Meta-analytic methods for health services research--an example from geriatrics

The authors recently published a meta-analysis of controlled trials of comprehensive geriatric assessment (CGA). The results supported the view that efficacy of CGA is strongly related to the patients, objectives, and basic design of CGA programs, and that particular program models and design features are associated with important health outcome improvements (e.g., survival, living at home, and functional improvement at follow-up). Present objectives include the outline of methods and how they were developed given the condition of the trial database and scientific context. Aspects of the approach, such as (a) survey of primary trialists to recover unpublished information and standardize data, (b) development of a program typology to guide the principal analysis, and (c) incorporation of program design features as covariates where statistical heterogeneity was detected, proved extremely useful, and have implications for other systematic reviews of similarly complex primary trials of new health care technologies, health services, and organizational interventions.     

Clinical results of the transurethreal resection and evaluation of superficial bladder carcinomas by means of fluorescence diagnosis after intravesical instillation of 5-aminolevulinic acid

BACKGROUND AND OBJECTIVE: The high recurrence rate of superficial bladder carcinomas requires new approaches in diagnosis and therapy. Particularly, an improvement in detection, resulting in better resection of flat lesions, which are poorly or not detectable under white light, is necessary. The effectiveness of fluorescence diagnosis for detection and transurethral resection of bladder carcinomas was investigated in a prospective study. MATERIALS AND METHODS: From 120 patients, 347 biopsies were taken or tumors resected with the aid of fluorescence from 5-aminolevulinic acid. Urothelial carcinomas and dysplasias were detected in 124 cases. RESULTS: Of the lesions, 119 were fluorescence positive (N = 74 pTaG1/2; N = 9 pT1G1/2; N = 11 pT1G3; N = 7 carcinoma in situ; N = 6 p > T1; N = 12 dysplasia II), and 5 were falsely negative (N = 3 pTaG1/2; N = 1 pT1G1/2; N = 1 dysplasia II). The sensitivity of the fluorescence diagnosis (96.0%) was significantly higher than the 67.5% sensitivity of white-light cystoscopy (P < 0.0001). Taking the data for primary or recurrent tumor resection and secondary resection separately, the sensitivity was 100% and 80%, respectively, and was significantly higher than that of white-light cystoscopy, which was 80.8% and 20 %, respectively (P < 0.0001 and P < 0.0008). The lower sensitivity of fluorescence diagnosis in secondary transurethral resection is attributed to the higher rate of false-negative findings in areas of former resection. CONCLUSIONS: The high rate of false-positive findings limits the correct interpretation of fluorescence findings. In spite of this, fluorescence diagnosis is superior to white-light cystoscopy in every case. By means of better detection of urothelial neoplasias and dysplasias, as well as more thorough and extensive resection under fluorescence control, it should be possible to reduce the recurrence rate of superficial bladder carcinomas.     

A multinational study of the relationships between nighttime urinary melatonin production, age, gender, body size, and latitude

Overnight urines were collected each month for 12–16 months from 321 normal subjects at 19 medical centers in 14 countries distributed on 5 continents at latitudes from 31 01 South to 77 00 North. Mean melatonin concentration was found to negatively correlate with age, weight, and height. When the sexes were considered separately melatonin only correlated with age for female and with age and weight for males. A weak correlation with latitude, but not longitude, was also found. Received: 26 February 1998 / Accepted: 9 September 1999     

In Vitro and In Vivo Activity of 16,17-dehydro-epipregnanolones: 17,20-Bond Torsional Energy Analysis and D-ring Conformation

Purpose. Certain neuroactive pregnane steroids (also known as “epalons”) are allosteric modulators of the GABA_A receptor and have been shown to be potent anticonvulsants, anxiolytics, sedative/hypnotics, and anesthetic agents. The purpose of this study was to calculate the structural consequences of introduction of a double bond in the 16,17-position and to determine if this modification would selectively reduce sedative activity, but maintain the potent anticonvulsant activity of neuroactive steroids. Methods. We have studied the biochemical and behavioral effects of introducing a 16,17 double bond into the naturally occurring neuroactive steroids, 3α-hydroxy-5α-pregnan-20-one (3α,5α-P) and 3α-hydroxy-5β-pregnan-20-one (3α,5β-P) and three synthetic neuroactive steroid derivatives, 3α-hydroxy-3β-methyl-5α-pregnan-20-one (3α,3βMe,5α-P), 3α-hydroxy-5α-androstane (3α,5α-A), and alphaxalone (3α,5α-11-one-P). Results. The 16-ene analogs of most of these neuroactive steroids were found to be 7- and 16-fold less potent in inhibiting [³⁵S]TBPS binding to GABA_A receptors and in a similar fashion, had reduced anticonvulsant and sedative potency in proportional amounts. The exception was the androstane (3α,5α-A) without a 17-acetyl group, that had virtually identical IC₅₀ and ED₅₀ values for the saturated and unsaturated derivatives. Calculation of the torsional energy profile for each of the 17-acetyl side chain conformations showed that the conformational energy minima found in the α,β-unsaturated keto systems, produce an orientation of the 20-keto group that is rotated by 165 degrees when compared to the non-conjugated acetyl group (determined by X-ray crystallography and its minimum energy conformation). Conclusions. The modified orientation of the 20-keto group of neuroactive steroids containing a 16-ene, provides an explanation for their decreased biological activity overall, but did not lead to an enhanced protective index.     

