Biomedical subjects

J Harder

Publications and source records attributed to J Harder.

At least 19 recordsLinked to original sources

PubMed2006

Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer.

This phase II study was conducted to determine the efficacy and toxicity of a gemcitabine (GEM) and oxaliplatin (OX) chemotherapy protocol in patients with unresectable biliary tract cancer (BTC). Patients were treated with GEM 1000 mg m-2 (30 min infusion) on days 1, 8, 15, and OX 100 mg m-2 (2 h infusion) on days 1 and 15 (gemcitabine and oxaliplatin (GEMOX-3 protocol), repeated every 28 days. The data were collected according to the Simon 2-stage design for a single centre phase II study (alpha=0.05; beta=0.2). Primary end point was response rate; secondary end points were time-to-progression (TTP), median survival, and safety profile. Thirty-one patients were enrolled in the study between July 2002 and April 2005. Therapeutic responses were as follows: partial response in eight patients (26%, 95% confidence interval (CI) 14-44), stable disease in 14 patients (45%, 95%CI 29-62), resulting in a disease control rate of 71%. Nine patients (29%, 95%CI 16-47) had progressive disease. Median TTP was 6.5 months. Median overall survival was 11 months. Common Toxicity Criteria (CTC) Grade 3-4 toxicities were transient thrombocytopenia (23%), peripheral sensory neuropathy (19%), leucopenia (16%), and anaemia (10%). In conclusion the GEMOX-3 protocol is active and well tolerated in patients with advanced BTC. It can be applied in an outpatient setting with three visits per month only.

Adenocarcinoma↗

PubMed2006

[Gastric cancer--risk factors and medical therapy].

Gastric cancer is the fourth common cancer worldwide and the second leading cause of cancer related deaths. Although the incidence of gastric cancer is declining, gastric cancer will remain a serious medical problem due to its high mortality rates. In contrast, cancer of the gastroesophageal junction is the most increasing neoplasm in the western world. Unfortunately, the vast majority of gastric cancer is diagnosed at an advanced stage, associated with a poor prognosis where the therapeutic options are limited. Over the past 15 years advances have been made in the knowledge of risk factors as well as the pathogenesis of gastric cancer. As the most important exogenous risk factor Helicobacter pylori was categorized as a class I carcinogen by the WHO. Additionally, genetic changes associated with the risk of gastric cancer have been defined. Progress, although slow, has also been made in the non-surgical therapy of gastric cancer due to multimodal therapeutic strategies. All these advances could lead to a better identification of patients being at risk of developing gastric cancer. Furthermore, new neoadjuvant and adjuvant therapy regimes as well as targeted therapeutic approaches in the future could lead to a better prognosis of gastric cancer.

Animals↗

PubMed2006

Antimicrobial skin peptides and proteins.

Human skin is permanently exposed to microorganisms, but rarely infected. One reason for this natural resistance might be the existence of a 'chemical barrier' consisting in constitutively and inducibly produced antimicrobial peptides and proteins (AMPs). Many of these AMPs can be induced in vitro by proinflammatory cytokines or bacteria. Apart from being expressed in vivo in inflammatory lesions, some AMPs are also focally expressed in skin in the absence of inflammation. This suggests that non-inflammatory stimuli of endogenous and/or exogenous origin can also stimulate AMP synthesis without inflammation. Such mediators might be ideal 'immune stimulants' to induce only the innate antimicrobial skin effector molecules without causing inflammation.

Animals↗

PubMed2005

[Seizures following Billroth II gastrectomy].

HISTORY: A 64-year old somnolent man was admitted to the emergency department with a reported seizure half an hour earlier. Due to similar episodes the patient had been treated with antiepileptics in the past. The patient s past history revealed a partial gastrectomy (Billroth II) more than ten years ago. DIAGNOSTIC FINDINGS AND THERAPY: At the time of admission blood glucose was 31 mg/dl. Other routine laboratory analyses and the clinical examination were normal. In addition, a detailed neurological examination and a cranial CT-scan were normal. Due to the hypoglycemia a dumping syndrome was suspected. A three hour oral glucose tolerance test (OGTT) resulted in a late hypoglycemia, establishing the diagnosis of late dumping. After adaptation of the patient's diet no further hypoglycemic episodes occurred. CONCLUSION: Manifestation of a dumping syndrome may occur even years after gastrectomy. Therefore, in patients presenting with hypoglycemia and a history of gut surgery, a dumping syndrome should be suspected. Furthermore, seizures due to hypoglycemia may be the only manifestation of late dumping.

