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PubMed1999

Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance.

Pharmacodynamic properties can be used to divide antibiotics into two major classes based on their mechanism of bactericidal action: (1) concentration-dependent drugs, such as aminoglycosides and fluoroquinolones, and (2) concentration-independent drugs, including the beta-lactams. Antibiotics also differ in the postantibiotic effect (PAE) that they exert. In general, concentration-dependent drugs have a more prolonged PAE than concentration-independent drugs, particularly against Gram-negative pathogens. Pharmacodynamic classifications have important implications for the planning of drug regimens. For concentration-dependent drugs, peak concentration to minimal inhibitory concentration (MIC) ratios of approximately 10 are associated with clinical success. Therefore, high drug levels should be the goal of therapy. This is best achieved by high doses taken once daily. This approach, however, is not feasible for the fluoroquinolones owing to dose-limiting CNS toxicity. Concentration-independent agents are most effective when the duration of serum concentrations is higher than the pathogen's MIC (time >MIC) for a significant proportion of the dosing interval. Frequent dosing or continuous infusions can increase the time >MIC. Concentrations of antibiotics that are sublethal can permit the emergence of resistant pathogens. Optimization of antibiotic regimens on the basis of pharmacodynamic principles could thus significantly diminish the emergence of antibiotic resistance.

Anti-Bacterial Agents↗
PubMed1978

Primary amoebic meningoencephalitis.

As a serendipitous by-product of polio virus research, a highly fatal amoebic meningoencephalitis was recognized in animals. The causative microorganisms, contaminants of the viral cultures, were identified as small soil amoebae. These organisms, previously considered non-pathogenic, are prevalent throughout the world. Based on animal studies, the original investigators suggested the possibility of a similar disease in humans. Seven years later, human cases of amoebic meningoencephalitis were reported from widely separated areas of the world. Since 1965, a total of 79 cases have been reported. The literature of primary amoebic meningoencephalitis is presented. The history of the discovery and elucidation of this disease is reviewed. The 79 cases reported in the world literature are divided into two groups, those diagnosed retrospectively after reviewing previous deaths from meningoencephalitis, and those diagnosed at the time of the illness. The classification, morphology, pathogenicity, virulence and distribution of pathogenic soil amoebae are reviewed. The presenting clinical findings, diagnostic procedures, pathology, and management of this recently recognized, highly fatal, human disease is presented along with a report of a new case. Otolaryngologists should become familiar with this serious disorder with a transnasal portal of entry.

Amebiasis↗
PubMed1999

Pathologic classification of chronic allograft nephropathy: pathogenic and prognostic implications.

BACKGROUND: After transplantation renal allografts frequently develop interstitial fibrosis and tubular atrophy, and these pathologic changes are the hallmarks of chronic allograft nephropathy (CN). However, the diagnosis of CN has no specific pathogenic implications. In this study we sought to determined whether a subclassification of CN according to vascular pathology correlates with posttransplant events, particularly acute rejection, and graft survival. METHODS: A total of 419 patients with moderate to severe CN were subdivided into: (1) transplant arteriopathy (TA, n=233, 56%); (2) arteriolar hyalinosis (AH, n=89, 21%); and (3) no characteristic vascular pathology (IFb, n=97, 23%). RESULTS: Patients with AH differed significantly from patients with TA or IFb in the following parameters: (1) AH was diagnosed later after transplantation (P=0.001); (2) fewer patients with AH had acute rejection (AR) before the diagnosis of CN (P<0.0001). For example, 44% of AH and 75% of TA had AR before CN; (3) patients with AH also had fewer AR episodes than the other two groups (P<0.0001); finally, (4) graft survival was better in patients with AH than in patients with TA (P=0.01 by chi2, P=0.001 by Cox). In contrast, there were no significant differences between patients with TA and IFb. By multivariate analysis the survival of grafts with CN correlated with: (1) serum creatinine at diagnosis (P<0.0001), (2) recipient's weight (P=0.004); (3) presence of FGS or level of proteinuria (P=0.03); and (4) the occurrence of AR after the diagnosis of CN (P<0.0001). Regarding the latter, AR were more common (P=0.007) and more numerous (P=0.005) in patients with TA or IFb than in AH. CONCLUSIONS: CN can be classified according to vascular pathology in the majority of cases, and this classification correlates with graft survival. Although some forms of CN are closely associated with the occurrence of AR others are not. This study also uncovered several variables that correlate with the survival of grafts with CN.

Adult↗
PubMed1999

Molecular characterization and module composition of P22-related Salmonella phage genomes.

