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Biomedical subjects

S I Miller

Publications and source records attributed to S I Miller.

At least 55 records · Page 3Linked to original sources
PubMed1997

The treatment of dangerous patients in managed care. Psychiatric hospital utilization and outcome.

The legal criteria for civil commitment dictates that individuals must be mentally ill, and either a danger to themselves, a danger to others, or substantially impaired in their ability to provide for their basic needs. These criteria, which have been adopted as medical necessity criteria by managed care programs, may result in a change in the clinical mix of the psychiatric inpatient population. The present study assesses the incidence of dangerousness among psychiatric inpatients and compares dangerous and nondangerous patients in terms of characteristics and treatment outcomes. The results indicate that for a large regional managed care program, 30% of psychiatric inpatients have a history of dangerousness in the past year. Patients who are rated as dangerous to others during admission have higher rates of complications for treatment and psychiatric disorders such as residential and vocational instability, family disruption, and higher premorbid dysfunction. They are also more likely to engage in disruptive and aggressive behavior during their hospital stays. Despite the higher incidence of acute and long-term dysfunction for dangerous patients, their hospitalization length of stay was comparable to that of patients not rated as dangerous.

Adolescent↗
PubMed1997

Predicting readmission to the psychiatric hospital in a managed care environment: implications for quality indicators.

OBJECTIVE: This study examined predictors of hospital readmission to determine whether readmissions can serve as a quality indicator for an inpatient psychiatric service. METHOD: A series of 255 patients consecutively admitted to any of seven psychiatric hospitals in a regional managed care program were followed to determine whether they were readmitted within 6 months of discharge. Case managers assessed patients with the use of a reliable outcome management/decision support system designed for acute psychiatric services. RESULTS: Patients with greater impairment in self-care, more severe symptoms, and more persistent illnesses were more likely to be readmitted than other patients. Suicidal patients were less likely to be readmitted. There was no evidence to suggest that poor hospital outcome or premature discharge was associated with readmission either within 30 days or within 6 months. CONCLUSIONS: Although patients at risk for hospital admission can be identified, it does not appear that the success of the hospital intervention per se influences the likelihood of readmission. Use of readmission rates as quality indicators for hospital care providers is not recommended.

Acute Disease↗
PubMed1997

Serotonin reuptake inhibitors and the adequacy of antidepressant treatment.

OBJECTIVE: To determine whether the use of serotonin reuptake inhibitors (SSRIs) improves antidepressant medication prescribing patterns for both psychiatric and non-psychiatric physicians. DATA SOURCES/SETTING: Drug utilization review of 4,103 prescriptions for antidepressant medications with patients diagnosed with depressive disorders over an eighteen-month period from the formulary records of a large insurance company. DESIGN: Using standards developed for clinical guidelines, variation in trial and treatment adequacy between drug types and physician specialty was studied. PRINCIPAL FINDINGS: Thirty-five percent of initial antidepressant trials were not prescribed for an adequate duration or at an adequate dosage level. SSRIs were more likely to be prescribed adequately than any other antidepressant reviewed. Psychiatrists were more likely to prescribe antidepressants at an adequate dosage level, whereas non-psychiatric physicians were more likely to attain adequate duration of treatment. CONCLUSIONS: A greater reliance on SSRIs may increase the likelihood of maintaining adequacy in antidepressant treatments. Although higher in cost than other treatment choices, their lower side effect profile is likely to maximize patient satisfaction and physician and patient adherence to guidelines. In order to ensure effective and efficient antidepressant usage, such patterns must be identified and appropriate performance improvement strategies (e.g., Total Quality Improvement, critical pathways) may be employed.

Antidepressive Agents↗
PubMed1996

New insights on molecular pathways utilized by salmonella species in cell binding.