Dumping Syndrome↗

PubMed2004

[Esophageal carcinoma: non-surgical therapy].

Esophageal carcinoma is one of the most common cancers in the world. There is a rising incidence of adenocarcinoma of the esophagus in Western countries. The present standard of care of patients with early tumors (Tis-T1 N0-N1 M0) is surgery and there is no role for chemo- or radiotherapy. Surgical treatment of stage II patients with locally resectable tumors is associated with poor survival figures due to an increase of regional and distant lymph node metastases. Adjuvant chemotherapy should be used only in the setting of clinical trials. The role of neoadjuvant chemo-radiotherapy in patients with resectable tumors is controversial. There is also evidence that some patients with a complete response after chemo-radiotherapy do not have a further benefit from surgical treatment. Therefore, the appropriate application of these varied therapeutic interventions should be performed at specialized centers. The role of chemotherapy and radiation is now established in locally advanced inoperable disease. How best to deliver these modes of therapy has yet to be defined. Prospective randomised trials are the only way to define the best therapeutic strategies for the different subgroups of patients with esophageal carcinoma. Progress with newer chemotherapy agents, optimal radiotherapy protocols and innovations are likely to improve responses to combination treatments, but may more importantly limit associated toxicity. Future trials should also assess quality of life indices as end points, that are of particular importance in populations with a median survival of approx, one year. Patients with stage IVb esophageal carcinoma have a life expectancy of less than six months and palliative teatment strategies should primarily aim at the improvement of tumor related symptoms and the maintenance of nutrition.

Antineoplastic Agents↗

PubMed2004

Hepatitis C virus infection in intravenous drug users.

Intravenous drug use (IVDU) remains a major means of hepatitis C virus (HCV) transmission. In this study, 101 drug users were studied prospectively after cessation of IVDU. Of these, 75.8% were anti-HCV positive, and 71.4% had elevated levels of alanine aminotransferase. These levels decreased significantly within 1 month of IVDU cessation (p 0.02). Liver biopsies showed minimal or mild fibrosis in 32 (71%) of 45 subjects, and severe fibrosis in two (4.4%) subjects. Anti-HCV-positive intravenous drug users in this study presented with mild liver disease and variable stages of disease progression. Biochemical disease activity might be affected by IVDU.

Adult↗

PubMed2004

NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression.

BACKGROUND: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human alpha defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. METHODS: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor alpha, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. RESULTS: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. CONCLUSION: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.

Adolescent↗

PubMed2002

[Cholangiocarcinoma].

Cholangiocarcinomas (CCC) are rare tumors with an incidence of 2-4/100,000 per year. They are a heterogeneous group of neoplasias that include the most common perihilar or Klatskin tumor (60%), the intrahepatic (peripheral) CCC, the extrahepatic bile duct cancer, the gallbladder cancer and the cancer of the ampulla of Vater. At the time of diagnosis only 20% of patients can be treated by surgery, that offers the only chance for cure. Due to high recurrence rates liver transplantation is not indicated. Patients with advanced unresectable carcinoma have a dismal prognosis with an overall survival rate of only 6-8 months. Neither chemotherapy nor radiation therapy improves survival. In patients not eligible for curative surgery prevention or treatment of cholestatis is the main objective. This can be achieved endoscopically, percutaneously or by surgical biliodigestive anastomosis. Palliative chemotherapy results in response rates up to 20%. The most frequently used agents are 5-FU and Gemcitabine that can be combined with external or internal radiation. By combining different treatment modalities significant survival can be achieved in some patients. Evidence Based Medicine studies are needed before treatment strategies can be recommended for clinical practice.

Bile Duct Neoplasms↗

PubMed2001

Estimation of spinal deformity in scoliosis from torso surface cross sections.