Fish oil treatment and apolipoprotein(a).

Two recent reports showed a lowering of elevated lipoprotein(a) levels upon treatment with fish oil. The aim of this paper was to confirm this finding and to establish a dose-effect relationship. A double blind, placebo controlled cross-over study was carried out in 48 subjects with apolipoprotein(a) ("Apo(a)") values between 34 and 1062 U/l (median 387 U/l). The subjects were divided into 3 groups receiving 3.5, 7.1 and 10.6 g omega-3 fatty acids/day during 28 days. Parameters measured were blood levels of eicosapentaenoic acid ("EPA"), Apo(a) and fasting blood lipids. EPA levels rose in the three dosage groups by factors 7, 9 and 14, respectively, if compared to values upon placebo. Triglycerides were significantly lowered in a dose depending manner. Apo(a), however, was not changed. This held true for different baseline Apo(a) values and different fish oil dosages. It is concluded that fish oil treatment during 4 weeks cannot lower elevated Apo(a) levels.     

G protein-mediated receptor-receptor interaction: studies with chemotactic receptors in membranes of human leukemia (HL 60) cells

Summary Differentiated human leukemia (HL 60) cells contain high numbers of receptors for the chemotactic factors, N-formylmethionyl-leucyl-phenylalanine (fMet-Leu-Phe) and complement component 5a (C5a), both coupled to pertussis toxin-sensitive guanine nucleotide-binding regulatory proteins (G proteins). Agonist activation of either receptor stimulated binding of the GTP analog, guanosine 5-[-thio]triphosphate (GTP[S]), to membrane G proteins and by a similar extent in a non-additive manner. The possible interaction of the two receptors was studied by measuring agonist binding to one receptor in the presence of the other receptor agonist. fMet-Leu-Phe and C5a had no effects on [¹²⁵I]C5a and fMet-Leu-[³H]Phe receptor binding, respectively, when studied in the absence of regulatory ligands. Similarly, the inhibitory effects of NaCl and GDP on agonist receptor binding were not altered in the presence of the other receptor agonist. In contrast, in the presence of the GTP analogs, GTP[S] and guanosine 5-[,-imino] triphosphate, fMet-Leu-Phe and C5a reduced the binding of [¹²⁵I]C5a and fMet-Leu-[³H]Phe, respectively, in a concentration-dependent manner. The potencies of the GTP analogs to inhibit binding of [¹²⁵I]C5a and fMet-Leu-[³H]Phe was increased about 3-fold by fMet-Leu-Phe and C5a, respectively. The data presented suggest that fMet-Leu-Phe and C5a receptors share the same G protein pool in membranes of HL 60 cells and that activation of these G proteins by one of the two receptors decreases the availability of G proteins for the other receptor. Correspondence to T. Wieland at the above address     

Divalent Cations Modulate the Inhibitory Substrate Properties of Murine Glia-derived J1-160 and J1-180 Extracellular Matrix Glycoproteins for Neuronal Adhesion

J1-160 and J1-180 are developmentally late appearing J1 extracellular matrix glycoproteins derived from oligodendrocytes. They prevent adhesion of neurons (but not of astrocytes or fibroblasts) when offered as a substrate in mixture with laminin (Pesheva et al., J. Cell Biol., 109, 1765 - 1778, 1989). In the present study we have examined the influence of divalent cations on the inhibitory substrate properties of J1-160/180 glycoproteins towards adhesion of neurons. By metal chelate affinity chromatography, we show that J1-180, but not J1-160, binds Ca2+, while both J1 components are capable of binding Zn2+ and other divalent metal ions. Divalent cation binding was observed by gel filtration, aggregation assays with coated latex beads and electron microscopic examination to elicit aggregation of the molecules. Divalent cation binding also affects their non-permissive substrate properties towards neurons from early postnatal mouse cerebellum. Without divalent cations, J1-160 and J1-180 are inhibitory for substrate adhesion of neurons independently of the adhesive substrate present (laminin or poly-l-lysine). This effect is neutralized when J1-180 is preincubated with Ca2+ or Zn2+ prior to coating as substrate. In contrast, preincubation with Ca2+ ions does not affect the inhibitory substrate properties of J1-160 under these conditions. These observations show that J1-160/180 molecules may undergo self-aggregation in a divalent cation-dependent mechanism, which correlates with the neutralization of their inhibitory effect on neuronal adhesion. The aggregation state of the molecules may thus influence the process of myelination by a homophilic binding mechanism and determine the effectiveness of neurite extension during central nervous system development and under traumatic conditions in the adult.     

Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats

The interaction of phenylbutazone with the enantiomers and racemic [ ³ H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 g/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(–), and R, S (±) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenyl-butazone. For racemic [ ³ H]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration-effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration-response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.This work was supported by the Deutsche Forschungsgemeinschaft.