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Biomedical subjects

B Kramer

Publications and source records attributed to B Kramer.

At least 55 records · Page 3Linked to original sources
PubMed1998

Alterations in rat vaginal histology by exogenous gonadotrophins.

Changes in vaginal epithelium are known to occur during the normal oestrous or menstrual cycle and in ovariectomised animals in response to various hormones. However, vaginal changes due to exogenous gonadotrophins superimposed on the normal hormonal milieu as occurs in in vitro fertilisation programmes have not previously been demonstrated. Female rats were hyperstimulated with follicle stimulating hormone and human chorionic gonadotrophin prior to mating. Control mated animals were not injected. Vaginal tissue was collected at 4.5, 5.5 and 6.5 d after mating. Tissue was processed for light microscopy. Hyperstimulation by the exogenous gonadotrophins caused mucification, a decrease in the number of epithelial layers and an increase in the thickness of the epithelium on d 4.5 of pregnancy. The mitotic index of the epithelial cells was depressed in the hyperstimulated rats with respect to control animals. Exposure to high levels of oestradiol and an altered progesterone:oestradiol ratio appear to have caused the changes in the vaginal epithelium.

Animals↗
PubMed1998

The natural history of degenerative ataxia: a retrospective study in 466 patients.

The aim of the present study was (i) to compare disease progression and survival in different types of degenerative ataxia, and (ii) to identify variables that may modify the rate of disease progression. We included patients suffering from Friedreich's ataxia (FRDA, n = 83), early onset cerebellar ataxia (EOCA, n = 30), autosomal dominant cerebellar ataxia (ADCA) type I (ADCA-I, n = 273), ADCA-III (n = 13) and multiple system atrophy (MSA, n = 67). Molecular genetic testing allowed us to assign 202 ADCA-I patients to one of the following subgroups: spinocerebellar ataxia type I (SCAI, n = 36), SCA2 (n = 56) and SCA3 (n = 110). To assess disease progression we defined the following disease stages: stage 0 = no gait difficulties; stage 1 = disease onset, as defined by onset of gait difficulties; stage 2 = loss of independent gait; stage 3 = confinement to wheelchair; stage 4 = death. Disease progression was most rapid in MSA, intermediate in FRDA, ADCA-I and ADCA-III and slowest in EOCA. The rate of progression was similar in SCA1, SCA2 and SCA3. The CAG repeat length was a significant risk factor for faster progression in SCA2 and SCA3, but not in SCA1. In FRDA, the time until confinement to wheelchair was shorter in patients with earlier disease onset, suggesting that patients with long GAA repeats and early disease onset have a poor prognosis. Female gender increased the risk of becoming dependent on walking aids or a wheelchair, but it did not influence survival in FRDA, SCA3 and MSA. In SCA2, female gender was associated with shortened survival. In MSA, later age of onset increased the risk of rapid progression and death.

Adolescent↗
PubMed1998

Modulation of IgE reactivity of allergens by site-directed mutagenesis: potential use of hypoallergenic variants for immunotherapy.

Specific immunotherapy is an efficient treatment for patients suffering from type I allergy. The mechanisms underlying successful immunotherapy are assumed to operate at the level of T helper cells, leading to a modulation of the immune response to allergens. During immunotherapy, increasing doses of allergens are given on a regular basis, and the beneficial effects for the patient depend on the concentration of allergen used. On the other hand, the risk of IgE-mediated anaphylactic side effects also increase with the amount of allergen applied per injection. Therefore, we have proposed the use of hypoallergenic (low IgE binding activity) forms of allergens for immunotherapy. We evaluated by site-directed mutagenesis the contributions of individual amino acid residues/positions for IgE binding to Bet v 1, the major allergen of birch pollen. We found that IgE binding to Bet v 1 depended on at least six amino acid residues/positions. Immunoblot analyses and inhibition experiments showed that the multiple-point Bet v 1 mutant exhibited extremely low reactivity with serum IgE from birch pollen-allergic patients. In vivo (skin prick) tests showed that the potency of the multiple-point mutant to induce typical urticarial type I reactions in pollen-allergic patients was significantly lower than for wild-type Bet v 1. Proliferation assays of allergen-specific T cell clones demonstrated that these six amino acid exchanges in the Bet v 1 sequence did not influence T cell recognition. Thus, the Bet v 1 six-point mutant displayed significantly reduced IgE binding activity, but conserved T cell activating capacity, which is necessary for immunomodulation. The approach described here may be generally applied to produce allergen variants to be used in a safe therapy form of immediate-type allergies.