Genomes of newly isolated Salmonella phages were analysed by comparison of their EcoRI restriction patterns and by hybridization. Characteristic hybridization probes from reference phages P22, ES18 and E. coli phage lambda were chosen. Four probes selected from the lysis region examined the dispersal of the lambdoid lysis genes. Other probes characterized were the replication genes and part of the structural genes. The complex immunity region was investigated by means of hybridization as well as biological tests. The results showed the relationship of the isolated phages to the P22 branch of the lambdoid phages and revealed their modular genome organization consisting of different proportions of P22-related sequences. DNA restriction patterns of phages released from Salmonella strains sampled in limited geographical areas were significantly less heterogeneous than those of phages released from the worldwide sampled SARA collection. The use of prophage restriction patterns as a tool for the typing of Salmonellae to support the epidemiologic classification of pathogenic strains is discussed.

Bacteriophage P22↗
PubMed1994

Escherichia coli serogroup O111 includes several clones of diarrheagenic strains with different virulence properties.

Genetic variation among isolates of Escherichia coli O111 obtained mostly from patients with diarrhea in Brazil was assessed by multilocus enzyme electrophoresis to characterize chromosomal genotypes and by gene probes and adherence assays to characterize virulence properties. Among the 152 isolates, we resolved 16 distinct electrophoretic types (ETs), which differed on average at 40% of the enzyme loci. We identified four major bacterial O111 clones of different disease classes: ET 12, which includes the bulk of the enteropathogenic E. coli strains, typically showing localized adherence and intimate attachment in tissue culture assays; ET 1, which includes strains with a different set of virulence markers; ET 9, which includes strains that show intimate attachment but lack localized adherence and Shiga-like toxin genes; and ET 8, which includes strains that are Shiga-like toxin producers and have the corresponding traits of enterohemorrhagic E. coli. Enteroaggregative strains constituted ET 10 and also occurred in ET 1. Isolates of the major clones were found in South and North America and matched in ET and virulence factors to previously described diarrheagenic clones that are widely disseminated in the human population. Because the major clones are genetically distantly related and exhibit different combinations of virulence factors, we hypothesize that they have distinct mechanisms of pathogenesis. The results indicate that genetic divergence of bacteria with the O111 antigen, as measured by allelic variation in enzyme loci, is accompanied by divergence in virulence properties of clones so that identification and classification of pathogenic E. coli strains cannot be based solely on serotyping or a single virulence factor.

Bacterial Adhesion↗
PubMed2026

Large-scale functional annotation establishes a reference framework for human LRRK2 variants.

Pathogenic variants in leucine-rich repeat kinase 2 (LRRK2)1are among the most frequent monogenic causes of Parkinson's disease (PD)2 and act through a gain-of-function mechanism of increased kinase activity. LRRK2-targeted therapies are in clinical development, but interpretation of the rapidly expanding catalogue of rare LRRK2 variants remains a barrier to translation. Here, we present functionally annotated data on >350 LRRK2 coding variants using a standardized cellular assay with Rab10 phosphorylation as a readout of kinase activity and integrated these data with curated genetic and clinical annotations from the Movement Disorders Society Genetic Mutation Database (MDSGene). Variants differed in activation magnitude, ranging from modest increases (e.g., p.G2019S) to strongly activating substitutions such as p.Y1699C or p.L1795F. Activating variants occurred across the full length of LRRK2, although the largest effects clustered within the ROC-COR regulatory hub, where structural analysis identified subdomains forming an allosteric scaffold controlling kinase output. All known/established pathogenic variants showed increased activity, whereas benign and likely benign variants remained within the wild-type range. Functional effect sizes correlated with pathway activation in patient-derived immune cells, altogether providing a framework for ACMG-based variant interpretation in which kinase activation can support PS3 functional evidence for reclassification of variants.

Protein phosphorylation↗
PubMed1989

[Teeth extractions on diabetics patients].

In this paper the writer primarily mentions the temporary theories on the classification and pathogenic origin of diabetes. Furthermore, he describes the most important etiological factors of the appearance of the disease and its clinical picture. He specially extends to mentioning the probability of appearance of acute complications during dental help to a diabetic patient. He also underlines that the degree the reformatory functions of the organism are influenced by the interference of chronic complications which he describes. After maintaining the basic precautionary lines during the extraction of teeth in diabetic patients he describes the basic approach necessary in case of acute complications of diabetes. In the paper are also mentioned the latest methods of direct calculation of the level of glucose both to blood and the urine of the patient.

