High-resolution ultrasonography of the carpal tunnel

Twenty-eight wrists of 25 patients with carpal tunnel syndrome (CTS) and 28 wrists of 14 normal control subjects were studied with high-frequency real-time ultrasonography. Three general findings could be observed in CTS, regardless of its cause: swelling of the median nerve at the entrance of the carpal tunnel; flattening of the median nerve in the distal carpal tunnel; and increased palmar flexion of the transverse carpal ligament. Quantitative analysis proved these findings to be significant. We conclude that high-resolution sonography is able to diagnose median nerve compression in the carpal tunnel syndrome and to detect some of its potential causes.     

Regression of rat Dunning R-3327-H prostate carcinoma by treatment with targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 containing 2-pyrrolinodoxorubicin

The effects of AN-207, a new targeted cytotoxic analog of LH-RH, were evalued in rats bearing hormone-dependent Dunning R-3327-H prostate carcinomas. AN-207 consists of the agonist [D-Lys(6)]LH-RH linked to 2-pyrrolino-doxorubicin, an intensely potent derivative of doxorubicin. In the first experiment, 2-pyrrolinodoxorubicin was administered at a concentration of 50 nmol/kg, as a single drug (AN-201) and as an unconjugated mixture with [D-Lys(6)]LH-RH or conjugated to the carrier [D-Lys(6)]LH-RH (AN-207). Following the second administration of radical AN-201 alone or mixed with the carrier, all rats died with signs of general toxicity, but all animals treated with the conjugate AN-207, survived. After 5 weeks of treatment with a total dose of 150 nmol/kg AN-207, the tumors regressed from an initial volume of 8.35 +/- 1.7 cm(3) to 4.47 +/- 0.8 cm(3), while tumors in the control group measured 17.84 +/- 2.2 cm(3). The therapy with AN-207 also significantly reduced tumor weight and tumor burden. In the second experiment, we compared the efficacy and toxicity of 3 injections of 25 nmol/kg AN-201 or 25 nmol/kg and 50 nmol/kg AN-207. The initial tumor volume in all groups was between 3.9 and 4.5 cm(3). After 5 weeks of therapy, the tumors of rats treated with 50 nmol/kg AN-207 regressed to 2.3 +/- 0.51 cm(3), whereas 25 nmol/kg AN-201 was still toxic in contrast to 25 nmol/kg AN-207, while the reduction in final tumor volume was similar (6.76 +/- 1.4 cm(3) and 6.74 +/- 1 cm(3), respectively), as compared to 15.6 +/- 2.2 cm(3) for untreated animals. High capacity LH-RH receptors were found in the membranes of untreated Dunning tumor specimens, but after treatment with AN-207, they could no longer be detected. This is the first demonstration that the new targeted cytotoxic LH-RH analog AN-207 is an effective antitumor agent. Our work indicates that the cytotoxic analog AN-207 is much less toxic than the antineoplastic radical (AN-201) incorporated, and significantly more active in inhibiting tumor growth. Further development of approaches based on targeted cytotoxic analog AN-207 may lead to major improvements in current palliative therapy of prostate cancer.     

Comparative pharmacodynamics of clarithromycin and azithromycin against respiratory pathogens

Summary The differences between the antibacterial activities of new macrolides such as clarithromycin (CLA) and azithromycin (AZI) against common respiratory tract pathogens are only minor. However, CLA and AZI constitute macrolides with extremely different pharmacokinetic profiles. This constellation presents an opportunity to evaluate the effect of the pharmacokinetic profile on antibacterial kinetics comparatively. In a pharmacodynamic model simulating the dynamics of serum concentrations in bacterial cultures, both CLA and AZI demonstrate bactericidal activity at concentrations reached in human blood at recommended dosages (CLA 250 mg b.i.d., AZI 500 mg o.i.d.). Bactericidal activity of CLA against the variety of pathogens included is superior to that of AZI in the rate and the extent of killing in this model. These results are considered to correlate with the antibacterial effect of macrolidesin vivo in cases where pathogens enter the blood stream. Furthermore, mutants with susceptibility reduced between 8 and 16 times in relation to the initial strain of all strains having an initial minimal inhibitory concentration (MIC) 0.25 mg/l, are selected during exposure to AZI, but not to CLA. The pharmacokinetic profiles of CLA and AZI thus strongly influence their antibacterial effect in the pharmacodynamic model, allowing both higher bactericidal activity and greater reduction of the risk of selection of resistant mutants with CLA than with AZI. As a whole, the pharmacodynamics of these macrolides are determined more by the proportion of the MICs to the maximum serum concentration than by the relation of the MICs to the area under the curve.