Allergens↗
PubMed1998

The myoepithelium of human major salivary glands revisited.

The presence of myoepithelial cells in salivary glands is of importance with regard to tumour histogenesis, yet there is no consensus in the literature as to the specific location of these cells. A major problem has been the methods of precise identification of myoepithelium at the light microscopic level. The present study therefore reviews the distribution of myoepithelial cells in the major salivary glands (parotid, submandibular and sublingual) of the human, utilising a monoclonal antibody specific to actin, a cytoplasmic component of the myoepithelial cell. Qualitative analysis was performed to assess the distribution of these cells in mucous and serous acini and in the different regions of the ductal system. As previously described, myoepithelial cells were found to be present around serous and mucous acini as well as the intercalated ducts of all the major glands. They appeared to be more abundant in mucous than in serous acini of the submandibular and sublingual glands. In addition, this study has demonstrated the presence of myoepithelial cells in the proximal portion of striated ducts in the submandibular gland--a location that has not previously been reported in the human.

Cell Transformation, Neoplastic↗
PubMed1997

Factors determining outcome in patients treated with interstitial implantation as a radiation boost for breast conservation therapy.

PURPOSE: To evaluate the relative utility of interstitial implant as a technique for tumor bed dose escalation and assess technical factors related to outcome. METHODS AND MATERIALS: From 1982-1994, a prospectively applied institutional policy of margin-directed boost dose escalation to the tumor bed was followed whereby interstitial implantation was commonly employed for a final margin status (FMS) < or = 2 mm. There were 509 treated breasts, of which 127 received an implant boost. For purposes of comparison, cases were broadly classed as "implant" (all FMS < or = 2 mm) and "nonimplant" (FMS < or = 2 mm or FMS > 2 mm). The implant target volume was determined at completion of whole breast irradiation by clinical assessment. All implants were constructed in accordance with a preplanning algorithm designed to maximize dose homogeneity within a prescription isodose goal of 0.50 Gy/h for 40 h. Local control and cosmetic outcome were evaluated with respect to extent of tumor, histopathology, FMS, extent of surgery, and systemic adjuvant therapy. Implant quality was assessed using four calculated parameters: strand separation quotient (SSQ), planar separation quotient (PSQ), global separation quotient (GSQ), and dose homogeneity index (DHI). The mean implant volume was 48.3 +/- 20 cc, the mean prescribed dose rate was 0.46 +/- 0.08 Gy/h, and the mean total implant dose was 19.94 +/- 1.52 Gy. RESULTS: Cosmetic outcome was good/excellent in 90% of implant and 83% of all nonimplant cases, which was not statistically different. Cosmesis was significantly superior with implant when compared to nonimplant cases receiving an external boost of 20 Gy. Logistic regression analyses of implant cases revealed that reexcision volume and decreased DHI were associated with adverse cosmesis. There were 10 local failures in the implanted patients (4 within the prescribed isodose volume, 5 at the periphery, and 1 elsewhere in the breast). The local failure rate at 5 and 7 years in the implanted group was 3.9 and 9.0%, respectively, compared to nonimplant cases with a margin < or = 2 mm of 3.2 and 3.2%, respectively. These differences were not significant. The crude local failure rate in patients with an associated DCIS component was 12% a compared to 3% in patients with pure invasive histology (p = 0.06). A proportional hazards survival model revealed a significant association of local failure with the performance of a reexcision and young age. CONCLUSION: We conclude that interstitial implant boost for breast conserving irradiation is associated with cosmesis that is superior than the same nominal dose of external beam boost, although this is highly dependent upon the technical quality of the source position and the relative uniformity of dose deposition. Breast implantation results in a rate of local control no better than dose-matched external beam boost in patients with a final margin < or = 2 mm. Local control with implantation might be further enhanced by increasing implant volume and/or improved target localization.

