nitrosourea-induced mesenchymal tumours of the rat urinary bladder.

The present study reports the induction, histopathology, immunocytochemistry, growth pattern and proliferative behaviour of mesenchymal tumours of the urinary bladder of rats induced by a single intravesical dose (5 mg/kg/body weight) of N-methyl-N-nitrosourea (MNU). In 14 of 283 female Wistar rats (incidence: 4.9%). 16 non-epithelial tumours had developed after an experimental period of 14 months. The most common histological type induced was of fibrohistiocytic origin (eight benign-appearing and three malignant fibrous histiocytomas). Furthermore, two pure histiocytomas (one benign and one malignant) and three capillary and cavernous haemangiomas were produced. Since no metastases occurred and no clear-cut distinction between a merely expansive and a truly invasive growth was possible, the diagnosis of malignancy was based on the degree of cellular atypia and the mitotic activity. The benign-appearing fibrous histiocytomas showed a mean mitotic index of 0.06% and the malignant fibrous histiocytomas of 0.34%. The mitotic activity of the malignant histiocytoma was threefold (0.78%) as high as in the benign-appearing histiocytoma (0.25%). There exist close morphological similarities between the induced mesenchymal tumours in the rat and those occurring in the human bladder. Although the spectrum of histological types of mesenchymal tumours seen in the rat bladder was narrower than that encountered in man, MNU seems suitable for further studying the histogenesis, histopathology and biology of experimentally induced non-epithelial bladder neoplasms to gain information for a better understanding of the pathogenesis of human disease.     

In Vitro Evaluation of High-Level,Gentamicin-Resistant Enterococci Isolated from Bacteremic Patients

We attempted to characterize the susceptibility of high-level, gentamicin-resistant (HLGR, minimum inhibitory concentration [MIC] >2000 μg/ml) enterococcal blood isolates and evaluated a small subset of these isolates for bactericidal synergy. Thirteen Enterococcus faecalis and three Enterococcus faecium isolates that were HLGR were prospectively collected. Standard broth macrodilution techniques were used to determine the MICs and minimum bactericidal concentrations to a variety of antibiotics. Two isolates were evaluated for synergy by time-kill curve methods using combinations of penicillin and streptomycin, teicoplanin and rifampin, and vancomycin and ciprofloxacin. Teicoplanin was the most active antibiotic tested, with all isolates exhibiting susceptibility to this agent. Four E. faecalis isolates and one E. faecium isolate expressed only low-level resistance to streptomycin (LLSR, MlCs 32–64 μg/ml). Penicillin and streptomycin produced bactericidal synergy in the LLSR isolate. The other antibiotic combinations did not result in bactericidal synergy in the two isolates tested. For HLGR enterococci that are only LLSR, the combination of penicillin-streptomycin appears to provide adequate bactericidal activity. Teicoplanin may potentially be useful for streptomycin-resistant HLGR isolates.