Biomedical subjects

Michael Hahn

Publications and source records attributed to Michael Hahn.

11 recordsLinked to original sources

PubMed2005

Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor.

Autoimmune diseases are caused by self-reactive lymphocytes that have escaped deletion. Here we have determined the structure of the trimolecular complex for a T cell receptor (TCR) from a patient with multiple sclerosis that causes autoimmunity in transgenic mice. The structure showed a TCR topology notably different from that of antimicrobial TCRs. Rather than being centered on the peptide-major histocompatibility complex, this TCR contacted only the N-terminal peptide segment and made asymmetrical interactions with the major histocompatibility complex helices. The interaction was dominated by the hypervariable complementarity-determining region 3 loops, indicating that unconventional topologies are possible because of the unique complementarity-determining region 3 sequences created during rearrangement. This topology reduces the interaction surface with peptide and alters the geometry for CD4 association. We propose that unusual TCR-binding properties can permit autoreactive T cells to escape deletion.

Amino Acid Sequence↗

PubMed2005

Unusual features of self-peptide/MHC binding by autoimmune T cell receptors.

Structural studies on T cell receptors (TCRs) specific for foreign antigens demonstrated a remarkably similar topology characterized by a central, diagonal TCR binding mode that maximizes interactions with the MHC bound peptide. However, three recent structures involving autoimmune TCRs demonstrated unusual interactions with self-peptide/MHC complexes. Two TCRs from multiple sclerosis patients bind with unconventional topologies, and both TCRs are shifted toward the peptide N terminus and the MHC class II beta chain helix. A TCR from the experimental autoimmune encephalomyelitis (EAE) model binds in a conventional orientation, but the structure is unusual because the self-peptide only partially fills the binding site. For all three TCRs, interaction with the MHC bound self-peptide is suboptimal, and only two or three TCR loops contact the peptide. Optimal TCR binding modes confer a competitive advantage for antimicrobial T cells during an infection, whereas altered binding properties may permit survival of a subset of autoreactive T cells during thymic selection.

Animals↗

PubMed2005

Intravenous proton pump inhibitors before endoscopy in bleeding peptic ulcer with high-risk stigmata: a multicentre comparative study.

BACKGROUND: It is not clear if starting intravenous proton pump inhibitors (IV PPI) before endoscopic therapy provides additional benefit over starting it afterward in patients with high-risk ulcer stigmata of peptic ulcer disease. METHODS: All patients who received IV pantoprazole bolus and infusion and underwent endoscopy in six Canadian hospitals over 20 months were reviewed. Only patients with high-risk ulcer stigmata (arterial bleeding, oozing, nonbleeding visible vessel or adherent clot) were included. Patients receiving IV PPI before endoscopy (before group) were compared with those who received it after endoscopy (after group) with respect to endoscopic findings and, secondarily, to patient demographics and clinical outcomes. RESULTS: The demographics and baseline characteristics of the before group (n=57) and the after group (n=109) were similar. The before group was more likely to have had IV PPI started outside of daytime hours, and median time to endoscopy in patients admitted with upper gastrointestinal bleeding was 24 h (interquartile range 9.5 to 35) in the before group and 11.3 h (interquartile range 3.7 to 17.2) in the after group (P<0.0001). At the time of endoscopy, 33% of patients in the before group had actively bleeding lesions (Forrest 1a or 1b) compared with 54% in the after group (P=0.01), but there were no significant differences in rebleeding, surgical rates, intensive care unit admission or death between the groups. CONCLUSION: IV PPI infusions before endoscopy may lower the proportion of actively bleeding peptic ulcer lesions at endoscopy, but this finding does not appear to affect rates of rebleeding, surgery or death.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2005

Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways.

