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Biomedical subjects

M Klein

Publications and source records attributed to M Klein.

At least 37 records · Page 2Linked to original sources
PubMed2001

Severe impairment of primary but not memory responses to influenza viral antigens in aged mice: costimulation in vivo partially reverses impaired primary immune responses.

Profound alterations in humoral and cellular immune responses are a hallmark of aging, and understanding the immunobiology of aging is key to the success of preventive vaccination strategies. With aging, while recall or memory responses to influenza viral antigens for the most part remained unaltered, primary immune responses are severely impaired. The impaired primary responses are partly due to a lack of costimulation, as providing costimulation at the time of induction of primary immune responses against influenza virus vaccine partially reversed aged-related immune dysfunction and conferred enhanced protection. Inclusion of immunomodulators that up-regulate the expression of costimulatory molecules must be considered to improve the efficacy of vaccination in the elderly, particularly to novel immunogens.

Adjuvants, Immunologic↗
PubMed2001

Endosymbiotic sulphate-reducing and sulphide-oxidizing bacteria in an oligochaete worm.

Stable associations of more than one species of symbiont within a single host cell or tissue are assumed to be rare in metazoans because competition for space and resources between symbionts can be detrimental to the host. In animals with multiple endosymbionts, such as mussels from deep-sea hydrothermal vents and reef-building corals, the costs of competition between the symbionts are outweighed by the ecological and physiological flexibility gained by the hosts. A further option for the coexistence of multiple symbionts within a host is if these benefit directly from one another, but such symbioses have not been previously described. Here we show that in the gutless marine oligochaete Olavius algarvensis, endosymbiotic sulphate-reducing bacteria produce sulphide that can serve as an energy source for sulphide-oxidizing symbionts of the host. Thus, these symbionts do not compete for resources but rather share a mutalistic relationship with each other in an endosymbiotic sulphur cycle, in addition to their symbiotic relationship with the oligochaete host.

Aerobiosis↗
PubMed2001

The Arabidopsis thaliana ABC transporter AtMRP5 controls root development and stomata movement.

In the present study, we investigated a new member of the ABC transporter superfamily of Arabidopsis thaliana, AtMRP5. AtMRP5 encodes a 167 kDa protein and exhibits low glutathione conjugate and glucuronide conjugate transport activity. Promotor- beta-glucuronidase fusion constructs showed that AtMRP5 is expressed mainly in the vascular bundle and in the epidermis, especially guard cells. Using reverse genetics, we identified a plant with a T-DNA insertion in AtMRP5 (mrp5-1). mrp5-1 exhibited decreased root growth and increased lateral root formation. Auxin levels in the roots of mrp5-1 plants were increased. This observation may indicate that AtMRP5 works as an auxin conjugate transporter or that mutant plants are affected in ion uptake, which may lead to changes in auxin concentrations. Experiments on epidermal strips showed that in contrast to wild type, the sulfonylurea glibenclamide had no effect on stomatal opening in mrp5-1 plants. This result strongly suggests that AtMRP5 may also function as an ion channel regulator.

ATP-Binding Cassette Transporters↗
PubMed2001

Safety and immunogenicity of a canarypox-vectored human immunodeficiency virus Type 1 vaccine with or without gp120: a phase 2 study in higher- and lower-risk volunteers.

Live attenuated viral vectors that express human immunodeficiency virus (HIV) antigens are being developed as potential vaccines to prevent HIV infection. The first phase 2 trial with a canarypox vector (vCP205, which expresses gp120, p55, and protease) was conducted in 435 volunteers with and without gp120 boosting, to expand the safety database and to compare the immunogenicity of the vector in volunteers who were at higher risk with that in volunteers at lower risk for HIV infection. Neutralizing antibodies to the MN strain were stimulated in 94% of volunteers given vCP205 plus gp120 and in 56% of volunteers given vCP205 alone. CD8(+) cytotoxic T lymphocyte cells developed at some time point in 33% of volunteers given vCP205, with or without gp120. Phase 3 field trials with these or similar vaccines are needed, to determine whether efficacy in preventing HIV infection or in slowing disease progression among vaccinees who become infected is associated with the level and types of immune responses that were induced by the vaccines in this study.

AIDS Vaccines↗
PubMed2001

The effects of 4'-alkyl substituents on the mutagenic activity of 4-amino- and 4-nitrostilbenes in Salmonella typhimurium.

