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Biomedical subjects

Michael Walter

Publications and source records attributed to Michael Walter.

At least 19 recordsLinked to original sources
PubMed2006

A hollow tetrahedral cage of hexadecagold dianion provides a robust backbone for a tuneable sub-nanometer oxidation and reduction agent via endohedral doping.

We show, via density functional theory calculations, that dianionic Au16(2-) cluster has a stable, hollow, Td symmetric cage structure, stabilized by 18 delocalized valence electrons. The cage maintains its robust geometry, with a minor Jahn-Teller deformation, over several charge states (q = -1,0,+1), forming spin doublet, triplet and quadruplet states according to the Hund's rules. Endohedral doping of the Au16 cage by Al or Si yields a geometrically robust, tuneable oxidation and reduction agent. Si@Au16 is a magic species with 20 delocalized electrons. We calculate a significant binding energy for the anionic Si@Au16/O2- complex and show that the adsorbed O2 is activated to a superoxo-species, a result which is at variance with the experimentally well-documented inertness of Au16- anion towards oxygen uptake.

Journal Article↗
PubMed2006

Theoretical characterization of cyclic thiolated gold clusters.

The density functional theory is used to explore structural, energetic, vibrational, and optical properties of thiolated gold clusters (MeSAu)x with x = 2-12. Clusters up to (MeSAu)4 adopt Au-S ring conformations, and crownlike structures are formed for larger sizes. The clusters are essentially polymeric and show convergence in structural and energetic properties at (MeSAu)4. The nature of the Au-S bond is polar covalent with a degree of cyclic electron delocalization. Vibrational analysis reveals characteristic Au-S stretch vibrations at approximately 300 cm(-1). Effects of ligand substitution are studied in the case of the tetramer by comparing the results for methylthiolate with hexylthiolate, benzenethiolate, and glutathionate (GS). The choice of ligand has clear effects on electronic properties. For example, the optical gap is approximately 1.5 eV lower for (GSAu)4 than for (MeSAu)4.

Journal Article↗
PubMed2006

Gene expression profiles reveal an upregulation of E2F and downregulation of interferon targets by HPV18 but no changes between keratinocytes with integrated or episomal viral genomes.

Persistent infections with human papillomaviruses type 18 can result in the development of cervical cancer. HPV18 genomes persist extrachromosomally in low-grade and precancerous lesions but are always integrated in cervical cancers, and this might contribute to the progression of HPV18-induced lesions. To address whether integration induces additional changes in host cells, several keratinocyte lines with wild type and replication-deficient E1 mutant HPV18 (E1C-TTL) genomes were analyzed with high density oligonucleotide arrays. In comparison to normal keratinocytes, wild type and integrated E1C-TTL HPV18 genomes deregulate the expression of 280 annotated genes. However, the comparison of wild type with E1C-TTL cell lines did not reveal any significant differences, indicating that neither the loss of E1 nor viral integration induces additional gene expression changes in low passage HPV18-positive keratinocytes. Half of the deregulated genes have been described as targets of the p16/Rb/E2F, p53, interferon or NFkappaB pathways consistent with the functions ascribed to the viral E6 and E7 oncoproteins, but the other half can currently not be ascribed to certain pathways.

Cell Line↗
PubMed2006

Divide and protect: capping gold nanoclusters with molecular gold-thiolate rings.

Density functional theory calculations are used to explore phosphine- and thiolate-protected gold nanoclusters, namely, Au(39)(PH(3))(14)Cl(6) and Au(38)(SCH(3))(24). For Au(38)(SCH(3))(24), a novel structural motif is predicted, consisting of ringlike (AuSCH(3))(4) units protecting a central Au(14) core. The calculated optical spectrum of this species features a large optical gap (about 1.5 eV) and a prominently peaked structure, correlating with experimental findings of "molecular-like spectra" of thiolate-protected 1.1 nm gold nanoparticles. Ligand-ligand interactions and steric effects in the ligand shell are suggested as possible driving forces toward an ordered gold core structure. A novel mechanism for ligand-exchange reactions on gold clusters is proposed.

Journal Article↗
PubMed2006

Progression-specific genes identified by expression profiling of matched ductal carcinomas in situ and invasive breast tumors, combining laser capture microdissection and oligonucleotide microarray analysis.