Interactions between the protein kinase C and Chk1 inhibitor UCN-01 and rapamycin in human leukemia cells have been investigated in relation to apoptosis induction. Treatment of U937 monocytic leukemia cells with rapamycin (10 nmol/L) in conjunction with a minimally toxic concentration of UCN-01 (100 nmol/L) for 36 hours resulted in marked potentiation of mitochondrial injury (i.e., loss of mitochondrial membrane potential and cytosolic release of cytochrome c, AIF, and Smac/DIABLO), caspase activation, and apoptosis. The release of cytochrome c, AIF, and Smac/DIABLO were inhibited by BOC-D-fmk, indicating that their release was caspase dependent. These events were associated with marked down-regulation of Raf-1, MEK, and ERK phosphorylation, diminished Akt activation, and enhanced phosphorylation of c-Jun NH2-terminal kinase (JNK). Coadministration of UCN-01 and rapamycin reduced the expression levels of the antiapoptotic members of the Bcl-2 family Mcl-1 and Bcl-xL and diminished the expression of cyclin D1 and p34(cdc2). Furthermore, enforced expression of a constitutively active MEK1 or, to a lesser extent, myristoylated Akt construct partially but significantly attenuated UCN-01/rapamycin-mediated lethality in both U937 and Jurkat cell systems. Finally, inhibition of the stress-related JNK by SP600125 or by the expression of a dominant-negative mutant of c-Jun significantly attenuated apoptosis induced by rapamycin/UCN-01. Together, these findings indicate that the mammalian target of rapamycin inhibitor potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types and suggest that inhibition of both Raf-1/MEK/ERK and Akt cytoprotective signaling pathways as well as JNK activation contribute to this phenomenon.

Antibiotics, Antineoplastic↗

PubMed2004

Increased mortality and spatial memory deficits in TNF-alpha-deficient mice in ceftriaxone-treated experimental pneumococcal meningitis.

Tumor necrosis factor-alpha (TNF-alpha) is critically involved in inflammation and may participate in hippocampal injury in bacterial meningitis. In a mouse model of ceftriaxone-treated pneumococcal meningitis, spatial memory and motor performance of TNF-alpha-deficient (n = 57) and control mice (n = 55) were investigated. After infection, therapy was initiated with ceftriaxone (100 mg/kg twice daily for 5 days). Sixty-three percent TNF-alpha-deficient mice and 40% control animals died within 6 days (Fisher's exact test: P = 0.02). TNF-alpha-deficient mice surviving pneumococcal meningitis took substantially longer to reach the hidden platform than controls, and the distance of swim tracks was longer (P = 0.02). The swim speed in both groups was similar (P = 0.59). The proliferation of dentate granule cells was lower in TNF-alpha-deficient than in wild-type mice (P = 0.03). In pneumococcal meningitis, TNF-alpha deficiency caused increased mortality and stronger deficits in spatial memory possibly due to impaired neurogenesis.

Animals↗

PubMed2004

Description of prescribing practices in patients with upper gastrointestinal bleeding receiving intravenous proton pump inhibitors: a multicentre evaluation.

BACKGROUND: Intravenous forms of proton pump inhibitors (IV PPI) are routinely used for patients with acute upper gastrointestinal bleeding, but a significant concern for their inappropriate use has been suggested. patients and METHODS: All consecutive patients who received IV PPI (pantoprazole) over 20 months in six Canadian hospitals were reviewed. Prescribing practices, endoscopic findings and outcomes were recorded. RESULTS: A total of 854 patients received IV PPI. Over 90% of patients were given IV PPI for treatment of known or suspected active upper gastrointestinal bleeding. Most patients (69%) underwent upper endoscopy, and 58% of these patients had peptic ulcer disease (PUD). The majority of patients who had endoscopy (57%) had IV PPI administered in advance of the procedure. Of the 334 patients who had IV PPI given in advance, 46 (13.8%) were found to have high risk bleeding PUD stigmata at endoscopy. The remaining 288 patients (86.2%) with advance IV PPI had low-risk PUD lesions or non-PUD lesions; IV PPI was continued after endoscopy in 164 (56.9%) of these patients. CONCLUSIONS: IV PPI is often used before endoscopy in suspected upper gastrointestinal bleed and maintained, regardless of endoscopic findings, after the endoscopy in many Canadian centres. Further study is required to support these clinical practices.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2003

Implant stability and histomorphometry: a correlation study in human cadavers using stepped cylinder implants.