Salmonella infections are a principal source of gastroenteritis and enteric fever in a variety of animals, including humans. An essential step in the development of Salmonella pathogenesis is the entry of bacteria into non-phagocytic cells, including those that line the intestinal epithelium. As a consequence of specific cues from the host intestinal micro-environment, Salmonella entry into the intestinal epithelium is the product of a multistep process that culminates in host cell membrane ruffling, and subsequent bacterial uptake. The events that trigger the internalization event appear to require an array of bacterial secreted proteins, exemplified by the formation of bacterial surface appendages (invasomes) which are important for the induction of host-cell signal transduction pathways that lead to membrane ruffling. In addition, during intestinal disease states induced by Salmonella typhimurium, transepithelial migration of neutrophils rapidly follows attachment of the bacteria to the epithelial membrane. Current evidence indicates that the intestinal epithelium plays a key role in orchestrating the inflammatory response to surface attached S. typhimurium. In this review, we explore current insights on the molecular pathways utilized by Salmonella spp. in cell binding that are important not only in the processes of Salmonella internalization but also in the generation of signals which lead to active states of intestinal inflammation.

Animals↗
PubMed1996

Evaluation of a phoP/phoQ-deleted, aroA-deleted live oral Salmonella typhi vaccine strain in human volunteers.

Improved live oral typhoid fever vaccines may be engineered by deletion of Salmonella-specific virulence genes in Salmonella typhi. Ty445, an aroA-deleted S. typhi Ty2 strain also deleted for the phoP/phoQ Salmonella typhimurium virulence regulatory locus, was tested in human volunteers. Volunteers received escalating single doses of the vaccine; subsequently 14 individuals received two doses of 10(10) c.f.u. without significant side-effects. Control vaccinees received four doses of the live oral typhoid vaccine Ty21a. Of controls, 5/8 seroconverted as measured by increases in serum IgG directed against S. typhi O antigen or whole bacterial antigens in ELISAs. Only 2/14 volunteers receiving the experimental vaccine Ty445 seroconverted. Although a delta aroA delta phoP/phoQ S. typhi strain is overattenuated for use as a typhoid fever vaccine, our data demonstrate that the deletion of the phoP/phoQ locus in S. typhi significantly attenuates this human pathogen.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
PubMed1996

Transcriptional activation of Salmonella typhimurium invasion genes by a member of the phosphorylated response-regulator superfamily.

The Salmonella typhimurium PhoP-repressed locus prgHIJK encodes components of a sec-independent type III secretion apparatus. This apparatus is composed of at least 17 proteins encoded on a 40 kb pathogenicity Island located at centisome 63 on the S. typhimurium chromosome. The secretion apparatus and some of its targets, SapB, SapC and SspD, are necessary for epithelial cell invasion. The transcription of many invasion genes, including prgHIJK, is coordinately activated by HilA, a transcription factor encoded within the pathogenicity island. In this report we identify sirA, a gene located outside the pathogenicity island that is essential for induction of prgHIJK and hilA transcription. sirA encodes a 234-amino-acid protein that is essential for S. typhimurium Ssp (Salmonella secreted protein) secretion and invasion and is similar to response regulators of two-component regulatory systems. sirA-mutant phenotypes could be suppressed by two DNA clones from unlinked loci, designated sirB and sirC. These data suggest that SirA may be phosphorylated in response to S. typhimurium sensing a mammalian microenvironment. Furthermore, SirA phosphorylation is predicted to initiate a cascade of transcription-factor synthesis which results in invasion-gene transcription, Ssp secretion, and bacterial invasion of epithelia.

Amino Acid Sequence↗
PubMed1996

phoP/phoQ-deleted Salmonella typhi (Ty800) is a safe and immunogenic single-dose typhoid fever vaccine in volunteers.