Adult↗
PubMed1997

The value of breast lumpectomy margin assessment as a predictor of residual tumor burden.

PURPOSE: Margin assessment is commonly used as a guide to the relative aggressiveness of therapy for breast conserving treatment (BCT), though its value as a predictor of the presence, type, or extent of residual tumor has not been conclusively studied. Controversy continues to exist as to what constitutes a margin that is "positive," "close," or "negative." We attempt to address these issues through an analysis of re-excision specimens. PATIENTS AND METHODS: As part of an institutional prospective practice approach for BCT, 265 cases with AJCC Stage I/II carcinoma with an initial excision margin that was < or = 2 mm or indeterminate were subjected to re-excision. The probability of residual tumor (+RE) was evaluated with respect to tumor size, histopathologic subtype, relative closeness of the measured margin, the extent of margin positivity graded as focal, minimal, moderate, or extensive, and the extent of specimen processing as reflected in the number of cut sections per specimen volume (S:V ratio). The amount of residual tumor was graded as microscopic, small, medium, or large. The histopathologic subtype of tumor in the re-excision specimen was classified as having an invasive component (ICa) or pure DCIS (DCIS). RESULTS: The primary excision margin was positive, > 0 < or = 1 mm, 1.1-2 mm, and indeterminate in 60%, 18%, 5%, and 17%, respectively. The predominant histopathologies in the initial excision specimens were invasive ductal (IDC) (50%) and tumors with an extensive intraductal component (EIC) (43%). The histopathology of the initial excision specimen was highly predictive of the histopathology of tumor found on re-excision, as residual DCIS was found in 60% of +RE specimens with initial histopathology of EIC compared to 26% for IDC (p = 0.001). Neither the extent of margin positivity nor the extent of tumor in the re-excision were significantly related to the initial histopathologic subtype; however, a +RE was seen in 59% of EIC, 43% of IDC, and 32% of invasive lobular ILC cases (p = 0.01). The extent of margin positivity was significantly related to the size of the tumor such that tumor size < or = 20 mm was associated with a greater probability of focal or minimal margin involvement. Positive margins graded as focal, minimal, moderate/extensive were associated with a +RE in 26%, 58%, and 84%, respectively (p = 0.001). Further, the extent of positivity was significantly correlated with the extent of residual tumor such that focal/minimal positivity was more commonly associated with micro/small +RE, whereas moderate/extensive positivity was associated with medium/large +RE. When the closest margin of the initial excision specimen was positive, > 0 < or = 1 mm, or 1.1-2 mm, a +RE was found in 56%, 41%, and 17%, respectively (p = 0.01) but did not correlate with the amount of residual tumor. The extent of specimen processing as reflected in the S:V ratio did not correlate with the probability of defining a measured margin as positive nor the probability of a +RE. In a univariate model, the extent of tumor in the re-excision and the histologic type of tumor in the re-excision were significantly associated with margin status and initial histopathology, respectively. The probability of finding a +RE, based on a multivariate model, was associated with the closeness and extent of margin involvement and initial histopathology of an EIC. CONCLUSION: The relative closeness of tumor to the specimen edge and the extent of margin positivity are predictive for residual tumor, though with an error consistent with its limitations as a sampling procedure. The histopathology of tumor in the initial excision is predictive of the type of residual tumor and the extent of margin positivity was correlated with the amount of residual tumor.

Adult↗
PubMed1997

CASP2 experiences with docking flexible ligands using FlexX.

We have applied our docking program FlexX to all eight CASP2 targets involving protein complexes with small ligands. Of the seven targets that were kept in the CASP2 experiment, we could solve two. We found important parts of the solution in four other examples, and were unsuccessful on the remaining example. This paper discusses all predictions in detail. Each of our prediction runs took just a few minutes of computer time on a standard workstation and could thus be demonstrated in real time at the CASP meeting. We believe that this speed is the prime strength of our program FlexX. In quality, our predictions are competitive with those produced by other predictors. The experiment showed that possible objectives of improvement of the FlexX program are to incorporate relevant aspects of receptor flexibility, deal with water molecules in the receptor pocket, allow for a postoptimization to refine favorable complexes, and improve the scoring function.