STUDY DESIGN: Correlation of torso scan and three-dimensional radiographic data in 65 scans of 40 subjects. OBJECTIVES: To assess whether full-torso surface laser scan images can be effectively used to estimate spinal deformity with the aid of an artificial neural network. SUMMARY OF BACKGROUND DATA: Quantification of torso surface asymmetry may aid diagnosis and monitoring of scoliosis and thereby minimize the use of radiographs. Artificial neural networks are computing tools designed to relate input and output data when the form of the relation is unknown. METHODS: A three-dimensional torso scan taken concurrently with a pair of radiographs was used to generate an integrated three-dimensional model of the spine and torso surface. Sixty-five scan-radiograph pairs were generated during 18 months in 40 patients (Cobb angles 0-58 degrees ): 34 patients with adolescent idiopathic scoliosis and six with juvenile scoliosis. Sixteen (25%) were randomly selected for testing and the remainder (n = 49) used to train the artificial neural network. Contours were cut through the torso model at each vertebral level, and the line joining the centroids of area of the torso contours was generated. Lateral deviations and angles of curvature of this line, and the relative rotations of the principal axes of each contour were computed. Artificial neural network estimations of maximal computer Cobb angle were made. RESULTS: Torso-spine correlations were generally weak (r < 0.5), although the range of torso rotation related moderately well to the maximal Cobb angle (r = 0.64). Deformity of the torso centroid line was minimal despite significant spinal deformity in the patients studied. Despite these limitations and the small data set, the artificial neural network estimated the maximal Cobb angle within 6 degrees in 63% of the test data set and was able to distinguish a Cobb angle greater than 30 degrees with a sensitivity of 1.0 and specificity of 0.75. CONCLUSIONS: Neural-network analysis of full-torso scan imaging shows promise to accurately estimate scoliotic spinal deformity in a variety of patients.

Adolescent↗

PubMed2001

Expression profile of human defensins and antimicrobial proteins in oral tissues.

Antimicrobial peptides and proteins are an important part of the innate host defense. In the present study, the expression profile of three human alpha-defensins, of two human beta-defensins (hBD) and of phospholipase A-2 (PLA-2) and lysozyme was determined by reverse transcription-polymerase chain reaction (RT-PCR) in 56 non-inflamed and 18 inflamed oral tissue samples and primary oral keratinocytes and fibroblasts. The transcripts for hBD-1 and -2 as well as for PLA-2 and lysozyme were found to be widely expressed. In the group of the alpha-defensins, the message for the human neutrophil peptide-1 (HNP-1) was frequently detected, whereas an expression of human Paneth's cell defensin-5 (HD-5) was identified in only a minority of samples. Transcripts for HD-6 were not detectable in any sample. Oral keratinocytes but not fibroblasts contained transcripts for the beta-defensins, suggesting that these defensins are produced in the epithelial compartment. In contrast, mRNA expression of neutrophil-derived HNP-1 and PLA-2 was not observed in any of these cells. These results suggest an important role for hBD-1 and hBD-2 in the innate oral epithelial host defense.

DNA, Complementary↗

PubMed2000

Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic.

The growing public health problem of infections caused by multiresistant Gram-positive bacteria, in particular Staphylococcus aureus, prompted us to screen human epithelia for endogenous S. aureus-killing factors. A novel 5-kDa, nonhemolytic antimicrobial peptide (human beta-defensin-3, hBD-3) was isolated from human lesional psoriatic scales and cloned from keratinocytes. hBD-3 demonstrated a salt-insensitive broad spectrum of potent antimicrobial activity against many potentially pathogenic microbes including multiresistant S. aureus and vancomycin-resistant Enterococcus faecium. Ultrastructural analyses of hBD-3-treated S. aureus revealed signs of cell wall perforation. Recombinant hBD-3 (expressed as a His-Tag-fusion protein in Escherichia coli) and chemically synthesized hBD-3 were indistinguishable from naturally occurring peptide with respect to their antimicrobial activity and biochemical properties. Investigation of different tissues revealed skin and tonsils to be major hBD-3 mRNA-expressing tissues. Molecular cloning and biochemical analyses of antimicrobial peptides in cell culture supernatants revealed keratinocytes and airway epithelial cells as cellular sources of hBD-3. Tumor necrosis factor alpha and contact with bacteria were found to induce hBD-3 mRNA expression. hBD-3 therefore might be important in the innate epithelial defense of infections by various microorganisms seen in skin and lung, such as cystic fibrosis.