The phoP/phoQ virulence regulatory genes of Salmonella typhi Ty2 were deleted, and the resultant strain (Ty800) was tested as a live attenuated typhoid fever vaccine in human volunteers. Groups of 2 or 3 subjects received single oral doses of 10(7), 10(8), 10(9), or 10(10) cfu. Two volunteers who received the largest dose had self-limited side effects; no bacteremias were detected. Ten of 11 subjects had evidence of intestinal immune responses to the vaccine as measured by increases in S. typhi lipopolysaccharide-specific IgA-secreting cells in peripheral blood samples. Humoral immune responses were measured and compared with those of control vaccinees who received 4 oral doses of S. typhi Ty21a. In the most sensitive assays, 9 of 11 volunteers and 5 of 8 Ty21a control vaccinees had evidence of IgG directed against S. typhi antigens. Ty800 is safe, and single oral doses are highly immunogenic in humans.

Adolescent↗
PubMed1996

Rapid and complete fusion of macrophage lysosomes with phagosomes containing Salmonella typhimurium.

The virulence of Salmonella typhimurium for mice results, in part, from its ability to survive after phagocytosis by macrophages. Although it is generally agreed that intracellular bacteria persist in membrane-bound phagosomes, there remains some question as to whether these phagosomes fuse with macrophage lysosomes. This report describes the maturation of phagosomes containing S. typhimurium inside mouse bone marrow-derived macrophages. Macrophages were infected briefly and incubated for various intervals; then they were examined by fluorescence microscopy for colocalization of bacteria with lysosomal markers. These markers included LAMP-1, cathepsin L, and fluorescent proteins or dextrans preloaded into lysosomes by endocytosis. By all measures, phagosomes containing S. typhimurium merged completely with the lysosomal compartment within 20 min of phagocytosis. The rate of phagosome-lysosome fusion was similar to the rate for phagocytosed latex beads. Phagolysosomes remained accessible to fluid-phase probes and contained lysosomal markers for many hours. Moreover, a large percentage of the wild-type bacteria that were viable 20 min after infection survived longer incubations inside macrophages, indicating that the survivors were not a minor subpopulation that avoided phagosome-lysosome fusion. Therefore, we conclude that S. typhimurium survives within the lysosomal compartments of macrophages.

Animals↗
PubMed1996

Transcriptional regulation of Salmonella virulence: a PhoQ periplasmic domain mutation results in increased net phosphotransfer to PhoP.

A mutation in the phoP/phoQ locus (pho-24) that results in unregulated expression of PhoP-activated genes (phenotype PhoP constitutive [PhoP(c)]) was mapped to phoQ. Change of a Thr to Ile at position 48 of PhoQ was responsible for the PhoP(c) phenotype (attenuation of mouse virulence, defects in epithelial cell invasion, and macrophage spacious phagosome formation). PhoP phosphorylation by membrane extracts required PhoQ, and PhoQ Ile-48-containing membranes demonstrated increased net phosphorylation of PhoP.

Amino Acid Sequence↗
PubMed1996

PhoP-PhoQ activates transcription of pmrAB, encoding a two-component regulatory system involved in Salmonella typhimurium antimicrobial peptide resistance.

Antimicrobial cationic peptides are a host defense mechanism of many animal species including mammals, insects, and amphibians. Salmonella typhimurium is an enteric and intracellular pathogen that interacts with antimicrobial peptides within neutrophil and macrophage phagosomes and at intestinal mucosal surfaces. The Salmonella spp. virulence regulators, PhoP and PhoQ, activate the transcription of genes (pag) within macrophage phagosomes necessary for resistance to cationic antimicrobial peptides. One PhoP-activated gene, pagB, forms an operon with pmrAB (5' pagB-pmrA-pmrB 3'), a two-component regulatory system involved in resistance to the antimicrobial peptides polymyxin, azurocidin (CAP37), bactericidal/permeability-increasing protein (BPI or CAP57), protamine, and polylysine. Expression of pmrAB increased transcription of pagB-pmrAB by activation of a promoter 5' to pagB. pmrAB is also expressed from a second promoter, not regulated by PhoP-PhoQ or PmrA-PmrB, located within the pagB coding sequence. S. typhimurium strains with increased pag locus expression were demonstrated to be polymyxin resistant because of induction of pagB-pmrAB; however, PmrA-PmrB was not responsible for the increased sensitivity of PhoP-null mutants to NP-1 defensin. Therefore, PhoP regulates at least two separate networks of genes responsible for cationic antimicrobial peptide resistance. These data suggest that resistance to the polymyxin-CAP family is controlled by a cascade of regulatory protein expression that activates transcription upon environmental sensing.

