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1.  Acne: a review of immunologic and microbiologic factors 
Postgraduate Medical Journal  1999;75(884):328-331.
Acne vulgaris is a self-limiting skin disorder seen primarily in adolescents, whose aetiology appears to be multifactorial. The four main aetiological factors are hypercornification of the pilosebaceous duct, increased sebum production, colonization with Propionibacterium acnes, and subsequently the production of inflammation. Considerable investigation has addressed the immunologic reaction to extracellular products produced by the acne-causing organism, P acnes. The immunologic response involves both humoral and cell-mediated pathways. Further research should clarify the role of complement, cytotoxins, and neutrophils in this acne-forming response.

Keywords: acne vulgaris; Propionibacterium acnes
PMCID: PMC1741272  PMID: 10435165
2.  Effect of age on intraoperative cerebrovascular autoregulation and near-infrared spectroscopy-derived cerebral oxygenation 
BJA: British Journal of Anaesthesia  2011;107(5):742-748.
Age is an important risk factor for perioperative cerebral complications such as stroke, postoperative cognitive dysfunction, and delirium. We explored the hypothesis that intraoperative cerebrovascular autoregulation is less efficient and brain tissue oxygenation lower in elderly patients, thus, increasing the vulnerability of elderly brains to systemic insults such as hypotension.
We monitored intraoperative cerebral perfusion in 50 patients aged 18–40 and 77 patients >65 yr at two Swiss university hospitals. Mean arterial pressure (MAP) was measured continuously using a plethysmographic method. An index of cerebrovascular autoregulation (Mx) was calculated based on changes in transcranial Doppler flow velocity due to changes in MAP. Cerebral oxygenation was assessed by the tissue oxygenation index (TOI) using near-infrared spectroscopy. End-tidal CO2, O2, and sevoflurane concentrations and peripheral oxygen saturation were recorded continuously. Standardized anaesthesia was administered in all patients (thiopental, sevoflurane, fentanyl, atracurium).
Autoregulation was less efficient in patients aged >65 yr [by 0.10 (se 0.04; P=0.020)] in a multivariable linear regression analysis. This difference was not attributable to differences in MAP, end-tidal CO2, or higher doses of sevoflurane. TOI was not significantly associated with age, sevoflurane dose, or Mx but increased with increasing flow velocity [by 0.09 (se 0.04; P=0.028)] and increasing MAP [by 0.11 (se 0.05; P=0.043)].
Our results do not support the hypothesis that older patients' brains are more vulnerable to systemic insults. The difference of autoregulation between the two groups was small and most likely clinically insignificant.
PMCID: PMC3192482  PMID: 21835838
age groups; anaesthesia; cerebrovascular circulation
3.  Antisense oligonucleotides to class III β-tubulin sensitize drug-resistant cells to Taxol 
British Journal of Cancer  1999;80(7):1020-1025.
A major impediment to the successful use of Taxol in the treatment of cancer is the development of drug resistance. The major cellular target of Taxol is the microtubule that is comprised of α- and β-tubulin heterodimers. Binding sites for Taxol have been delineated on the β-tubulin subunit that has six isotypes. We have recently described increased expression of the brain-specific human class III β-tubulin isotype, encoded by the Hβ4 gene, in both Taxol-resistant ovarian tumours and non-small-cell lung cancer cell lines. To evaluate directly the role of the class III β-tubulin isotype in mediating Taxol resistance, antisense phosphorothioate oligodeoxynucleotides (ODN) targeted against various regions of the Hβ4 gene have been designed and examined for their efficacy in reducing Hβ4 gene and protein expression. Taxol-resistant lung cancer cells, A549-T24, which are 17-fold resistant to Taxol and display a fourfold increase in Hβ4 expression compared to the parental A549 cells, were treated with 1 μM antisense ODNs. Two ODNs, AS1 and AS3, were found to reduce mRNA expression by 40–50%, as determined by reverse transcription polymerase chain reaction. A concentration-dependent reduction in Hβ4 mRNA expression was demonstrated with AS1 ODN. Immunofluorescence staining of cells treated with AS1 ODN revealed a decrease in class III protein expression which corresponded to a 39% increase in sensitivity to Taxol (P < 0.005). These findings support an important role for Hβ4 (class III) β-tubulin expression in Taxol resistance and have potential implications for the treatment of Taxol-resistant tumours. © 1999 Cancer Research Campaign
PMCID: PMC2363042  PMID: 10362110
Taxol; antisense; tubulin; lung cancer; drug resistance
4.  Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. 
Journal of Clinical Investigation  1997;100(5):1282-1293.