Amiloride↗
PubMed1997

Changes in vascular permeability and deciduoma formation during the peri-implantation period of the rat in response to exogenous gonadotropins.

BACKGROUND: Permeability of thin-walled vessels of the endometrium could be a prerequisite for deciduoma formation. Exogenous gonadotropins alter endometrial morphology and inhibit vascular permeability on the day of implantation. The aim of this study was to investigate the effect of exogenous gonadotropins on vascular permeability in the peri-implantation period and relate this to deciduoma formation. METHODS: Female rats were hyperstimulated with follicle-stimulating hormone and human chorionic gonadotropin prior to mating. Control animals were not injected. Endometrial tissue was collected at 4.5, 5.5, and 6.5 days after mating. Tissue was processed for electron microscopy. RESULTS: The presence of thin-walled fenestrated vessels and decidualised stromal cells were found in all control groups. With the exception of one fenestration, which occurred in a vessel from one hyperstimulated animal on 5.5 days of pregnancy, no fenestrations were found in the vessels of hyperstimulated animals. Decidualisation of stromal cells did not occur in these animals. CONCLUSION: Hyperstimulation with exogenous gonadotropins inhibits vascular permeability and subsequent decidualisation. Implantation thus fails to occur.

Animals↗
PubMed1997

Calculations of the CD spectrum of bovine pancreatic ribonuclease.

CD spectra of bovine pancreatic ribonuclease A (RNase A) and its subtilisin-modified from (RNase S) have been calculated, based upon high-resolution structures from x-ray diffraction. All known transitions in the peptide and side-chain groups, especially the aromatic and disulfide groups, have been included. Calculations have been performed with both the matrix method and with first-order perturbation theory. A newly developed method for treating the electrostatic interactions among transition charge densities and between static charge distributions and transition charge densities is used. The effects of local electrostatic fields upon the group transition energies are included for all transitions. Rotational strengths generated by the matrix method were combined with Gaussian band shapes to generate theoretical CD spectra. The calculated spectra reproduce the signs and approximate magnitudes of the near-uv CD bands of both RNase A and S. Agreement is most satisfactory for the negative 275 nm band, dominated by tyrosine contributions. In agreement with two previous studies by other workers, coupling between Tyr 73 and Tyr 115 is the single most important factor in this band. The positive band observed near 240 nm is dominated by disulfide contributions, according to our results. The far-uv CD spectrum is poorly reproduced by the calculations. The observed 208 nm band, characteristic of alpha-helices, is absent from the calculated spectrum, probably because the helices in RNase are short. A strong positive couplet centered near 190 nm is predicted but not observed. Possible reasons for these incorrect predictions of the current theoretical model in the far-uv are discussed.

Animals↗
PubMed1997

Effects of exercise on fatigue, aerobic fitness, and disease activity measures in persons with rheumatoid arthritis.

The effects of 12 weeks of low-impact aerobic exercise on fatigue, aerobic fitness, and disease activity were examined in a quasi-experimental time series study of 25 adults with rheumatoid arthritis (RA). Measures were obtained preintervention, midtreatment (after 6 weeks of exercise), end of treatment (after 12 weeks of exercise), and at a 15-week follow-up. ANOVAS for repeated measures showed that those subjects who participated more frequently reported decreased fatigue, while those who participated less frequently reported an increase in fatigue. All subjects, on average, showed increased aerobic fitness and increased right and left hand grip strength, decreased pain, and decreased walk time. There were no significant increases in joint count or sedimentation rate. Significant improvements in measures at the 15-week follow-up also were found. Findings indicate that persons with RA who participate in appropriate exercises may lessen fatigue levels and experience other positive effects without worsening their arthritis.

Adult↗
PubMed1997

Chinese hamster ovary cells are non-permissive towards infection with coxsackievirus B3 despite functional virus-receptor interactions.