Becoming invasive is a crucial step in breast cancer oncogenesis. At this point, a lesion carries the potential for spreading and metastasis--a process, whose molecular characteristics still remain poorly understood. In this article, we describe a matched-pair analysis of ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of nine breast ductal carcinomas to identify novel molecular markers characterizing the transition from DCIS to IDC. The purpose of this study was to better understand the molecular biology of this transition and to identify candidate genes whose products might serve as prognostic markers and/or as molecular targets for treatment. To obtain cellular-based gene expression profiles from epithelial tumor cells, we combined laser capture microdissection with a T7-based two-round RNA amplification and Affymetrix oligonucleotide microarray analysis. Altogether, a set of 24 tumor samples was analyzed, comprised of nine matched DCIS/IDC and replicate DCIS/IDC preparations from three of the nine tumors. Cluster analysis on expression data shows the robustness and reproducibility of the techniques we established. Using multiple statistical methods, 546 significantly differentially expressed probe sets were identified. Eighteen candidate genes were evaluated by RT-PCR. Examples of genes already known to be associated with breast cancer invasion are BPAG1, LRRC15, MMP11, and PLAU. The expression of BPAG1, DACT1, GREM1, MEF2C, SART2, and TNFAIP6 was localized to epithelial tumor cells by in situ hybridization and/or immunohistochemistry, confirming the accuracy of laser capture microdissection sampling and microarray analysis.

Breast Neoplasms↗
PubMed2006

A process for making cutaneous radiation applicators based on digital data.

An optical modeling process for facial regions and other body surfaces has been developed. The body part in question is digitized using optical 3-D metrology to obtain a comprehensive dataset. The data is then prepared for further use by smoothing the point clusters. The radiophysically significant position of the radioactive material, e. g., seeds, aluminum tubes, etc., can be accurately determined using CAD modeling. Subsequently, a rapid prototyping process (fused deposition modeling [FDM]) is used to implement the CAD model directly in order to create a radiation applicator that can be used in practice. Biologically compatible polycarbonate can be used for this purpose.

Brachytherapy↗
PubMed2006

Respiratory viral infection in obliterative airway disease after orthotopic tracheal transplantation.

BACKGROUND: The long-term survival after human lung transplantation is limited by bronchiolitis obliterans syndrome (BOS). Clinically, community-acquired respiratory viral infections have been correlated with an increased incidence of BOS. The goal of this study was to investigate the role of respiratory viral infections in chronic lung allograft rejection using the murine orthotopic tracheal transplantation model. METHODS: Eighty orthotopic tracheal transplants were performed using BALB/c and C57BL/6 mice. Recipient mice were infected intranasally with Sendai virus (SdV), a murine parainfluenza type I virus. Experiments altering the infectious dose, infection time, harvest time, allogeneic response, and viral response were performed. Tracheal allograft rejection was monitored using percent fibrosis and lamina propria to cartilage ratio measurements. Interferon-gamma ELISPOT analysis against irradiated donor (BALB/c) splenocytes was used as immunologic indicator of alloreactivity after transplantation. RESULTS: Sendai virus infection revealed a dose-dependent transient suppression of alloreactivity with a decrease in tracheal allograft fibrosis and frequency of alloreactive T cells at 30 days. This immunosuppression was reversed by day 60, leading to increased tracheal allograft fibrosis with a concomitant increase in the frequency of interferon-gamma producing alloreactive T cells. Pretransplant sensitization with donor antigens prevented the initial suppression of alloreactivity due to SdV infection. Furthermore, pretransplant immunization against SdV infection resulted in rapid clearing of the infection and reduced the immunopathology of rejection. CONCLUSIONS: Respiratory viral infections can cause enhanced tracheal allograft rejection despite the initial phase of transient immunosuppression. Early treatment or vaccination against the respiratory infections may represent a viable intervention to reduce the risk of chronic rejection.

Animals↗
PubMed2006

Role of airway epithelial injury in murine orthotopic tracheal allograft rejection.

BACKGROUND: Murine tracheal transplantation is a model used to study bronchiolitis obliterans syndrome, a major cause of morbidity and mortality after lung transplantation. Unlike murine heterotopic tracheal transplants, orthotopic transplantation does not cause luminal obliteration despite major histocompatibility antigen mismatch. Repopulation of the tracheal allografts with recipient-derived epithelium confers protection against luminal obliteration. The purpose of this study was to determine whether (1) orthotopic tracheal transplantation showed signs of allograft rejection, and (2) airway epithelial cell injury promoted orthotopic tracheal allograft rejection. METHODS: Forty isogeneic (C57BL/6 to C57BL/6) and 40 allogeneic (BALB/c to C57BL/6) orthotopic tracheal transplants were performed. Damage to airway epithelial cells was induced by Sendai viral (SdV) infection and tracheal transplantation into non-reepithelializing matrix metalloproteinase-7 knockout (MMP7-KO) recipient mice. Percent fibrosis and lamina propria to cartilage ratio were calculated with computer assistance on harvested allografts. RESULTS: Allografts showed significantly more intramural fibrosis compared with isografts at 30, 60, and 180 days after transplant without luminal occlusion. Tracheal allografts infected with SdV showed an increase in fibrosis and lamina propria to cartilage ratio compared with noninfected controls. Allografts retrieved from MMP7-KO recipients also showed a significant increase in fibrosis and lamina propria to cartilage ratio. CONCLUSIONS: Although orthotopic tracheal transplantation does not cause luminal obliteration, it results in increased fibrosis in allografts. Damage to the respiratory epithelium by viral infection or defective reepithelialization after transplant as seen in MMP7-KO recipient mice leads to changes consistent with chronic allograft rejection, suggesting a role for epithelial injury in bronchiolitis obliterans syndrome development.

