Osteolytic lesions and pathological fractures are common in multiple myeloma. Because clodronate inhibits osteoclastic resorption, we did a randomised, controlled trial in 350 patients from 23 ...hospitals. All patients received standard melphalan-prednisolone, and were randomised to receive clodronate 2·4 g daily or placebo for 24 months. The proportion of patients with progression of osteolytic bone lesions was twice as high in the placebo group (n = 168 at baseline) than in the clodronate group (n = 168 at baseline) in an intention-to-treat analysis (24 vs 12%, p=0·026). Progression of vertebral fractures was lower in the clodronate group, but the difference was not significant (30 vs 40%). Serum calcium and urinary calcium excretion decreased significantly in both groups, but the changes were greater in the clodronate group. The percentage of patients feeling no pain increased more in the clodronate group (from 24 to 54%, p<0·001) than in the placebo group (from 29 to 44%, p<0·01). Side-effects were similar in both groups. We conclude that clodronate is an effective and safe adjunct in the management of multiple myeloma. The drug delays osteolytic bone lesions, reduces the degree of hypercalcaemia and hypercalciuria, and decreases pain.
The prevalence of isolates of Streptococcus pneumoniae (pneumococcus) that are resistant to antimicrobial agents is increasing globally. We studied the connection between antimicrobial resistance of ...pneumococci and regional use of antimicrobial agents in Finland. In 1997, a total of 6106 pneumococcal isolates were identified in clinical microbiology laboratories in Finland. Most of the pneumococci were isolated from respiratory tract samples, 8% were from blood culture samples, and 0.5% were from cerebrospinal fluid samples. The regional levels of resistance for pneumococci in 1997 were compared with the regional rates of use of antimicrobial agents from 1995 through 1996. We found that resistance to macrolides correlated highly significantly with macrolide use (P = .006). A significant correlation was also found between resistance to trimethoprim-sulfamethoxazole and trimethoprim-sulfamethoxazole use (P = .043). We did not find a correlation between penicillin resistance and the use of any antimicrobial agent. The positive correlation between macrolide-resistant pneumococci and the use of macrolides is worrying, because macrolides are used worldwide in the treatment of patients with respiratory tract infections, which are often caused by pneumococci.
Genes coding for the main virulence determinants of the plant pathogen Erwinia carotovora subsp. carotovora, the plant cell wall-degrading enzymes, are under the coordinate control of global ...regulator systems including both positive and negative factors. In addition to this global control, some virulence determinants are subject to specific regulation. We have previously shown that mutations in the pehR locus result in reduced virulence and impaired production of one of these enzymes, an endopolygalacturonase (PehA). In contrast, these pehR strains produce essentially wild-type levels of other extracellular enzymes including pectate lyases and cellulases. In this work, we characterized the pehR locus and showed that the DNA sequence is composed of two genes, designated pehR and pehS, present in an operon. Mutations in either pehR or pehS caused a Peh-negative phenotype and resulted in reduced virulence on tobacco seedlings. Complementation experiments indicated that both genes are required for transcriptional activation of the endopolygalacturonase gene, pehA, as well as restoration of virulence. Structural characterization of the pehR-pehS operon demonstrated that the corresponding polypeptides are highly similar to the two-component transcriptional regulators PhoP-PhoQ of both Escherichia coli and Salmonella typhimurium. Functional similarity of PehR-PehS with PhoP-PhoQ of E. coli and S. typhimurium was demonstrated by genetic complementation.
Attacins are antibacterial proteins synthesized by pupae of the giant silk moth, Hyalophora cecropia, in response to a bacterial infection. In this report we show that the previously described, ...attacin-induced alteration in the structure and the permeability of the outer membrane of Escherichia coli is associated with a specific inhibition of the synthesis of several outer membrane proteins, including OmpC, OmpF, OmpA, and LamB. The inhibition is expressed as a reduction in the steady-state mRNA levels and is at least in part the result of a block in transcription of the corresponding genes. Transcription directed by the promoter of ompR, the positive regulator of ompC and ompF expression in response to environmental conditions, is also affected by attacin. The effects on mutant strains show that the primary activity of attacin is not mediated by the ompR-envZ regulatory system. Instead our data suggest the existence in E. coli of a previously unknown system for the transcriptional regulation of a large set of outer membrane proteins previously not known to be coordinately regulated. We propose that the activity of attacin is directed towards this system
Introduction and hypothesis
This is a randomized multicenter study comparing two mid-urethra tape procedures, the tension-free vaginal tape (TVT) with the tension-free vaginal tape-obturator (TVT-O) ...in terms of cure rate and complication rate.
Methods
Seven Finnish hospitals participated. Power calculations required 130 women in each group to detect a 10% difference in cure rate. A total of 267 underwent the allocated operation. Follow-up was scheduled at 2, 12, 36 and 60 months. A cough stress test was used as an objective outcome measure. Subjective outcome was assessed by five different condition-specific quality of life questionnaires.
Results
At 36 months of follow-up, 96% of the patients were evaluated. Objective cure rate was 94.6% in the TVT group and 89.5% in the TVT-O group (
p
= 0.131). Subjective cure rates were significant with no difference between the groups.
Conclusion
The TVT and the TVT-O are equally effective in the treatment of stress urinary incontinence after 36-month follow-up with no difference in complication rates.