Viral infection is a complex process which includes binding and interaction of the virus with specific cell surface receptors, uptake and uncoating of the virus, and finally replication. Chinese hamster ovary (CHO) cells are non-permissive towards infection with coxsackieviruses of group B (CVB), although they do express a putative CVB-specific receptor protein. In order to localize the block of infection in CHO cells, these cells were tested for binding of radiolabelled CVB3, receptor-mediated transformation of virions into A-particles, and replication of the viral genome. Binding of CVB3 to CHO cells was found to be comparable to the binding of this virus to permissive cell lines. Detergent-solubilized membrane proteins of CHO cells were tested in virus overlay protein-binding assays (VOPBAs) and shown to express a 100 kDa CVB-binding membrane protein similar to the CVB receptor protein which we recently described for permissive HeLa cells. Incubation of CVB3 with intact CHO cells resulted in transformation of cell-bound virions into non-infectious A-particles (deprived of capsid protein VP4), demonstrating the functional activity of the CVB receptor protein on CHO hamster cells. Transfection of recombinant CVB3 cDNA or viral RNA into CHO cells resulted in the production of infectious CVB3 virions, implying that the failure of CVB to infect CHO cells is not caused by a defect in virus replication but results from a block in the uptake of virus particles into the cell after the initial steps of virus-receptor interactions.

Animals↗
PubMed1997

Multiple automatic base selection: protein-ligand docking based on incremental construction without manual intervention.

A possible way of tackling the molecular docking problem arising in computer-aided drug design is the use of the incremental construction method. This method consists of three steps: the selection of a part of a molecule, a so-called base fragment, the placement of the base fragment into the active site of a protein, and the subsequent reconstruction of the complete drug molecule. Assuming that a part of a drug molecule is known, which is specific enough to be a good base fragment, the method is proven to be successful for a large set of docking examples. In addition, it leads to the fastest algorithms for flexible docking published so far. In most real-world applications of docking, large sets of ligands have to be tested for affinity to a given protein. Thus, manual selection of a base fragment is not practical. On the other hand, the selection of a base fragment is critical in that only few selections lead to a low-energy structure. We overcome this limitation by selecting a representative set of base fragments instead of a single one. In this paper, we present a set of rules and algorithms to automate this selection. In addition, we extend the incremental construction method to deal with multiple fragmentations of the drug molecule. Our results show that with multiple automated base selection, the quality of the docking predictions is almost as good as with one manually preselected base fragment. In addition, the set of solutions is more diverse and alternative binding modes with low scores are found. Although the run time of the overall algorithm increases, the method remains fast enough to search through large ligand data sets.

Automation↗
PubMed1997

Extraction Atherectomy for Recently Occluded Saphenous Vein Grafts: A Retrospective Study.

BACKGROUND: Over 300,000 coronary artery bypass operations are performed annually in the U.S., in which saphenous vein grafts remain the most often utilized conduit for myocardial revascularization. Still, the relatively short life-span of reverse saphenous vein grafts (SVG) demands that revascularization techniques be developed for SVG occlusions. Extraction atherectomy (EA) as a pre-treatment to percutaneous transluminal coronary angioplasty (PTCA) may offer advantages to PTCA alone in the treatment of these lesions. While a randomized study would best define the potential advantages of this treatment strategy, a retrospective comparison to historical data may provide some practical insights. PATIENTS AND METHODS: One hundred and six patients treated with EA + PTCA (Group 1) were retrospectively compared to a historical subset of 101 patients treated with PTCA alone (Group 2). Both groups presented with similar clinical profiles with respect to gender, age, graft age, percent diameter stenosis, and location of the target lesion. However, Group 1 had a significantly higher incidence of pre-procedure class III-IV angina than did Group 2 (92.4% vs. 70.3%, p < 0.002), and more recent occlusions. Both groups were compared at one year for the presence of angina, myocardial infarction, and death. Chi-square analysis was performed on the categorical variables. RESULTS: At one-year follow-up, 62.1% of the Group 1 patients were free from cardiac events (defined as absence of angina, myocardial infarction or death) and 58.9% of the Group 2 patients were event free (p = 0.78). A total of 27.0% of the Group 1 patients suffered from class I or Il angina compared to 35.9% of the Group 2 patients (p = 0.40). A total of 10.8% of the Group 1 patients had suffered a myocardial infarction compared to 28.2% of the Group 2 patients (p = 0.06). A total of 2.7% of the Group 1 patients had died compared to 10.5% of the Group 2 patients (p = 0.16). CONCLUSIONS: Patients with recently occluded SVGs (within 3 months) and refractory angina (class III or IV) treated with EA + PTCA have a similar clinical outcome at 1 year follow-up to a historical population treated with PTCA alone, despite the higher incidence of class III-IV angina, and more recent occlusions upon presentation. However, 1-year follow-up results reveal a trend towards less frequent myocardial infarctions for patients treated with EA + PTCA than the historical group of patients treated with PTCA alone (p = 0.06).