Animals↗
PubMed2006

Vascular risk factors in sudden hearing loss.

Low density lipoprotein (LDL) and fibrinogen apheresis was recently reported to be an effective therapy in sudden hearing loss (SHL). In this study, we investigated whether lipoprotein and/or fibrinogen plasma concentrations, related gene polymorphisms and other cardiovascular risk factors are also risk factors for SHL. Total cholesterol, HDL and LDL cholesterol plasma concentrations, fibrinogen levels, and two functionally relevant fibrinogen polymorphisms were determined in 142 consecutive patients and in 84 age- and sex-matched control subjects of the same ethnic background, using routine laboratory methods and PCR analysis. In addition, we determined the platelet glycoprotein Ia (GPIa) C807T polymorphism, which was recently proposed to be a genetic risk factor for SHL, and we compared the patients' and controls' clinical characteristics. Total and LDL cholesterol concentrations were not different between patients and controls. Fibrinogen plasma levels were significantly increased in SHL patients (260+/-57 vs. 239+/-110 mg/dl, p=0.002). However, fibrinogen was not related to SHL in multivariate analysis, and none of the investigated fibrinogen polymorphisms was associated with SHL. By contrast, T allele carriers of the GPIa 807 polymorphic site had an increased risk to develop SHL (OR 1.81) and were more likely not to recover from SHL, compared to C allele carriers (OR 3.0). Moreover, significantly more SHL patients were current smokers (56.3% vs. 19.3% in the control group, p<0.0001). In conclusion, there is a partial overlap between classical coronary risk factors and risk factors for SHL. Hypercholesterolemia and hypoalphalipoproteinemia (low HDL cholesterol levels) are apparently no major risk factors for SHL, whereas the GPIa C807T polymorphism, elevated fibrinogen levels, and smoking are associated with an increased risk for SHL. Altogether these findings suggest a vascular involvement in the pathogenesis of SHL and may have important implications for the development of therapeutic and preventive strategies.

Adolescent↗
PubMed2006

Pediatric obesity: are we under-diagnosing? Assessing pediatric obesity at an urban community health clinic.

Pediatric care providers are often discouraged by the scope and magnitude of our current childhood overweight epidemic. Numerous studies have shown the adverse consequences of pediatric obesity, ranging from short-term physical and psychosocial consequences to long-term consequences that manifest in adulthood. In this study we investigated rates of overweight and at-risk for overweight children in a community health center in urban Honolulu, Hawai'i which serves a large multi-cultural and multi-ethnic population with a large presence of Asians and Pacific Islanders. This was done by conducting a chart review of the pediatric patients in the clinic. Twenty-four children had been formally diagnosed and recorded in their charts as obese/overweight during the last 2 years, out of 4,640 pediatric patients seen (less than 0.5%). However, according to this study roughly 140 overweight children are seen monthly at this clinic, indicating a prevalence of more than 50%. Samoan and Micronesian children were found to be primarily impacted.

Adolescent↗
PubMed2005

[Health services research in Germany--status quo in the field of oral health].

BACKGROUND: Within the last years, health services research has gained increasing attention in Germany. This trend could also be observed in dentistry although this research field must be considered rather young. The methodical approach of health services research is complementary to the traditional clinical research paradigm. The latter focuses on the comprehension of causal mechanisms and the efficacy of interventions under ideal and standardized study conditions. In contrast to that, health services research focuses on the effectiveness under everyday conditions and the efficacy in the normal course of medical care. RESEARCH PROJECTS: In the field of dentistry, various investigations exist that belong to that area of research in a broader sense. Articles in professional dental journals deal increasingly with topics related to health services research. Political discussions look in that subject more frequently. Concrete results, however, are rare and limited to selected aspects. At the beginning of 2005, the reimbursement policy of the German health insurance funds relative to prosthetic treatment changed completely. The resulting consequences are unknown and unexplored. Dramatic changes are to be expected. This clearly exemplifies the significance of scientific evaluations when changing key aspects of daily health care. SUMMARY AND OUTLOOK: Hence it can be said that dental health services research in Germany is not sufficiently established yet. It can be assumed that the cumulating problems to be expected within the health care system will lead to an increasing demand for the respective research.