The treatment of advanced ovarian cancer with taxol is hindered by the development of drug resistance. The cellular target for taxol is the microtubule that is stabilized by the drug. Taxol preferentially binds to the beta subunit of tubulin of which there are six distinct isotypes in mammalian cells. We have used highly specific oligonucleotides and polymerase chain reaction to analyze expression of all six beta-tubulin genes. Human lung cancer cells (A549) were selected in 12 and 24 nM taxol resulting in cell lines that were 9- and 17-fold resistant, respectively. These cells displayed an altered ratio of classes I, II, III, and IVa beta-tubulin isotypes. Ovarian tumors, seven untreated primary and four taxol- resistant tumor-bearing ascites, displayed significant increases (P < 0.005) in classes I (3.6-fold), III (4.4-fold), and IVa (7.6-fold) isotypes in the taxol-resistant samples as compared with untreated primary ovarian tumors. The increased expression appears to be related to the resistance phenotype, as the basal levels of the class III and IVa isotypes in the untreated tumors were extremely low. This is the first report of altered expression of specific beta-tubulin genes in taxol-resistant ovarian tumors and we propose that the latter may play a role in clinical resistance to taxol.
PMCID: PMC508306  PMID: 9276747
5.  Vesicular stomatitis virus Indiana glycoprotein as a T-cell-dependent and -independent antigen. 
Journal of Virology  1994;68(6):3650-3655.
The neutralizing immunoglobulin M (IgM) response to vesicular stomatitis virus (VSV) has been shown to be largely T-cell independent in several T-cell-deficient models of mice. By using different antigen froms of VSV, VSV antigen doses could be graded in vivo (infectious > > UV inactivated > formalin inactivated). The present study reveals a T-cell-dependent component of the neutralizing IgM response in nude mice given intravenous injections of low doses of noninfectious UV-inactivated VSV serotype Indiana (VSV-IND) only if the mice are transfused with VSV-IND-specific helper T cells. Instead, nude mice immunized with infectious VSV, which leads to greater antigen doses in vivo, were able to mount an IgM response in the absence of T cells. These results indicate that the IgM response to low doses of VSV-IND glycoprotein (G) is T-cell dependent. Nude mice immunized with infectious VSV also made a variable but low VSV-IND-neutralizing IgG response. A VSV-IND matrix (M)-specific helper T-cell line rendered this response more consistent, much higher, and longer lasting. Thus (i) VSV-G induces a mostly T-cell-independent but partially T-cell-dependent IgM (the latter can be visualized best at low doses of antigen) and (ii) the antibody response to VSV in nude mice proceeds through steps, i.e., IgM and IgG, that are dose dependent. The results suggest that the predominant role of helper T cells may be to expand and maintain the individual steps of differentiating B cells.
PMCID: PMC236869  PMID: 7910641
6.  Characterization of T-helper epitopes of the glycoprotein of vesicular stomatitis virus. 
Journal of Virology  1994;68(3):1573-1580.
The T-helper (Th) cell epitopes in the glycoprotein (GP) of vesicular stomatitis virus serotype Indiana (VSV-IND) were analyzed with a complete panel of overlapping synthetic peptides. Three Th-cell epitopes in C57BL/6 (H-2b) mice and two epitopes in BALB/c (H-2d) mice were defined by their ability to stimulate in vitro proliferation of virus-primed, CD8+ T-cell-depleted spleen cells in a class II-restricted manner. A series of CD4+, I-Ab-restricted T-cell hybridomas from VSV-primed C57BL/6 mice were characterized by their production of interleukin-2 and interleukin-3 upon stimulation with VSV-IND or purified VSV GP in vitro. Of nine hybridomas derived from three independent fusions, five were specific for amino acids (aa) 415 to 433 (p8) of VSV-IND GP, three recognized aa 52 to 71 (p41), and one reacted against aa 316 to 335 (p17). Fluorocytometric analysis of Th hybridomas or VSV-stimulated T-cell lines with monoclonal antibodies specific for the T-cell receptor V beta chain did not reveal obvious correlations between the T-cell receptor V beta gene segment used and the epitope recognized. All three peptides recognized by H-2b mice and both epitopes recognized by H-2d mice which were characterized in primed T-cell populations were capable of activating specific Th cells in vivo as measured by the induction of antibody class switch from immunoglobulin M (IgM) to IgG. Thus, the epitopes are relevant for VSV GP-specific Th response in vivo and are able to provide functional help for the production of anti-VSV-specific neutralizing IgG antibodies.
PMCID: PMC236614  PMID: 7508998

Results 1-6 (6)