The role of Lactobacillus cell wall components in the protection against pathogen infection in the gut is still largely unexplored. We have previously shown that L. amylovorus DSM 16698
is able to ...reduce the enterotoxigenic F4
Escherichia coli (ETEC) adhesion and prevent the pathogen-induced membrane barrier disruption through the regulation of IL-10 and IL-8 expression in intestinal cells. We have also demonstrated that L. amylovorus DSM 16698
protects host cells through the inhibition of NF-kB signaling. In the present study, we investigated the role of L. amylovorus DSM 16698
cell wall components in the protection against F4
ETEC infection using the intestinal Caco-2 cell line.
Purified cell wall fragments (CWF) from L. amylovorus DSM 16698
were used either as such (uncoated, U-CWF) or coated with S-layer proteins (S-CWF). Differentiated Caco-2/TC7 cells on Transwell filters were infected with F4
ETEC, treated with S-CWF or U-CWF, co-treated with S-CWF or U-CWF and F4
ETEC for 2.5 h, or pre-treated with S-CWF or U-CWF for 1 h before F4
ETEC addition. Tight junction (TJ) and adherens junction (AJ) proteins were analyzed by immunofluorescence and Western blot. Membrane permeability was determined by phenol red passage. Phosphorylated p65-NF-kB was measured by Western blot.
We showed that both the pre-treatment with S-CWF and the co- treatment of S-CWF with the pathogen protected the cells from F4
ETEC induced TJ and AJ injury, increased membrane permeability and activation of NF-kB expression. Moreover, the U-CWF pre-treatment, but not the co-treatment with F4
ETEC, inhibited membrane damage and prevented NF-kB activation.
The results indicate that the various components of L. amylovorus DSM 16698
cell wall may counteract the damage caused by F4
ETEC through different mechanisms. S-layer proteins are essential for maintaining membrane barrier function and for mounting an anti-inflammatory response against F4
ETEC infection. U-CWF are not able to defend the cells when they are infected with F4
ETEC but may activate protective mechanisms before pathogen infection.
Cold acclimation of plants is a complex process involving a number of biochemical and physiological changes. The ability to cold acclimate is under genetic control. The development of freezing ...tolerance in woody plants is generally triggered by non-freezing low temperatures but can also be induced by mild drought or exogenous abscisic acid, as well as by short photoperiod. In nature, the extreme freezing tolerance of woody plants is achieved during sequential stages of cold acclimation the first of which is initiated by short photoperiods and non-freezing low temperatures, and the second by freezing temperatures. Although recent breakthroughs have increased our knowledge on the physiological molecular basis of freezing tolerance in herbaceous species, which acclimate primarily in response to non-freezing low temperatures, very little is known about cold acclimation of woody plants. This article attempts to review our current understanding of the physiological aspects that underline cold acclimation in woody plants.
Spontaneous neural activity is crucial for the formation of the intricate patterns of cortical connectivity during development. In particular, temporal correlations in presynaptic and postsynaptic ...activity have been hypothesized to be a critical determinant in the selection of neurons that are to become wired together. To date, however, temporally correlated activity in the neonatal brain has been believed to take place with a precision of tens of milliseconds to seconds. Here we describe a novel type of a fast network oscillation associated with millisecond synchronization of pyramidal cell firing in newborn rat hippocampus in vitro. Individual pyramidal neurons fired mainly at lower gamma frequencies (20-40 Hz) but were synchronized into a high-frequency (100-400 Hz) population oscillation that was reflected in field potential spikes and intracellular AMPA-kainate receptor-mediated currents. The high-frequency population oscillation was patterned by a gamma-frequency modulatory oscillation. The gamma modulation was imposed by GABAergic currents, which exerted an inhibitory action on pyramidal neurons. Patterned activity based on GABAergic inhibition and glutamatergic excitation thus occurs already in newborn hippocampus. The network oscillations described here may be a mechanism for selective coincidence detection with a millisecond range temporal precision to shape the patterns of connectivity within the emerging hippocampal synaptic circuitry.
The main virulence factors of Erwinia carotovora subsp. carotovora, the secreted, extracellular cell-wall-degrading enzymes, are controlled by several regulatory mechanisms. We have isolated ...transposon mutants with reduced virulence on tobacco. One of these mutants, with a mutation in a gene designated expM, was characterized in this study. This mutant produces slightly reduced amounts of extracellular enzymes in vitro and the secretion of the enzymes is also affected. The expM wild-type allele was cloned together with an upstream gene, designated expL, that has an unknown function. The expM gene was sequenced and found to encode a protein with similarity to the RssB/SprE protein of Escherichia coli and the MviA protein of Salmonella typhimurium. These proteins belong to a new type of two-component response regulators that negatively regulate the stability of the Sigma factor RpoS (sigma) at the protein level. The results of this study suggest that ExpM has a similar function in E. carotovora subsp. carotovora. We also provide evidence that the overproduction of RpoS in the expM mutant is an important factor for the reduced virulence phenotype and that it partly causes the observed phenotype seen in vitro. However, an expM/rpoS double mutant is still affected in secretion of extracellular enzymes, suggesting that ExpM in addition to RpoS also acts on other targets.
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