Blood Glucose↗
PubMed1977

X-ray microanalysis as applied to fungal tissues.

Analytical electron microscopy combines the techniques of high-resolution electron microscopy and high-sensitivity X-ray microanalysis of samples. Spectrometry of the elements (characteristic X-rays produced by a scanning electron microprobe) was employed to detect some elements of Mendeleev's classification in pathogenic fungi for humans. X-ray microanalysis applied in wavelength dispersive spectrometry was used to study Coccidioïdes immitis, Paracoccidioïdes brasiliensis and Trichosporum cutaneum.

Coccidioides↗
PubMed1994

[Urethro-adnexitis in the man and acute urethral syndrome in the woman. Microbiological and immunologic studies of etiologic classification].

Both common pathogens and unconventional, fastidious bacteria, viruses, parasites, and fungi are causative agents in male urethro-adnexitis and in female acute urethral syndrome. Uropathogens, Neisseria gonorrhoeae, Treponema pallidum, Mycobacterium tuberculosis, Chlamydia trachomatis, Mycoplasma spp., Haemophilus ducreyi, Calymmatobacterium granulomatis, Gardnerella vaginalis, anaerobic bacteria, Herpes simplex virus type II (HSV II), papillomaviruses (HPV), Trichomonas vaginalis and Candida spp. must be considered. The various diagnostic procedures and criteria applied for aetiological classification in cases of balanitis, urethritis, prostatitis, epididymitis, orchitis, and acute urethral syndrome are reviewed and evaluated.

Acute Disease↗
PubMed1996

Emended description of Herbaspirillum; inclusion of [Pseudomonas] rubrisubalbicans, a milk plant pathogen, as Herbaspirillum rubrisubalbicans comb. nov.; and classification of a group of clinical isolates (EF group 1) as Herbaspirillum species 3.

[Pseudomonas] rubrisubalbicans, a mild plant pathogen. Herbaspirillum seropedicae, and EF group 1 strains (clustered by an immunological method) were investigated by a polyphasic approach with DNA-rRNA and DNA-DNA hybridizations and auxanography on 147 substrates. Our results show that they all belong to the genus Herbaspirillum. In addition to H. seropedicae, two other species are described: Herbaspirillum rubrisubalbicans and a new unnamed species, Herbaspirillum species 3, containing mainly strains of clinical origin. The three species can be differentiated on the basis of their auxanographic features and DNA-DNA similarities. The type strain of H. rubrisubalbicans is NCPPB 1027 (=LMG 2286); representative strains of the third Herbaspirillum species are strains CCUG 189 (=LMG 5523), CCUG 10263 (=LMG 5934), and CCUG 11060 (=LMG 5321). It has been confirmed that H. rubrisubalbicans is an endophytic diazotroph. It colonizes the roots, the stems, and predominantly the leaves of sugarcane (Saccharum spp.), while Herbaspirillum seropedicae colonizes in large numbers many different species of the Gramineae. Both diazotrophic Herbaspirillum species could be differentiated with meso-erythritol and N-acetylglucosamine. Oligonucleotide probes based on partial sequences of the 23S rRNA of H. seropedicae and H. rubrisubalbicans (HS and HR probes, respectively), were constructed and used as diagnostic probes.

Base Sequence↗
PubMed1992

[Classification of septicemias. A clinical and pathogenic approach].

Classic sepsis is characterized by the presence of bacteria in blood originating from a primary infection site with secondary location at other sites. Some infectious diseases like typhoid and paratyphoid fever, brucellosis an others share this pathogenetic mechanism but have a characteristic clinical course and usually a good prognosis. After analyzing the differences between the 2 types the author proposes the terms "non specific" and "specific" for each type of sepsis, respectively. The differences between the 2, the organism involved and different reaction of the host in types, may be related to different pathogenetic effects of each case.

Brucellosis↗
PubMed1990

Numerical classification and identification of Bacillus sphaericus including some strains pathogenic for mosquito larvae.

Ninety-one strains of Bacillus sphaericus, including representatives of all the established DNA homology groups, related round-spored and oval-spored species, and six strains pathogenic for mosquito larvae, were examined for 155 characters. Numerical analyses (Jaccard coefficient/average linkage clustering) based on the 88 variable features revealed 14 clusters at the 79% similarity level that contained more than one strain and 17 single member clusters. All insect pathogenic strains were recovered in a single cluster and the classification was in accord with an established classification based on DNA sequence homology. Two frequency matrices for probabilistic identification were constructed and tested. A comprehensive matrix comprising 14 mesophilic, round-spored taxa and 27 tests gave good results for identification of hypothetical median organisms, cluster overlap and identifications of representative strains (based on data generated in the classification study). Reference strains for the 14 taxa and eight additional insect pathogenic strains were examined for the 27 tests and were correctly identified with high scores using this matrix. A second matrix comprising seven taxa and 13 tests also performed well in the theoretical evaluation and correctly identified the reference strains and insect pathogenic strains.