The aim of the present study was to determine the correlation between the primary stability of dental implants placed in edentulous maxillae and mandibles, the bone mineral density and different histomorphometric parameters. After assessing the bone mineral density of the implant sites by computed tomography, 48 stepped cylinder screw implants were installed in four unfixed human maxillae and mandibles of recently deceased people who had bequeathed their bodies to the Anatomic Institute I of the University of Erlangen-Nuremberg for medical-scientific research. Peak insertion torque, Periotest values and resonance frequency analysis were assessed. Subsequently, histologic specimens were prepared, and bone-to-implant contact, the trabecular bone pattern factor (TBPf), the density of trabecular bone (BV/TV) and the height of the cortical passage of the implants were determined. The correlation between the different parameters was calculated statistically. The mean resonance frequency analysis values (maxilla 6130.4+/-363.2 Hz, mandible 6424.5+/-236.2 Hz) did not correlate with the Periotest measurements (maxilla 13.1+/-7.2, mandible -7.9+/-2.1) and peak insertion torque values (maxilla 23.8+/-2.2 N cm, mandible 45.0+/-7.9 N cm) (P=0.280 and 0.193, respectively). Again, no correlations could be found between the resonance frequency analysis, the bone mineral density (maxilla 259.2+/-124.8 mg/cm(3), mandible 349.8+/-113.3 mg/cm3), BV/TV (maxilla 19.7+/-8.8%, mandible 34.3+/-6.0%) and the TBPf (maxilla 2.39+/-1.46 mm-1, mandible -0.84+/-3.27 mm-1) (P=0.140 and 0.602, respectively). However, the resonance frequency analysis values did correlate with bone-to-implant contact of the oral aspect of the specimens (maxilla 12.6+/-6.0%, mandible 35.1+/-5.1%) and with the height of the crestal cortical bone penetrated by the implants in the oral aspect of the implant sites (maxilla 2.1+/-0.7 mm, mandible 5.1+/-3.7 mm) (P=0.024 and 0.002, respectively). The Periotest values showed a correlation with the height of the crestal cortical bone penetrated by the implants in the buccal aspect of the implant sites (maxilla 2.5+/-1.2 mm, mandible 5.4+/-1.2 mm) (P=0.015). The resonance frequency analysis revealed more correlations to the histomorphometric parameters than the Periotest measurements. However, it seems that the noninvasive determination of implant stability has to be improved in order to give a more comprehensive prediction of the bone characteristics of the implant site.

Aged↗

PubMed2003

Anatomic site evaluation of the zygomatic bone for dental implant placement.

Thirty human zygomatic bone specimens (15 females mean age 81.60 +/- 11.38 years, 15 males, mean age 78.47 +/- 6.58 years) were examined by quantitative computed tomography and histomorphometry. The aim of the study was to assess the bone mineral density, the trabecular bone volume and the trabecular bone pattern factor. Moreover, the anterior-posterior and the medio-lateral dimensions and the estimated implant length within the zygomatic bone were determined. For quantitative computed tomography the specimens were scanned together with a bone mimicking anthropomorphic reference phantom. The bone mineral density was calculated for the specimens in the plane of the intended direction of the implant placement. Subsequently, with the sawing and grinding technique, the specimens were prepared in the same plane for histomorphometry. The trabecular bone mineral density was 369.95 +/- 188.80 mg/cm3 for the female and 398.94 +/- 99.11 mg/cm3 for the male specimens (P = 0.23). The male trabecular bone volume showed a value of 27.32 +/- 9.49%, while the female group reached a value of 19.99 +/- 7.60% (P = 0.23). The trabecular bone pattern factor was 1.2 x 10-2 +/- 1.28 mm-1 for the male and 1.02 +/- 0.96 mm-1 for the female specimens (P = 0.045). The study reveals that the zygomatic bone consists of trabecular bone with parameters that are unfavourable for implant placement. However, the success of implants placed in the zygomatic bone is secured by the employment of at least four cortical portions.