Anti-Bacterial Agents↗
PubMed1995

Macrophage-inducible expression of a model antigen in Salmonella typhimurium enhances immunogenicity.

Attenuated Salmonella are useful oral vaccine vectors capable of carrying multiple heterologous antigen genes, but optimal expression of foreign antigens has not yet been achieved. We hypothesized that Salmonella phoP-activated genes, which are transcriptionally activated within antigen-processing macrophages, could prove useful for delivery of heterologous antigens to the immune system. We have created a suicide vector that allows the stable chromosomal insertion of heterologous antigen genes within the phoP-activated gene C (pagC) of Salmonella and permits the expression of heterologous antigens as fusion proteins between the first 84 amino acids of PagC and the chosen antigen. The Escherichia coli phoA gene encoding alkaline phosphatase was cloned into this vector; the resultant plasmid was used to construct Salmonella typhimurium strains that express PagC-alkaline phosphatase fusion proteins from a single chromosomal gene copy. Such strains were administered orally and i.p. as vaccines to BALB/c mice and compared with control strains expressing alkaline phosphatase constitutively. After 3 weeks, mouse sera were analyzed for IgG responses to S. typhimurium lipopolysaccharide and alkaline phosphatase. Remarkably, though all mice had comparable antibody responses to lipopolysaccharide, only mice immunized with strains bearing phoP-activated fusion genes had antibody responses to the heterologous antigen. We conclude that expression of a heterologous antigen from an S. typhimurium in vivo-induced promoter that is activated within macrophages markedly enhances the immunogenicity of a model antigen expressed from a single chromosomal gene copy.

Alkaline Phosphatase↗
PubMed1995

Surface attachment of Salmonella typhimurium to intestinal epithelia imprints the subepithelial matrix with gradients chemotactic for neutrophils.

During intestinal disease induced by Salmonella typhimurium transepithelial migration of neutrophils (PMN) rapidly follows attachment of the bacteria to the epithelial apical membrane. Among the events stimulated by these interactions is the release of chemotaxins that guide PMN through the subepithelial matrix and subsequently through the epithelium itself (McCormick, B.A., S.P. Colgan, C. Delp-Archer, S.I. Miller, and J.L. Madara. 1993. J. Cell Biol. 123:895-907). Given the substantial volume flow that normally characterizes matrix compartments underlying transporting epithelia, it is unclear how such transmatrix signaling is sustained. Here we show that when underlying matrices are isolated from biophysically confluent polarized monolayers of the human intestinal epithelial cell line T84, they fail to support substantial transmatrix migration of PMN unless an exogenous chemotactic gradient is imposed. In contrast, such matrices isolated from confluent monolayers apically colonized with S. typhimurium support spontaneous transmatrix migration of PMN. Such chemotactic imprinting of underlying matrices is resistant to volume wash and is paralleled by secretion of the known matrix-binding chemokine IL-8. Chemotactic imprinting of the matrix underlying S. typhimurium-colonized monolayers is dependent on epithelial protein synthesis, is directional implying the existence of a gradient, and is neutralized by antibodies either to IL-8 or to the IL-8 receptor on PMN. An avirulent S. typhimurium strain, PhoPc, which attaches to epithelial cells as efficiently as wild-type S. typhimurium, fails to induce basolateral secretion of IL-8 and likewise fails to imprint matrices. Together, these observations show that the epithelial surface can respond to the presence of a luminal pathogen and subsequently imprint the subepithelial matrix with retained IL-8 gradients sufficient to resist washout effects of the volume flow that normally traverses this compartment. Such data further support the notion that the primary role for basolateral secretion of IL-8 by the intestinal and likely other epithelia is recruitment of PMN through the matrix to the subepithelial space, rather than directing the final movement of PMN across the epithelium.