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Vergleich der Pharmakodynamik von Clarithromycin und Azithromycin bei Erregern von Atemwegsinfektionen

Zusammenfassung Die antibaktericlle Aktivität neuer Makrolide, z. B. von Clarithromycin (CLA) oder Azithromycin (AZI), gegenüber Atemwegspathogenen ist nahezu identisch. CLA und AZI unterscheiden sich jedoch beträchtlich in ihren pharmakokinetischen Eigenschaften. Dies eröffnet die Möglichkeit, den Einfluß der Pharmakokinetik auf die bakterielle Abtötekinetik zu untersuchen. In einem pharmakodynamischen Modell, bei dem die Serumkonzentrationsverläufe in der Bakterienkultur simuliert werden, zeigten sowohl CLA als auch AZI bei üblichen Dosierungen (CLA 250 mg 2 × tgl., AZI 500 mg 1 × tgl.) bakterizide Aktivität. CLA erwies sich in diesem Modell als schneller und stärker bakterizid als AZI gegenüber den untersuchten Erregern. Diese Ergebnisse sollten Bedeutung haben für die Therapie von Infektionen mit Makroliden, wenn die Erreger auch im Blut auftreten können (z. B.Streptococcus pneumoniae undHaemophilus influenzae). Mutanten mit verminderter Empfindlichkeit im Vergleich zum Ausgangsstamm wurden in den Experimenten mit AZI, nicht jedoch mit CLA selektioniert, u. z. bei allen Stämmen mit einer Anfangs-MHK von 0.25 mg/l. Die pharmakokinetischen Eigenschaften von CLA und AZI beeinflussen demnach ihre antibakterielle Aktivität, u. z. sowohl die Bakterizidie als auch das Risiko der Selektion resistenter Mutanten. Ausschlaggebend für den antibakteriellen Effekt dieser Makrolide ist also das Verhältnis MHK zu maximaler Serumkonzentration und nicht das Verhältnis MHK zu AUC.

     

Antibacterial activity of cefpodoxime in comparison with cefixime,cefdinir, cefetamet,ceftibuten, loracarbef,cefprozil, BAY 3522, cefuroxime,cefaclor and cefadroxil