Aged↗

PubMed2003

Expression of Drosophila Ca2+ permeable transient receptor potential-like channel protein in a prostate cancer cell line decreases cell survival.

The effects of expression of Drosophila melanoga ster Ca(2+) permeable transient receptor potential-like (TRPL) channels, under the control of the cytomegalovirus (CMV) or prostate cell-specific promoters, on cell survival and apoptosis in the androgen-sensitive LNCaP prostate cancer cell line were investigated. A prostate-specific antigen (PSA) promoter construct (designated PSAEn/PSAPr) composed of a 0.6 kb region of the promoter and a 1.45 kb region of the enhancer resulted in androgen-dependent and prostate-specific expression of a luciferase reporter gene in transiently transfected LNCaP cells. Expression of the enhanced green fluorescence protein-TRPL chimeric protein under the control of the CMV promoter was confirmed by Western blot. Whereas the majority of the expressed protein was located in the cytoplasmic space, confocal microscopy with the CD-9 protein as a plasma membrane marker demonstrated that approximately 10% of the expressed TRPL protein was located in a band in the plasma membrane. Using recombinant adenoviruses, expression of the TRPL protein was associated with an increase in both the initial and sustained rates of Ca(2+) inflow. Expression of TRPL under the control of the CMV promoter for 96 hours decreased cell number and increased the number of cells undergoing apoptosis by 23 and 27%, respectively. Apoptosis was inhibited by a caspase-3 inhibitor, Z-DEVD-fmk. It is concluded that, when heterologously expressed in LNCaP cells, the TRPL protein leads to a reduction in cell survival due, in part, to the induction of apoptosis. The effects of TRPL are likely caused by enhanced Na(+) and Ca(2+) inflow to the cells. This finding suggests a novel approach to modify the growth of prostate cancer cells that fail to undergo apoptosis following androgen ablation therapy.

Adenoviridae↗

PubMed2002

The influence of material and design features on the mechanical properties of transpedicular spinal fixation implants.

This study describes the finding and performance of mechanical strength and corrosion testing procedures for comparative examination of multiple internal transpedicular spine fixators. Seven different implant models from five different manufacturers were compared regarding their bending strength and fatigue resistance. Because of the unacceptably high levels of time and material that they require, ISO and ASTM testing standards are not applicable to comparative testing. In addition, there is a lack of knowledge about clinically defined and proven strength-limit values. Therefore, actual standard testing procedures have been modified and extended to corrosion testing. Overall, the effort necessary to obtain reproducible comparative data has been reduced significantly. Although a reduced number of implants of each type were available for destructive testing, the results revealed fundamental differences in the tested implants between different materials and design features. During fatigue testing some of the implants showed poor corrosion properties. Because spinal fixation implants tend to be used as long-duration implants, corrosion testing as well as comparative strength testing with clinically successful implant models should be performed as preclinical evaluations.

Biocompatible Materials↗

PubMed2002

Tunneled lumbar drain. Technical note.

The authors report a simple and rapid procedure for tunneling a lumbar drain subcutaneously to facilitate chronic cerebrospinal fluid (CSF) drainage. A standard lumbar puncture (LP) is performed with a large-bore Tuohy needle (14- to 16-gauge), the drainage catheter is advanced into the subarachnoid space, and the needle is removed. The free Tuohy needle is then passed from a lateral position and brought out through the initial LP site. The free catheter is fed through the needle, and the needle is removed. The drain is attached to an external drainage bag in the usual manner. The authors have found this method particularly useful in some skull base and spinal surgical applications in which longer term continuous CSF drainage is desired.

Brain Diseases↗