Adult↗
PubMed2005

Current understanding of the role of high-density lipoproteins in atherosclerosis and senescence.

Numerous epidemiologic and interventional studies revealed that high-density lipoprotein (HDL) is an important risk factor for coronary heart disease. There are several well documented HDL functions that may account for the antiatherogenic effects of this lipoprotein. The best recognized of these is the capacity of HDL to transport cholesterol from the periphery to the liver, and thereby prevent cholesterol deposition in the arterial wall. Further properties of HDL that may also be antiatherogenic include its potent anti oxidative and anti-inflammatory action. In addition, HDL seems to be involved in processes related to senescence at both the cellular and whole-organism level. Both protein components of HDL (such as apolipoprotein A-I) and its lipid components (such as, lysosphingolipids) appear to mediate the antiatherogenic and anti-aging effects of HDL. The purpose of this review is to summarize the novel functions of HDL that may protect from atherosclerosis and senescence.

Aging↗
PubMed2004

The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease.

Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid beta (Abeta) secretion in vitro. The effect was attributed primarily to the ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. We now examined the effect of the synthetic LXR ligand T0901317, which can be used in vivo, on Abeta production in vitro and in APP23 transgenic mice. T0901317 applied to a variety of in vitro models, including immortalized fibroblasts from Tangier patients, and primary embryonic mouse neurons caused a concentration-dependent decrease in Abeta secretion, and this effect was increased by the addition of apolipoprotein A-I. The inhibition of Abeta production by T0901317 was cell-type specific, being more prominent in primary neurons than in non-neuronal cells. Tangier fibroblasts lacking a functional ABCA1 secreted more Abeta than control fibroblasts, thus demonstrating the role of ABCA1 in amyloid precursor protein (APP) processing and Abeta generation. T0901317 treatment of 11-week-old APP23 mice for 6 days showed a significant increase in ABCA1 expression and a decrease in the ratio of soluble APP (sAPP)beta- to sAPPalpha-cleavage products. Most importantly, the treatment caused a statistically significant reduction in the levels of soluble Abeta40 and of Abeta42 in the brain these mice. Our experiments demonstrate that T0901317 decreases amyloidogenic processing of APP in vitro and in vivo, thus supporting the search for potent and specific LXR ligands with properties allowing therapeutic application.

Alzheimer Disease↗
PubMed2004

The establishment of telomerase-immortalized Tangier disease cell lines indicates the existence of an apolipoprotein A-I-inducible but ABCA1-independent cholesterol efflux pathway.

Tangier disease (TD) is a human genetic disorder associated with defective apolipoprotein-I-induced lipid efflux and increased atherosclerotic susceptibility. It has been linked to mutations in the ATP-binding cassette protein A1 (ABCA1). Here we describe the establishment of permanent Tangier cell lines using telomerase. Ectopic expression of the catalytic subunit of human telomerase extended the life span of control and TD skin fibroblasts, and (in contrast to immortalization procedures using viral oncogenes) did not impair apolipoprotein A-I-induced lipid efflux. The key characteristics of TD fibroblasts (reduced cholesterol and phospholipid efflux) were observed both in primary and telomerase-immortalized fibroblasts from two unrelated homozygous patients. Surprisingly, the apolipoprotein-inducible cholesterol efflux in TD cells was significantly improved after immortalization (up to 40% of normal values). In contrast to ABCA1-dependent cholesterol efflux, this efflux was not inhibited by brefeldin A, glybenclamide, or intracellular ATP depletion but was inhibited in the presence of cytochalasin D. Apolipoprotein A-I-dependent cholesterol efflux was inversely correlated with the population doubling number in cell culture and was inhibited up to 40% in near-senescent normal diploid fibroblasts. This inhibition was completely reversed by telomerase. Thus ectopic expression of telomerase is a way to circumvent the lack of critical experimental material and represents a major improvement for studying cholesterol efflux pathways in lipid disorders. Our findings indicate the existence of an ABCA1-independent but cytoskeleton-dependent cholesterol removal pathway that may help to prevent early atherosclerosis in Tangier disease but may also be sensitive to aging phenomena ex vivo and possibly in vivo.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Phenotypic variations in patients with a 1630 A>T point mutation in the PAX6 gene.