Six derivatives of trans-4-aminostilbene bearing different alkyl groups in the 4'-position and six of the corresponding nitro compounds were synthesized and tested for their mutagenic potency in Salmonella typhimurium strains TA98 and TA100. Regarding the test series in presence of S9-mix, maximum activity was observed for those trans-4-aminostilbenes and trans-4-nitrostilbenes bearing small alkyl substituents like methyl and ethyl. More bulky substituents reduced the mutagenic potential in the order iso-propyl ethyl>iso-propyl>sec-butyl>tert-butyl). These trends have been compared with quantitative structure activity relationship (QSAR) model predictions, leading to the conclusion that steric demand is an important factor for mutagenicity of substituted aminostilbenes and nitrostilbenes. The unexpected result for the tert-butyl nitrostilbene tested with metabolic activation may be attributed to a different metabolic pathway.

Magnetic Resonance Spectroscopy↗
PubMed2001

Therapeutic vaccines against melanoma and colorectal cancer.

Our overall strategy is to develop multivalent recombinant vaccines capable of eliciting broad immune responses in patients with malignant melanoma or colorectal cancer. We report herein results from initial studies conducted in cancer patients to evaluate the effect of intratumoral administration of recombinant canarypox viruses carrying cytokine genes. Our current focus is on the induction of tumor-specific T-cell responses using a prime/boost immunization schedule with a unique vector system derived from the canary pox virus called ALVAC, in which we incorporate genes encoding Tumor Associated Antigens (TAAs) of interest. Clinical studies in colorectal cancer evaluating an ALVAC CEA candidate vaccine have shown that this approach is safe and can induce tumor-specific T cell responses. Additional clinical studies evaluating candidate vaccines against melanoma and colorectal cancer, targeting either the gp100, Mage 1, Mage 3 or p53 molecules are ongoing.

Antigens, Neoplasm↗
PubMed2001

Current progress in the development of human immunodeficiency virus vaccines: research and clinical trials.

In spite of extensive prevention programs, the HIV pandemic is still spreading worldwide, particularly in developing countries. AIDS is the leading cause of death in Africa and the fourth cause worldwide. WHO estimates that there are 16000 new cases of HIV infection daily and that 100 million individuals will be infected during the next decade. In spite of the spectacular results of triple therapy, the best strategy for controlling the HIV epidemics remains the development of an efficacious prophylactic vaccine. However, the development of such a vaccine remains a formidable challenge to both the industry and the scientific community (Esparza J. Bhamarapravati N. Accelerating the development and future availability of HIV-1 vaccines: why, when, where, and how? Lancet 2000; 355: 2061-6 [1]).

AIDS Vaccines↗
PubMed2001

Cognitive status and quality of life in patients with suspected versus proven low-grade gliomas.

BACKGROUND: The preferred management of patients with suspected low-grade gliomas (S-LGG) remains controversial. The benefits of resection or radiotherapy early in the course of the disease have not been proven in terms of survival. Little is known about the effects of early therapy on quality of life (QOL) and cognitive status. The authors compared functional status, QOL, and cognitive status of patients suspected of having a LGG, in whom treatment was deferred, and patients with proven LGG (P-LGG), who underwent early surgery. METHODS: The authors recruited 24 patients suspected of having an LGG. These patients were matched with 24 patients with a histologically proven LGG and healthy control subjects for educational level, handedness, age, and gender. The two patient groups were also matched for tumor laterality, use of anticonvulsants, and interval between diagnosis and testing. Functional status was determined in both patient groups. QOL and cognitive status were compared between the three groups. RESULTS: Matching criteria and functional status did not differ significantly between groups. Both patient groups scored worse on QOL scales than healthy control subjects. Unoperated patients with S-LGG scored better on most items than patients with P-LGG. Cognitive status was worse in both groups than in healthy control subjects, but, again, patients with S-LGG performed better than patients with P-LGG. CONCLUSION: These data suggest that a wait-and-see policy in patients with S-LGG has no negative effect on cognitive performance and QOL.

Adolescent↗
PubMed2001

Carbonyl- and carboxyl-substituted enediynes: synthesis, computations, and thermal reactivity.

The influence of electron-withdrawing groups (carbonyl and carboxyl) at the alkyne termini on the reactivity of enediynes was investigated by a combination of experimental and computational techniques. While the general chemical reactivity of such enediynes, especially if non-benzannelated, is increased markedly, the thermal cyclization, giving rise to Bergman cyclization products, is changed little relative to the parent enediyne system. This is evident from kinetic measurements and from density functional theory (DFT, BLYP/6-31G + thermal corrections) computations of the experimental systems which show that the Bergman cyclization barriers slightly (3-4 kcal/mol) increase, in contrast to earlier theoretical predictions. The effect on the endothermicities is large (DeltaDeltaH(r) = 7-12 kcal/mol). Hence, the increased reactivity of the substituted enediynes is entirely due to nucleophiles or radicals present in solution. This was demonstrated by quantitative experiments with diethylamine and tetramethyl piperidyl oxide (TEMPO) which both give fulvenes through 5-exo-dig cyclizations.

