A randomized, double-blind, placebo-controlled study of brain-derived neurotrophic factor (rhBDNF) was conducted in 30 patients with insulin-treated diabetes mellitus, with obligatory abnormalities of sural nerve conduction studies and vibration perception threshold (VPT) at the great toe on recruitment. Nine patients received placebo, 11 rhBDNF (25 microg/ kg) and 10 rhBDNF (100 microg/kg) s.c. daily for 3 months, and were assessed at days 0, 8, 15, 29, 43, 57 and 85 with nerve conduction and quantitative sensory and autonomic tests including VPT, thermal and light touch thresholds, and cutaneous axon-reflexes. No statistically significant differences were found among the 3 treatment groups between baseline and day 85 values. To examine possible reasons for lack of effect, post hoc analysis was performed. In the subset of patients with abnormal but detectable cool detection threshold (CDT) at baseline, there was improvement of CDT at day 85 when compared to baseline in the treated (p < 0.02) but not placebo group. Further, from days 43 to 85, in the treated group but not the placebo group, CDT was indistinguishable from a group of matched normal subjects (p > 0.05). Skin biopsies failed to show evidence of structural change; assessment of innervation of hair follicles, which is partly dependent on BDNF, was not possible because of the marked loss of this end-organ in diabetic neuropathic skin. The only side effects of rhBDNF were infrequent non-painful injection-site skin reactions and increased gut motility at the higher dose. We conclude that further preclinical studies are warranted before any future clinical trials to see if rhBDNF improves CDT and constipation in diabetics.
Pneumolysin, neuraminidases A and B, and hyaluronidase are virulence factors of Streptococcus pneumoniae that appear to be involved in the pathogenesis of meningitis. In a murine model of meningitis after intracerebral infection using mutants of S. pneumoniae D39, only mice infected with a pneumolysin-deficient strain were healthier at 32 and 36 h, had lower bacterial titers in blood at 36 h, and survived longer than the D39 parent strain. Cerebellar and spleen bacterial titers, meningeal inflammation, and neuronal damage scores remained uninfluenced by the lack of any of the virulence factors.Streptococcus pneumoniae meningitis frequently causes severe neurological sequelae and death (9,15,23). A number of pneumococcal proteins have been characterized as putative virulence factors, among them pneumolysin, the neuraminidases A and B, and hyaluronidase (7,8,16,17,21,22,27). Pneumolysin, a cytoplasmic protein, is released during autolysis of the bacterium and probably also via an autolysis-independent mechanism (3, 21). It interacts with cholesterol in the cell wall of host cells and forms transmembrane pores by oligomerization, leading to loss of membrane integrity of host cells. In sublytic concentrations it is capable of inhibiting respiratory burst, chemotaxis, and bactericidal activity of polymorphonuclear leukocytes (20). Furthermore, it leads to complement consumption (6), thereby reducing serum opsonic activity (1, 2). Neuraminidase activity has been indirectly linked to virulence in human pneumococcal meningitis on the basis of elevated cerebrospinal fluid concentrations of N-acetylneuraminic acid in patients with coma and bacteremia (19). A deficiency of neuraminidase A led to decreased virulence in a model of pneumococcal pneumonia (17). The role of hyaluronidase has not been studied extensively. Strains causing meningitis showed a higher in vitro expression of hyaluronidase (16). Intranasal instillation of pneumococci with addition of hyaluronidase to the inoculum was followed by meningitis in a model of pneumococcal pneumonia (28). We used a mouse model based on intracerebral infection (14, 26) to assess the role of pneumolysin, neuraminidases A and B, and hyaluronidase in meningitis by using mutants of an S. pneumoniae type 2 strain deficient in these putative virulence factors.(This work was presented, in part, at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 17 to 20 September 2000 [abstr. 433]).Bacteria. Mutant strains of S. pneumoniae D39 were generated by insertion duplication mutagenesis as described in detail before (30). In brief, internal gene fragments amplified from chromosomal DNA were ligated with the insertion vector pJDC9 by standard DNA techniques (12). The insertion was performed at position 547 of the 1,416-bp ply gene, position 605 of the 3,108-bp nanA gene, position 735 of the 2,094-bp nanB gene, and position 534 of the 2,850-bp hyl gene. Erythromycin-resistant transformants were selected with 1 g of erythromycin/ml on Luria-Bertani ag...
Tumor necrosis factor alpha (TNF-␣) and TNF- are key mediators in bacterial inflammation. We therefore examined the role of TNF-␣ and its two receptors in murine pneumococcal central nervous system infection. TNF-␣ knockout mice and age-and sex-matched controls and TNF receptor (p55 and p75)-deficient mice and heterozygous littermates were infected intracerebrally with a Streptococcus pneumoniae type 3 strain. Mice were monitored until death or were killed 36 h after infection. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration and neuronal damage were assessed by histological scores. TNF-␣-deficient mice died earlier than the controls after intracerebral infection although overall survival was similar. TNF-␣ deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in brain homogenates. However, it caused a substantial rise of the concentration of S. pneumoniae cells in blood and spleen. Spleen bacterial titers were also increased in p55-and p75-deficient mice. TNF receptor-deficient mice showed decreased meningeal inflammation. Neuronal damage was not affected by either TNF-␣ or TNF receptor deficiency. In a murine model of pneumococcal peritonitis, 10 2 CFU of S. pneumoniae produced fatal peritonitis in TNF-␣-deficient, but not wild-type, mice. Early leukocyte influx into the peritoneum was impaired in TNF-␣-deficient mice. The lack of TNF-␣ or its receptors renders mice more susceptible to S. pneumoniae infections.
Compared with beta-lactam antibiotics, rifampin releases smaller quantities of proinflammatory cell wall products from Streptococcus pneumoniae in vitro. Mice infected intracerebrally with S. pneumoniae were treated subcutaneously with 2-mg doses of rifampin or ceftriaxone (n=43 each) every 12 h for 3 days and then observed for another 3 days. Rifampin reduced overall mortality from 49% to 26% (P=.04). Kaplan-Meyer analysis revealed a substantial reduction of mortality during the first 24 h in mice receiving rifampin (difference in survival time: P=.007). Eight h after receiving a single 2-mg dose of rifampin or ceftriaxone, rifampin-treated mice had lower serum and cerebrospinal fluid concentrations of lipoteichoic and teichoic acids than did ceftriaxone-treated mice (median serum level: <0.5 vs. 27.0 ng/mL, P=.02; median cerebrospinal fluid level of pooled specimens: 97.5 vs. 206.0 ng/mL). Thus, the use of rifampin appears promising for reducing the release of proinflammatory bacterial components and decreasing early mortality in bacterial meningitis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.