Amino Acid Sequence↗

PubMed2000

Anaerobic oxidation of alkanes by newly isolated denitrifying bacteria.

The capacity of denitrifying bacteria for anaerobic utilization of saturated hydrocarbons (alkanes) was investigated with n-alkanes of various chain lengths and with crude oil in enrichment cultures containing nitrate as electron acceptor. Three distinct types of denitrifying bacteria were isolated in pure culture. A strain (HxN1) with oval-shaped, nonmotile cells originated from a denitrifying enrichment culture with crude oil and was isolated with n-hexane (C6H14). Another strain (OcN1) with slender, rod-shaped, motile cells was isolated from an enrichment culture with n-octane (C8H18). A third strain (HdN1) with oval, somewhat pleomorphic, partly motile cells originated from an enrichment culture with aliphatic mineral oil and was isolated with n-hexadecane (C16H34). Cells of hexane-utilizing strain HxN1 grew homogeneously in the growth medium and did not adhere to the alkane phase, in contrast to the two other strains. Quantification of substrate consumption and cell growth revealed the capacity for complete oxidation of alkanes under strictly anoxic conditions, with nitrate being reduced to dinitrogen.

Alkanes↗

PubMed2000

Anaerobic utilization of essential oils by denitrifying bacteria.

Plant volatile organic compounds are a major carbon source in nature. We studied the degradability of these substances by anaerobic microorganisms in enrichment cultures with representative essential oils as organic substrates and nitrate as electron acceptor. Lemon and pine needle oil supported microbial growth in the presence of pure oil, whereas parsley seed, camphor, sage, fennel, and mint oil supported growth only when the essential oils were dissolved in an overlying phase of 2,2,4,4,6,8,8-heptamethylnonane. Thyme oil did not support denitrification. Analyses of the microbially degraded oils revealed the disappearance of monoterpenes, of several monoterpenoids, and of methoxy-propenyl-benzenes, including apiole and myristicin. Most-probable-number determinations for denitrifying communities in sewage sludge and forest soil yielded 10(6) to 10(7) monoterpene-utilizing cells ml(-1), representing 0.7 to 100% of the total cultivable nitrate-reducing microorganisms. The utilization of essential oils together with the common occurrence of this metabolic trait are indications for an environmentally important, but currently unexplored anaerobic turnover of plant volatile organic compounds in soil.

Alcaligenes↗

PubMed2000

[hBD-2 gene expression in nasal mucosa].

BACKGROUND: Chronic sinusitis is one of the frequent inflammatory diseases and has a complex pathogenesis. A substantial factor seems to be recurrent bacterial infections. Pseudomonas aeruginosa (PA) frequently can be found in nasal smears of patients with persistent sinus symptoms after sinus surgery. Lately a new antimicrobial peptide of epithelial origin, human Beta-Defensin-2 (hBD-2), with a strong antibacterial effect against PA could be identified within lesional skin scales of patients suffering psoriasis. Aim of this study was to investigate hBD-2-mRNA expression in nasal cells and tissue. METHODS: Total RNA was extracted from nasal polyps and turbinates following TRIzol protocol. Epithelial cells and fibroblasts of nasal human tissue were isolated and cultivated. The cells were stimulated with PA using different time points and different concentrations. Total RNA was isolated as mentioned above, reverse transcribed and amplified in a Semi-quantitative Reverse Transcriptase PCR (SQRT-PCR) with genespecific hBD-2 primers. RESULTS: PA induces time- and dose-dependently hBD-2 gene expression in nasal epithelial cells. Unstimulated epithelial nasal cells were able to express hBD-2 mRNA constitutively, whereas nasal fibroblasts showed no hBD-2 mRNA expression. Nasal polyps showed a comparable less hBD-2 gene expression then nasal turbinates. CONCLUSIONS: hBD-2 possibly mediates a specific, early starting antimicrobial defense strategy of the nasal mucosa. This hypothesis would explain persistent infections with PA through diminished hBD-2 gene expression.

Cells, Cultured↗

PubMed2000

Reconstruction of laser-scanned 3D torso topography and stereoradiographical spine and rib-cage geometry in scoliosis.