Journal Article↗
PubMed2001

Epithelioid hemangioma of bone.

Although no specific radiographic appearance has emerged to date for the epithelioid subtype of hemangioma, these lesions most typically exhibit well-defined osteolysis. Other relatively common features include surrounding sclerosis, cortical expansion and cortical destruction. We present a case of epithelioid hemangioma of the spine with an unusual radiological appearance which to our knowledge has not previously been reported: diffuse sclerosis of the involved vertebral body. The diffuse sclerosis seen in this case resembles the osteosclerotic process seen not only in benign entities such as subacute and chronic osteomyelitis, but also in malignant lesions such as osteoblastic metastatic disease and lymphoma.

Adult↗
PubMed2001

Detection of moderate hyperhomocysteinemia: comparison of the Abbott fluorescence polarization immunoassay with the Bio-Rad and SBD-F high-performance liquid chromatographic assays.

The importance of accurate methods for homocysteine measurement has been emphasized. We compared the results obtained with the most commonly used high-performance liquid chromatography (HPLC) assay, and two recently commercially available methods: another HPLC and a fluorescence polarization immunoassay, in plasmas from normo- or hyperhomocysteinemic patients. A significant agreement between the different methods in classifying the results as hyper or normal-homocysteinemia was observed. However, a significant difference between the results was found. Standardization is urgently necessary to improve the concordance of homocysteine determination.

Chemistry, Clinical↗
PubMed2001

The ABC-like vacuolar transporter for rye mesophyll flavone glucuronides is not species-specific.

In many cases, the vacuolar uptake of secondary metabolites has been demonstrated to be strictly specific for a given compound and plant species. While most plants contain glycosylated secondary substances, few cases are known where flavonoids may also carry negative charges, e.g. as glucuronide conjugates. Vacuolar transport of glucosylated phenylpropanoid derivatives has been shown to occur by proton substrate antiport mechanisms (Klein, M., Weissenböck. G., Dufaud, A., Gaillard, C., Kreuz, K., Martinoia, E., 1996. Different energization mechanisms drive the vacuolar uptake of a flavonoid glucoside and a herbicide glucoside. J. Biol. Chem. 271, 29,666-29,671). In contrast, flavone glucuronides appearing specifically in rye mesophyll vacuoles are taken up by direct energisation utilising MgATP, strongly arguing for the presence of an ATP-binding cassette (ABC) transporter belonging to the subfamily of multidrug resistance-associated proteins (MRP) on the rye vacuolar membrane (Klein, M., Martinoia, E., Hoffmann-Thoma, G., Weissenböck, G., 2000. A membrane-potential dependent, ubiquitous ABC-like transporter mediates the vacuolar uptake of rye flavone glucuronides regulation of glucturonide uptake by glutathione and its conjugates. Plant Journal 21, 289-304). MRPs are known to transport negatively charged organic anions. Results presented here suggest that the vacuolar directly energised MRP-like glucuronate pump for plant-specific flavone glucuronides is ubiquitously present in diverse plant species since rye flavone glucuronides are taken up into vacuoles isolated from the barley mesophyll or from the broccoli stalk parenchyma representing two species which do not synthesise glucuronidated secondary compounds. According to the transport characteristics and inhibition profile observed we propose the existence of a high-capacity, uncoupler-insensitive vacuolar ABC transporter for flavone glucuronides and possibly other negatively charged organic compounds -- plant-born or xenobiotic -- irrespective of the plant's capability to endogenously produce glucuronidated compounds.

ATP-Binding Cassette Transporters↗
PubMed2001

Myocardial revascularization in patients with end-stage renal disease: comparison of percutaneous transluminal coronary angioplasty and coronary artery bypass grafting.