Animals↗
PubMed1999

Bacterial phylogenetic clusters revealed by genome structure.

Current bacterial taxonomy is mostly based on phenotypic criteria, which may yield misleading interpretations in classification and identification. As a result, bacteria not closely related may be grouped together as a genus or species. For pathogenic bacteria, incorrect classification or misidentification could be disastrous. There is therefore an urgent need for appropriate methodologies to classify bacteria according to phylogeny and corresponding new approaches that permit their rapid and accurate identification. For this purpose, we have devised a strategy enabling us to resolve phylogenetic clusters of bacteria by comparing their genome structures. These structures were revealed by cleaving genomic DNA with the endonuclease I-CeuI, which cuts within the 23S ribosomal DNA (rDNA) sequences, and by mapping the resulting large DNA fragments with pulsed-field gel electrophoresis. We tested this experimental system on two representative bacterial genera: Salmonella and Pasteurella. Among Salmonella spp., I-CeuI mapping revealed virtually indistinguishable genome structures, demonstrating a high degree of structural conservation. Consistent with this, 16S rDNA sequences are also highly conserved among the Salmonella spp. In marked contrast, the Pasteurella strains have very different genome structures among and even within individual species. The divergence of Pasteurella was also reflected in 16S rDNA sequences and far exceeded that seen between Escherichia and Salmonella. Based on this diversity, the Pasteurella haemolytica strains we analyzed could be divided into 14 phylogenetic groups and the Pasteurella multocida strains could be divided into 9 groups. If criteria for defining bacterial species or genera similar to those used for Salmonella and Escherichia coli were applied, the striking phylogenetic diversity would allow bacteria in the currently recognized species of P. multocida and P. haemolytica to be divided into different species, genera, or even higher ranks. On the other hand, strains of Pasteurella ureae and Pasteurella pneumotropica are very similar to those of P. multocida in both genome structure and 16S rDNA sequence and should be regarded as strains within this species. We conclude that large-scale genome structure can be a sensitive indicator of phylogenetic relationships and that, therefore, I-CeuI-based genomic mapping is an efficient tool for probing the phylogenetic status of bacteria.

Base Sequence↗
PubMed1996

Classifying extraintestinal non-typhoid Salmonella infections.

Non-typhoid Salmonella infection in man has been divided into five clinical groups: gastroenteritis, enteric fever, bacteraemia, chronic carrier state and localized infection. This classification has neither pathogenic nor prognostic significance. We retrospectively reviewed the charts of 183 patients with extraintestinal salmonellosis who presented to our institution during a period of 32 years. Patients were classified into four groups: primary bacteraemia (PB), enteritis-associated bacteraemia (secondary bacteraemia) (SB), digestive focal infection (DI) and non-digestive focal infection (NDI). Sex, age, acquisition, underlying disease and outcome were compared between patients with bacteraemia and diseases with focal infection. The differences found between PB and SB were: community acquisition (66% in PB and 85% in SB, p = 0.06) severe immunosuppression (53% in PB and 15% in SB, p < 0.001) and mortality (37% in PB and 3% in SB, p < 0.001). The differences found between NDI and DI were: age over 60 years (45% in NDI and 18% in DI, p < 0.05), severe immunosuppression (51% in NDI and 12% DI, p < 0.001) and associated bacteraemia (38% in NDI and 6% in DI, p < 0.001). This classification of extraintestinal salmonellosis may have pathogenic and prognostic implications, and could help us to understand the clinical significance of this disease.

Aged↗
PubMed1980

Inoculation of pigs with Streptococcus spp. isolated from arthritic porcine joints.

The intricacies of the serological grouping of streptococci are discussed. The pathogenicity and accurate classification of streptococci isolated from arthritic porcine joints were in doubt. Pure cultures of these isolates were inoculated intravenously into healthy pigs to ascertain their pathogenicity and in an attempt to fulfil Koch's postulates. The pathogenesis of streptococcal arthritis in swine is discussed. On intravenous inoculation into experimental pigs the streptococcal isolates showed varying degrees of pathogenicity and arthritogenesis.

Animals↗