Summary The new oral cephalosporins cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten demonstrate enhanced activity against Enterobacteriaceae susceptible to the established compounds as well (e.g. cefuroxime, cefaclor, cefadroxil). In addition, cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten include in their spectrum species hitherto resistant to oral cephalosporins (Proteus vulgaris, Providencia spp.,Yersinia enterocolitica). Besides, the majority of these compounds demonstrate relevant activity (MIC₅₀ equal to or below 2 mg/l) againstEnterobacter spp.,Citrobacter freundii, Serratia spp. andMorganella morganii. Ceftibuten is the most potent oral cephalosporin against most of the Enterobacteriaceae. Non-fermentative bacilli (Acinetobacter spp.,Pseudomonas spp.) remain completely resistant to oral cephalosporins (except someAcinetobacter species against cefdinir andPseudomonas cepacia against ceftibuten). Antistaphylococcal activity for oral cephalosporins is highest for cefdinir followed by BAY 3522, cefprozil, cefuroxime and cefpodoxime. Loracarbef, cefaclor and cefadroxil are about equally active, while the other compounds are only weakly active (cefixime) or inactive (cefetamet, ceftibuten). Enterococci are insensitive to new generation oral cephalosporins as they have been to established compounds. The most active oral cephalosporins against hemolytic streptococci are cefdinir and cefprozil.Streptococcus pneumoniae, Streptococcus milleri andStreptococcus mitior are most susceptible to cefpodoxime, cefdinir, cefuroxime and BAY 3522. Penicillin resistant pneumococci have to be regarded as resistant to all oral cephalosporins. Fastidious pathogens likeHaemophilus spp.,Moraxella catarrhalis andNeisseria gonorrhoeae are more susceptible to cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten than to the other oral cephalosporins. The activity of oral cephalosporins is only weak againstListeria spp.,Helicobacter pylori and anaerobic pathogens (except BAY 3522).Bordetella pertussis remains resistant to all absorbable cephalosporins. Progress in antibacterial activity of oral cephalosporins was mainly achieved by cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten against Enterobacteriaceae and the fastidious pathogens and against staphylococci and the nonenterococcal streptococci by cefdinir, BAY 3522, cefprozil and cefpodoxime.

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Antibakterielle Aktivität von Cefpodoxim im Vergleich mit anderen oralen Cephalosporinen

Zusammenfassung Die neuen oralen Cephalosporine Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten zeigen eine verstärkte Aktivität auch gegen solche Enterobacteriaceae, die gegen etablierte Substanzen empfindlich sind (z.B. Cefuroxim, Cefaclor, Cefadroxil). Zusätzlich schließt das Spektrum von Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten Spezies ein, die gegen die bisherigen oralen Cephalosporine resistent waren (Proteus vulgaris, Providencia spp.,Yersinia enterocolitica). Daneben zeigt die Mehrheit der neuen Substanzen erhöhte Aktivität (MHK₅₀<2 mg/l) gegenEnterobacter spp.,Citrobacter freundii, Serratia spp. undMorganella morganii. Gegen die meisten Enterobacteriaceae ist Ceftibuten das wirksamste orale Cephalosporin. Non-Fermenter (Acinetobacter spp.,Pseudomonas spp.) bleiben gegenüber oralen Cephalosporinen vollständig resistent (mit Ausnahme einigerAcinetobacter-Spezies gegen Cefdinir undPseudomonas cepacia gegen Ceftibuten). Die Antistaphylokokken-Aktivität oraler Cephalosporine ist am höchsten bei Cefdinir, gefolgt von BAY 3522, Cefprozil, Cefuroxim und Cefpodoxim. Loracarbef, Cefaclor und Cefadroxil sind etwa gleich aktiv, während die anderen Substanzen nur schwach aktiv (Cefixim) oder inaktiv sind (Cefetamet, Ceftibuten). Enterokokken sind gegenüber der neuen Generation oraler Cephalosporine ebenso unempfindlich wie gegenüber den etablierten Substanzen. Die aktivsten oralen Cephalosporine gegen hämolysierende Streptokokken sind Cefdinir und Cefprozil.Streptococcus pneumoniae, Streptococcus milleri undStreptococcus mitior sind am empfindlichsten gegen Cefpodoxim, Cefdinir, Cefuroxim und BAY 3522. Penicillin-resistente Pneumokokken müssen als resistent gegenüber allen oralen Cephalosporinen betrachtet werden. Anspruchsvolle Erreger wieHaemophilus spp.,Moraxella catarrhalis undNeisseria gonorrhoeae sind gegen Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten empfindlicher als gegen die anderen oralen Cephalosporine. Die Aktivität oraler Cephalosporine gegenListeria spp.,Helicobacter pylori und Anaerobier (Ausnahme BAY 3522) ist nur schwach.Bordetella pertussis bleibt gegen alle resorbierbaren Cephalosporine resistent. Der Fortschritt in der antibakteriellen Aktivität oraler Cephalosporine wurde gegen Enterobacteriaceae und anspruchsvolle Erreger hauptsächlich durch Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten erlangt, gegen Staphylokokken und Streptokokken (außer Enterokokken) durch Cefdinir, BAY 3522, Cefprozil und Cefpodoxim.