BACKGROUND: Ischemic heart disease is the major cause of death in patients with end-stage renal disease. The high prevalence of coronary artery disease results in a rising number of dialysis patients requiring myocardial revascularisation. OBJECTIVE: The objective of this study was to compare the outcomes of recurrent angina, myocardial infarction, rate of reinterventions and cardiovascular death following percutaneous coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) in patients with end-stage renal disease. PATIENTS AND METHODS: In a retrospective investigation 40 patients with chronic renal failure undergoing primarily PTCA and 65 patients undergoing CABG were included. Both groups were comparable for gender, duration on dialysis and the number of cardiovascular risk factors per patient. Patients undergoing PTCA were younger (53 +/- 12 years vs. 57 + 8 years; p < 0.05) and more often diabetics (30% vs. 14%; p < 0.05). RESULTS: Most patients in both groups had a multi-vessel disease (95% in the CABG group vs. 74% in the PTCA group), in the CABG group there were significantly more patients with a triple-vessel disease (62% with vs. 40% in the PTCA group; p < 0.01), PTCA was primarily successful in 95% of the patients while complete revascularization was achieved in 88% of patients undergoing CABG. The perioperative mortality after CABG was 4.8% as compared to none after interventional revascularisation. The cumulative freedom of angina after 6, 12 and 24 months after intervention was significantly lower after PTCA (54%, 40%, 29%) than after bypass grafting (97%, 94%, 90%, p < 0.001). The frequency of reinterventions following PTCA was significantly higher compared to patients following CABG (p < 0.001). After PTCA 15 patients needed further revascularisations, 8 of them underwent CABG, whereas after CABG only two patients required additional myocardial revascularisation. There was no significant difference in the overall mortality between both groups; the survival rate after 12 and 24 months was 95% and 82% after PTCA and 93% and 86% after CABG, respectively. CONDITION: Although patients receiving CABG had a more severe coronary artery disease the overall mortality was comparable and clinical and functional outcome was improved compared to patients after coronary angioplasty.

Adult↗
PubMed2001

Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder.

Genes involved in the regulation of synaptic vesicle function are potential candidates for the development of psychiatric disorders. In addition to experimental and theoretical considerations, a number of genes involved in synaptic vesicle function map to regions of the genome that have been linked to bipolar disorder (BPD) and schizophrenia (SZ). One is synaptojanin 1 (SYNJ1) which maps to 21q22.2, a chromosomal region that has been linked to BPD in a subset of families in several studies. Synaptojanin 1 is an inositol 5-phosphatase that has an important role in synaptic vesicle endocytosis. Mutation screening of 32 exons, intron--exon junctions, and 839 bases of 5'-flanking DNA resulted in the identification of 11 mutations of which four were very common and seven were very rare. Of the 11 mutations identified, several may have functional significance including two coding variants, two that may affect the binding of a transcription factor, and two that involve known splicing regulatory domains. Five bipolar patients out of 149 analyzed were found who have one of the four rare variants that were most likely to have functional significance compared with 0/148 controls. The allele frequencies for three of the four common variants were very similar in bipolar patients and controls. A slight difference in allele frequency was found for an interesting mutation we detected in intron 12 in which two non-adjacent thymidine residues are deleted in a poly-AT tract located near the exon 12 splice donor site (chi(2) = 2.45, P = 0.12, 2-tailed). Although we failed to unequivocally identify a specific SYNJ1 allele that could be responsible for putative chromosome 21q22-linked BPD, several interesting variants were found to be increased in bipolar subjects and should be further investigated.

5' Untranslated Regions↗
PubMed2001

The bioavailability of oral fludarabine phosphate is unaffected by food.

INTRODUCTION: A prospective, open and randomized, two-way crossover study was conducted to evaluate the pharmacokinetics and bioavailability of oral fludarabine phosphate when taken on a full versus an empty stomach. The effectiveness of therapy was also assessed after two cycles of treatment, four weeks apart MATERIALS AND METHODS: Patients with chronic lymphocytic leukemia or low-grade non-Hodgkin's lymphoma were randomly assigned to two groups, both of which received two cycles of treatment with 90 mg of oral fludarabine phosphate administered when either fed or fasted. Patients in Group 1 (n = 8) received oral treatment on a full stomach for the first cycle then on a fasted stomach for the second, while those in Group 2 (n = 10) received their treatment in the reverse sequence. Oral fludarabine phosphate was administered on the first day of the two study cycles and intravenous fludarabine phosphate was administered on days 3-6. RESULTS AND CONCLUSION: Of 22 patients recruited, 18 (CLL n = 10; NHL n = 8) were eligible for efficacy and safety evaluation, and 16 for bioavailability and pharmacokinetic analyses. The response to oral 2-F-ara-AMP was rapid: by two treatment cycles, 12 out of 18 patients (66.7%) had achieved partial response. Of the six patients who did not respond, five patients (27.7%) had stable disease. There was no notable difference in the rate of response between patients with B-CLL and lg-NHL. There was a marginal increase in total systemic availability of fludarabine phosphate when administered orally on a fed stomach (2-F-ara-A AUC((0-24 h)) = 3.28 +/- 1.48 microg.h/ml) compared to a fasted stomach (2-F-ara-A AUC((0-24 h)) = 3.05 +/- 1.56 microg.h/ml). Time to peak plasma concentration was slightly extended by the presence of food (2.2 +/- 1.0 versus 1.3 +/- 0.74 h) but the terminal half-life was unaffected. The minor differences in the pharmacokinetics of oral fludarabine phosphate when taken after food were not statistically significantly different and seem unlikely to be clinically relevant. The efficacy and safety data closely paralleled previous experience with the intravenous formulation.