BACKGROUND: The extreme clinical case-to-case variability of aniridia, even within families, can cause difficulties in making the correct diagnosis, prognosis and treatment plan. We describe seven patients from two families demonstrating variable expression of this syndrome, all with the same single point mutation within the PAX6 gene. METHODS: Case presentations. The authors review the clinical ophthalmic findings of the aniridia-keratopathy syndrome from two families, one involving four generations, the other with two generations. Polymerase chain reaction amplification of all 14 exons of the PAX6 gene was performed for five patients. RESULTS: The iris findings varied from classic total absence to nearly normal iris appearance. Corneal changes were minimal in the younger patients but vision-impairing in the older. None of the patients had glaucoma. The five patients who underwent DNA analysis shared the same PAX6 point mutation defect (1630A>T). INTERPRETATION: Bilateral corneal changes progressing from mild opacification at the limbus to vascularized central keratopathy, especially in the presence of nystagmus, are highly suggestive of a PAX6 mutation. Such patients may theoretically benefit from early limbal stem cell replacement therapy.

Adenine↗
PubMed2004

Visualization of protein interactions in living plant cells using bimolecular fluorescence complementation.

Dynamic networks of protein-protein interactions regulate numerous cellular processes and determine the ability to respond appropriately to environmental stimuli. However, the investigation of protein complex formation in living plant cells by methods such as fluorescence resonance energy transfer has remained experimentally difficult, time consuming and requires sophisticated technical equipment. Here, we report the implementation of a bimolecular fluorescence complementation (BiFC) technique for visualization of protein-protein interactions in plant cells. This approach relies on the formation of a fluorescent complex by two non-fluorescent fragments of the yellow fluorescent protein brought together by association of interacting proteins fused to these fragments (Hu et al., 2002). To enable BiFC analyses in plant cells, we generated different complementary sets of expression vectors, which enable protein interaction studies in transiently or stably transformed cells. These vectors were used to investigate and visualize homodimerization of the basic leucine zipper (bZIP) transcription factor bZIP63 and the zinc finger protein lesion simulating disease 1 (LSD1) from Arabidopsis as well as the dimer formation of the tobacco 14-3-3 protein T14-3c. The interaction analyses of these model proteins established the feasibility of BiFC analyses for efficient visualization of structurally distinct proteins in different cellular compartments. Our investigations revealed a remarkable signal fluorescence intensity of interacting protein complexes as well as a high reproducibility and technical simplicity of the method in different plant systems. Consequently, the BiFC approach should significantly facilitate the visualization of the subcellular sites of protein interactions under conditions that closely reflect the normal physiological environment.

Arabidopsis↗
PubMed2004

A-type and B-type natriuretic peptides in cardiac surgical procedures.

UNLABELLED: This study was performed to determine the secretion pattern and prognostic value of A-type (ANP) and B-type (BNP) natriuretic peptide in patients undergoing cardiac surgical procedures. We measured ANP and BNP in patients undergoing coronary artery bypass grafting (CABG) with (n = 28) or without (n = 32) ventricular dysfunction and in patients undergoing mitral (n = 21) or aortic (n = 24) valve replacement, respectively. Postoperative mortality was recorded up to 730 days after operation. ANP, but not BNP, concentrations were closely associated with volume reloading of the heart after aortic cross-clamp in all patients. The secretion pattern of BNP during surgery was much less uniform. BNP, but not ANP, concentrations correlated with aortic cross-clamp time (r(2) = 0.32; P = 0.006) and postoperative troponin I concentrations (r(2) = 0.22; P = 0.0009) in bypass patients, and preoperative BNP increases were associated with a more frequent postoperative (2-yr) mortality in these patients. Markedly increased preoperative BNP concentrations in mitral (3-fold) and aortic (14-fold) valve disease patients did not further increase during cardiopulmonary surgery. The data suggest that ANP is primarily influenced by intravascular volume reloading of the heart after cross-clamp, whereas the secretion of BNP is related to other factors, such as duration of ischemia and long-term left ventricular pressure and/or excessive intravascular volume. BNP, but not ANP, was shown to be a mortality risk predictor in patients undergoing CABG. IMPLICATIONS: A-type natriuretic peptide is primarily influenced by volume reloading of the heart after cross-clamp, whereas the secretion of B-type natriuretic peptide (BNP) is related to the duration of ischemia and long-term left ventricular pressure and/or volume overload. Preoperative BNP, but not postoperative BNP, concentrations predict long-term outcome after coronary artery bypass grafting.

Aged↗