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Supported by Luitpold-Werk, a company of the Sankyo group.     

Functional activation of integrin alpha V beta 3 in tumor cells expressing membrane-type 1 matrix metalloproteinase

Matrix metalloproteinases (MMPs) and integrins have been implicated in a variety of processes involved in tumor progression. To evaluate the individual roles of integrin alphavbeta3 and membrane-type 1 matrix metalloproteinase (MT1-MMP), as well as the effects of their joint expression on tumor cell functions, MCF7 breast carcinoma cells were transfected stably with either the MT1-MMP, the beta3 integrin subunit or both MT1-MMP and beta3 cDNAs. MT1-MMP expression is accompanied by the functional activation of integrin alphaVbeta3, thereby increasing vitronectin-mediated adhesion and migration of MCF7 cells transfected with MT1-MMP and integrin alphaVbeta3. MT1-MMP-dependent functional activation of alphaVbeta3 correlates with modification(s) of the beta3 subunit, including its higher electrophoretic mobility and affected the LM609-binding site. MCF7 cells jointly expressing MT1-MMP and alphaVbeta3 were the most efficient in adhesion to the recombinant C-terminal domain of MMP-2 as well as in generating soluble and cell surface associated mature MMP-2 enzyme. These findings suggest a mechanism of selective docking of MMP-2 at tumor cell surfaces, specifically at the sites that include MT1-MMP and activated integrin alphaVbeta3. These mechanisms may provide a link between spatial regulation of focal proteolysis by the cell surface associated MMPs and the regulation of integrin-mediated motility of tumor cells.     

Mitochondrial genotype and risk for Alzheimer’s disease: cross-sectional data from the Vienna-Transdanube-Aging “VITA” study

Summary. The Vienna Transdanube Aging (VITA) study searches for early markers of Alzheimers disease (AD) by examining the mental status in a community-based cohort of 606, 75-years old volunteers that are then related to various clinical and genetic analyses. To determine whether mutations in mtDNA are involved in expression of AD, the mtDNA of 79 control participants is screened for alterations by sequencing of hot-spot-regions. This study on mtDNA mutations has eliminated the influence of aging on the occurrence of mtDNA alterations by sequencing samples from persons at the age of exactly 75 years. Thus, our cohort reveals a snap-shot of mitochondrial sequences of elderly persons.So far, a high percentage (56%) of persons with known or unknown mutations in the fragments analyzed were found. These data will be compared in due time to a cohort of participants with proven late-onset AD.     

Acrosome reaction in Chlamydia-positive and negative patients

Chlamydia trachomatis infections might have a detrimental effect on various sperm functions. Data concerning the effect of C. trachomatis on the capacitation activity of sperms are lacking. The study was undertaken to evaluate whether chlamydial infection influences acromsome reaction (AR). Three groups of men were investigated for ARs -Chlamydia negative (n = 46) and positive (n = 30) patients, and healthy men (n = 53) undergoing vasectomy. The fluorescence technique for the evaluation of AR was applied. The normal range for the induction of AR was assumed DeltaAR > 12.5% for this technique. Seminal plasma was examined for IgA antibodies against C. trachomatis. There was a significant difference in AR between healthy volunteers, Chlamydia-negative and Chlamydia-positive patients. DeltaARs were 15.8 +/- 1.6% in healthy volunteers versus 12.15 +/- 2.4% in Chlamydia-negative and 9.08 +/- 1.8% in Chlamydia-postive patients, respectively (P < 0.05). Significant elevated titres of C. trachomatis-specific IgA in seminal plasma showed a negative correlation with the AR of spermatozoa. AR seems to be a valuable marker, especially in couples with idiopathic infertility.