Journal Article↗
PubMed1997

A simple method for the determination of sex from the pulp of freshly extracted human teeth utilizing the polymerase chain reaction.

The polymerase chain reaction (PCR) has been used to amplify a region of the ZFX and ZFY genes from DNA in human blood and other tissues, for determination of the sex of an individual. In the present study DNA was extracted from the pulp of 21 male and 24 female fresh human third molar teeth. A region of the ZFX and ZFY genes was amplified by PCR and analysed by digestion of the amplified DNA with HaeIII restriction endonuclease. The digested PCR products were run on a 2 per cent agarose gel. Males were distinguished from females by having a fragment of 317 base pairs which was absent in females. Identification of the sex of the individual was 100 per cent accurate in each case. A blind study of random samples of the same teeth, used to assess the reproducibility of the technique evoked an identical result. This method provides an accurate alternative to skeletal measurements and histological staining techniques for the sexing of individuals from small amounts of DNA.

Base Sequence↗
PubMed1996

A fast flexible docking method using an incremental construction algorithm.

We present an automatic method for docking organic ligands into protein binding sites. The method can be used in the design process of specific protein ligands. It combines an appropriate model of the physico-chemical properties of the docked molecules with efficient methods for sampling the conformational space of the ligand. If the ligand is flexible, it can adopt a large variety of different conformations. Each such minimum in conformational space presents a potential candidate for the conformation of the ligand in the complexed state. Our docking method samples the conformation space of the ligand on the basis of a discrete model and uses a tree-search technique for placing the ligand incrementally into the active site. For placing the first fragment of the ligand into the protein, we use hashing techniques adapted from computer vision. The incremental construction algorithm is based on a greedy strategy combined with efficient methods for overlap detection and for the search of new interactions. We present results on 19 complexes of which the binding geometry has been crystallographically determined. All considered ligands are docked in at most three minutes on a current workstation. The experimentally observed binding mode of the ligand is reproduced with 0.5 to 1.2 A rms deviation. It is almost always found among the highest-ranking conformations computed.

Algorithms↗
PubMed1996

Prospective study of extraction atherectomy in patients with acute myocardial infarction.

Although percutaneous transluminal coronary angioplasty (PTCA) has been an effective treatment for primary reperfusion in acute myocardial infarction, patients with thrombolytic ineligibility, thrombolytic failure, cardiogenic shock, and vein graft occlusion remain at high risk for complications with PTCA treatment. The transluminal extraction catheter may be useful for treatment for such patients owing to its ability to aspirate thrombus. At 2 clinical centers, extraction atherectomy was prospectively evaluated in 100 patients (age 62 +/- 10 years). High-risk features included thrombolytic failure in 40%, postinfarct angina in 28%, presence of angiographic thrombus in 66%, presence of cardiogenic shock in 11%, and a saphenous vein graft occlusion in 29%. Procedural success, defined as a final residual stenosis <50% and Thrombolysis in Myocardial Infarction 2 or 3 grade flow, was seen in 94%. Events during the hospitalization included death in 5%, bypass surgery in 4%, and blood transfusion in 18%. In a substudy, patients enrolled at William Beaumont Hospital (n = 65) underwent elective predischarge angiography, which revealed a patent infarct-related vessel in 95%. These patients were also followed for 6 months with angiographic follow-up in 60%. Target vessel revascularization was necessary in 38%, and 6-month mortality was 10%. Although long-term vessel patency was 90%, angiographic restenosis occurred in 68%. Acute myocardial infarction patients can be treated with extraction atherectomy with a high technical success rate and a low incidence of complication. Infarct artery patency at 1 week and 6 months was excellent; however, angiographic restenosis remains a problem. Extraction of thrombus in this high-risk group of patients is associated with low in-hospital mortality and a high rate of vessel patency at 6 months.

Angina Pectoris↗