Bacterial Proteins↗
PubMed1995

PhoP/PhoQ transcriptional repression of Salmonella typhimurium invasion genes: evidence for a role in protein secretion.

Previously, the PhoP-repressed locus prgH was identified as important for signalling epithelial cells to endocytose Salmonella typhimurium. Characterization of prgH revealed that it is an operon of four genes encoding polypeptides of 392 (prgH), 80 (prgI), 101 (prgJ) and 252 amino acid residues (prgK). Synthesis of the 2.6 kb prgHIJK transcript was repressed in bacteria that activate PhoP/PhoQ, indicating that PhoP/PhoQ regulates prgHIJK by transcriptional repression. The prgI, prgJ and prgK predicted gene products were similar to Shigella flexneri and Yersinia enterocolitica proteins required for secretion of Ipa and Yop virulence factors. Analysis of the culture supernatants from wild-type S. typhimurium demonstrated that at least 25 polypeptides larger than 14 kDa could be detected. In contrast, prgH1::TnphoA, phoP-constitutive and hil-deletion mutants had significant defects in their supernatant protein profiles. The invasion and supernatant protein profile defects of the prgH1::TnphoA mutant were both complemented by a 5.1 kb plasmid that included prgHIJK. These results suggest that PhoP/PhoQ regulates extracellular transport of proteins by transcriptional repression of secretion determinants and that secreted proteins may be involved in signalling epithelial cells to endocytose bacteria.

Amino Acid Sequence↗
PubMed1995

Salmonella typhimurium secreted invasion determinants are homologous to Shigella Ipa proteins.

Salmonella typhimurium secreted proteins (Ssp) were previously implicated in epithelial cell invasion. Here we describe four genes (SspB, sspC, sspD, and sspA), located between spaT and prgH, which encode proteins of 63, 42, 36, and 87 kDa, respectively. These Ssp are homologous to Shigella flexneri secreted proteins IpaB, IpaC, IpaD and IpaA. A non-invasive mutant with a transposon insertion in sspC lacks Ssp of 87, 42 and 36 kDa. Complementation and analyses show that sspC and sspD encode the 42 and the 36 kDa Ssp, while the 87 kDa Ssp is encoded by sspA. sspC and sspD, but not sspA, are required for invasion. Amino-terminal sequencing shows that SspC and SspA are secreted without amino-terminal processing. We further demonstrate that Ssp secretion requires proteins encoded by prgHIJK, homologous to the Shigella Ipa secretion system, since SspA is abundantly secreted by wild-type bacteria but is completely retained within the cellular fraction of a prgHIJK mutant. A precipitate containing abundant SspC and three other major Ssp of 63, 59 and 22 kDa was isolated from culture supernatants of wild-type bacteria. These data indicate that major secreted invasion determinants of S. typhimurium are structurally and functionally homolgous to S. flexneri Ipa proteins.

Amino Acid Sequence↗
PubMed1995

Spacious phagosome formation within mouse macrophages correlates with Salmonella serotype pathogenicity and host susceptibility.