Assessments of scoliosis are routinely done by means of clinical examination and full spinal x-rays. Multiple exposure to ionization radiation, however, can be hazardous to the child and is costly. Here, we explain the use of a noninvasive imaging technique, based on laser optical scanning, for quantifying the three-dimensional (3D) trunk surface topography that can be used to estimate parameters of 3D deformity of the spine. The laser optical scanning system consisted of four BIRIS laser cameras mounted on a ring moving along a vertical axis, producing a topographical mapping of the entire torso. In conjunction with the laser scans, an accurate 3D reconstruction of the spine and rib cage were developed from the digitized x-ray images. Results from 14 scoliotic patients are reported. The digitized surfaces provided the foundation data to start studying concordance of trunk surface asymmetry and spinal shape in idiopathic scoliosis.

Calibration↗

PubMed2000

Geranic acid formation, an initial reaction of anaerobic monoterpene metabolism in denitrifying Alcaligenes defragrans.

Monoterpenes with an unsaturated hydrocarbon structure are mineralized anaerobically by the denitrifying beta-proteobacterium Alcaligenes defragrans. Organic acids occurring in cells of A. defragrans and culture medium were characterized to identify potential products of the monoterpene activation reaction. Geranic acid (E,E-3,7-dimethyl-2,6-octadienoic acid) accumulated to 0.5 mM in cells grown on alpha-phellandrene under nitrate limitation. Cell suspensions of A. defragrans 65Phen synthesized geranic acid in the presence of beta-myrcene, alpha-phellandrene, limonene, or alpha-pinene. Myrcene yielded the highest transformation rates. The alicyclic acid was consumed by cell suspensions during carbon limitation. Heat-labile substances present in cytosolic extracts catalyzed the formation of geranic acid from myrcene. These results indicated that a novel monoterpene degradation pathway must be present in A. defragrans.

Alcaligenes↗

PubMed2000

Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia.

Cultured lung epithelial cells release antibacterial activity upon contact with Pseudomonas aeruginosa (PA), which is impaired in cystic fibrosis (CF). In order to identify the factors responsible for killing PA by a biochemical approach, we purified antimicrobial activity from supernatants of the A549 lung epithelial cell line, previously stimulated with PA bacteria, by subsequent high performance liquid chromatography. NH(2)-terminal sequencing of a major bactericidal compound revealed it to be identical with human beta-defensin-2 (hBD-2). A mucoid phenotype of PA, but not two nonmucoid PA strains, high concentrations (> 10 microg/ml) of PA lipopolysaccharide, tumor necrosis factor alpha, and interleukin (IL)-1beta, but not IL-6, dose-dependently induced hBD-2 messenger RNA in cultured normal bronchial, tracheal, as well as normal and CF-derived nasal epithelial cells. Genomic analysis of hBD-2 revealed a promoter region containing several putative transcription factor binding sites, including nuclear factor (NF) kappaB, activator protein (AP)-1, AP-2, and NF-IL-6, known to be involved in the regulation of inflammatory responses. Thus, hBD-2 represents a major inducible antimicrobial factor released by airway epithelial cells either on contact with mucoid PA or by endogenously produced primary cytokines. Therefore, it might be important in lung infections caused by mucoid PA, including those seen in patients with CF.

Amino Acid Sequence↗

PubMed1999

Human beta-defensin-2.

Human beta-defensin-2 (HBD-2) is a cysteine-rich cationic low molecular weight antimicrobial peptide recently discovered in psoriatic lesional skin. It is produced by a number of epithelial cells and exhibits potent antimicrobial activity against Gram-negative bacteria and Candida, but not Gram-positive Staphylococcus aureus. HBD-2 represents the first human defensin that is produced following stimulation of epithelial cells by contact with microorganisms such as Pseudomonas aeruginosa or cytokines such as TNF-alpha and IL-1 beta. The HBD-2 gene and protein are locally expressed in keratinocytes associated with inflammatory skin lesions such as psoriasis as well as in the infected lung epithelia of patients with cystic fibrosis. It is intriguing to speculate that HBD-2 is a dynamic component of the local epithelial defense system of the skin and respiratory tract having a role to protect surfaces from infection, and providing a possible reason why skin and lung infections with Gram-negative bacteria are rather rare.

Amino Acid Sequence↗