Administration, Oral↗
PubMed2001

Bone tunnel remodeling at the site of biodegradable interference screws used for anterior cruciate ligament reconstruction: 5-year follow-up.

PURPOSE: The purpose of this prospective study was to review, using expanded clinical-assessment tools, the long-term results of the local effects of a bioabsorbable interference screw (copolymer 85/15 D,L lactide/glycolide) in anterior cruciate ligament (ACL) reconstruction. TYPE OF STUDY: This prospective study was initiated in May 1993. The inclusion criteria for patient selection included rupture of the ACL in athletic patients without involvement of the collateral ligaments, arthroscopic ACL reconstruction using middle third of the ligamentum patella, and magnetic resonance imaging (MRI) and plain radiographic examinations of the knee joint during follow-up. MATERIALS: Between May 1993 and October 1994, 32 patients were enlisted in the study; 48 patients did not fit the inclusion criteria. There were 25 men 7 women. The average age was 29.1 years (range, 19 to 50 years). There were 21 right knees and 11 left knees. The follow-up examinations were performed by an independent examiner. There were 28 patients available for follow-up at a medium of 5.2 years (range, 4.1 to 6.4 years). The evaluation included various testing systems (i.e., OAK, IKDC, Lysholm) as well as MRI and plain radiographic studies to investigate the longevity of the implant and potential adverse effects of this new bioabsorbable material. RESULTS: The clinical results were good. The OAK score (Orthopädische Arbeitsgruppe Knie) showed 93% excellent and good results, and 7% fair results. The IKDC and Lysholm scores were 92% and 96% good and excellent results, respectively. MRI showed bone remodeling and new bone formations at the site of the implant in the femoral as well as in the tibial bone tunnel at follow-up. No cystic or osteolytic changes where seen on MRI or plain radiographs. CONCLUSIONS: This study showed the correlation between histology and MRI: there was minimal surgical-site edema, minimal reaction to this material, and complete replacement by new bone formation of the previous site of this implant. At 5 years, this bioabsorbable interference screw appeared clinically safe and effective for fixation of bone blocks during ACL reconstruction and MRI showed complete absorption and replacement with new bone.

Absorbable Implants↗
PubMed2001

Intraoperative computed tomography with the mobile CT Tomoscan M during surgical treatment of orbital fractures.

Up to now it has only been possible to monitor the alignment of orbital floor fractures postoperatively with a computed tomography (CT) examination with coronal sectioning. If this showed an incorrect positioning, renewed surgery and anaesthetics were often required. The purpose of this study was the implementation and definition of the spectrum of indications for intraoperative CT examinations while keeping patient radiation exposure to a minimum. Thirty-two orbital fracture cases were examined pre- and intraoperatively using the mobile computer tomograph Tomoscan M in coronal sectioning. In this patient collective, 12 cases showed an isolated orbital floor fracture and twenty cases an orbital floor fracture associated with a zygomatic fracture. The technical prerequisite for these examinations was the construction of a suitable radiolucent operating table which permitted coronal sections to be made with the CT-Gantry tilted. The authors aimed to reduce radiation exposure by optimizing the technical setting parameters and closely defining the scan region for the operator. In three of 32 cases there were no surgical indications following clinical and preoperative CT examination. In three of the 20 cases with associated zygomatic fracture a closed reduction with a reduction hook was carried out, and no revision was necessary after the intraoperative CT examination. In 26 cases an open reduction was carried out. Of these open reduced fractures, four had to be revised after intraoperative CT monitoring; one of the isolated orbital floor fractures and three of those associated with a zygomatic fracture. Intraoperative CT monitoring of orbital floor fractures is considered a useful surgical aid. Its advantages are immediate monitoring of the surgical reduction, the presence of the surgeon during scanning enabling him to determine directly the relevant sections to scan, and the resulting radiation exposure.

Adult↗