Light microscopic studies indicated a correlation between the virulence for mice of different Salmonella serotypes and the ability to form or maintain spacious phagosomes (SP) within mouse macrophages. Although Salmonella typhimurium induced membrane ruffling, macropinocytosis, and SP formation in macrophages from BALB/c mice, serotypes which are nonpathogenic for mice produced markedly fewer SP. SP formation correlated with both serotype survival within mouse macrophages and reported lethality for mice. Time-lapse video microscopy demonstrated that the human pathogen S. typhi induced generalized macropinocytosis and SP formation in human monocyte-derived macrophages, indicating a similar morphology for the initial phases of this host-pathogen interaction. In contrast to bone marrow-derived macrophages from BALB/c mice, macrophages from S. typhimurium-resistant outbred (CD-1) and inbred (CBA/HN) mice did not initiate generalized macropinocytosis after bacterial infection and formed markedly fewer SP. These deficiencies were not due to the Ihy resistance genotype of these mice, as macrophages from mice that were congenic except for the Ihy locus demonstrated equal SP formation in response to S. typhimurium. The observation that S. typhimurium-resistant CD-1 and CBA/HN mice are deficient in the ability to form and/or maintain SP indicates that a variable host component is important for SP formation and suggests that the ability to induce or form SP affects susceptibility to S. typhimurium. When serotypes nonpathogenic for mice were used to infect BALB/c macrophages, or when CD-1 or CBA/HN mouse macrophages were infected by S. typhimurium, some of the SP that formed shrank within seconds. This rapid shrinkage suggests that SP maintenance is also important for S. typhimurium survival within macrophages. These studies indicate that both host and bacterial factors contribute to SP formation and maintenance, which correlate with Salmonella intracellular survival and the ability to cause lethal enteric (typhoid) fever.

Animals↗
PubMed1995

Transepithelial signaling to neutrophils by salmonellae: a novel virulence mechanism for gastroenteritis.

Salmonella serotypes which elicit human enteritis cannot be distinguished from those that do not on the basis of their in vitro interactions with eukaryotic cells. We have recently reported that an enteritis-producing strain of Salmonella typhimurium signals intact intestinal epithelium to recruit subepithelial neutrophils to migrate across the epithelial (B. A. McCormick, S. P. Colgan, C. D. Archer, S. I. Miller, and J. L. Madara, J. Cell Biol. 123:895-907, 1993). We now utilize a cell culture model of human intestinal epithelium (with T84 cells) to examine whether such transepithelial signaling to neutrophils by salmonellae is predictive of potential to elicit gastroenteritis. Various Salmonella serotypes, including S. typhimurium, S. enteritidis, S. pullorum, S. arizonae, S. typhi, and S. paratyphi, as well as invasion-defective mutants of S. typhimurium, were studied. Strains or serotypes which elicit diffuse enteritis in humans (defined histologically as transepithelial migration of neutrophils) exhibited transepithelial signaling to neutorphils across epithelial cell monolayers, while those which do not elicit diffuse enteritis in humans did not display transepithelial signaling. In contrast, the ability to enter the apical surface of T84 cells did not differentiate strains or serotypes which induce diffuse enteritis from those which do not. These results strongly suggest that the ability of salmonellae to elicit transepithelial signaling to neutrophils is a key virulence mechanism underlying Salmonella-elicited enteritis.

Cells, Cultured↗
PubMed1995

Characterization of the Salmonella typhimurium pagC/pagD chromosomal region.

The PhoP/PhoQ two-component system regulates Salmonella typhimurium genes that are essential to bacterial virulence and survival within macrophages. The best characterized of these PhoP-activated genes (pag) is pagC, which encodes a 188-amino-acid envelope protein (W. S. Pulkkinen and S. I. Miller, J. Bacteriol. 173:86-93, 1991). We here report the identification of four genes (pagD, envE, msgA, and envF) located 5' to pagC. Each gene is transcribed from its own promoter, two of which (msgA and pagD) were defined by primer extension analysis. Three of these genes (pagD, envE, and envF) are predicted to encode envelope proteins. The pagD gene is transcribed in a direction opposite from that of and adjacent to pagC and is positively regulated by PhoP/PhoQ. Transposon insertions within pagD and msgA attenuate bacterial virulence and survival within macrophages; however, deletion of pagD has no effect on virulence. The product of the envF gene is predicted to be a lipoprotein on the basis of the presence of a consensus lipid attachment site. The low G + C content of these genes and the homology of msgA to Shigella plasmid DNA suggest that this region may have been acquired by horizontal transmission.

Amino Acid Sequence↗