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Biomedical subjects

E Feldmann

Publications and source records attributed to E Feldmann.

At least 19 recordsLinked to original sources
PubMed2001

Accurate in vitro end joining of a DNA double strand break with partially cohesive 3'-overhangs and 3'-phosphoglycolate termini: effect of Ku on repair fidelity.

To examine determinants of fidelity in DNA end joining, a substrate containing a model of a staggered free radical-mediated double-strand break, with cohesive phosphoglycolate-terminated 3'-overhangs and a one-base gap in each strand, was constructed. In extracts of Xenopus eggs, human lymphoblastoid cells, hamster CHO-K1 cells, and a Chinese hamster ovary (CHO) derivative lacking the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), the predominant end joining product was that corresponding to accurate restoration of the original sequence. In extracts of the Ku-deficient CHO derivative xrs6, a shorter product, consistent with 3' --> 5' resection before ligation, was formed. Similar results were seen for a substrate with 5'-overhangs and recessed 3'-phosphoglycolate ends. Supplementation of the xrs6 extracts with purified Ku restored accurate end joining. In Xenopus and human extracts, but not in hamster extracts, gap filling and ligation were blocked by wortmannin, consistent with a requirement for DNA-PKcs activity. The results suggest a Ku-dependent pathway, regulated by DNA-PKcs, that can accurately restore the original DNA sequence at sites of free radical-mediated double-strand breaks, by protecting DNA termini from degradation and maintaining the alignment of short partial complementarities during gap filling and ligation.

Androstadienes↗
PubMed2000

Phenylpropanolamine and the risk of hemorrhagic stroke.

BACKGROUND: Phenylpropanolamine is commonly found in appetite suppressants and cough or cold remedies. Case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, we designed a case-control study. METHODS: Men and women 18 to 49 years of age were recruited from 43 U.S. hospitals. Eligibility criteria included the occurrence of a subarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of a previously diagnosed brain lesion. Random-digit dialing identified two matched control subjects per patient. RESULTS: There were 702 patients and 1376 control subjects. For women, the adjusted odds ratio was 16.58 (95 percent confidence interval, 1.51 to 182.21; P=0.02) for the association between the use of appetite suppressants containing phenylpropanolamine and the risk of a hemorrhagic stroke and 3.13 (95 percent confidence interval, 0.86 to 11.46; P=0.08) for the association with the first use of a product containing phenylpropanolamine. All first uses of phenylpropanolamine involved cough or cold remedies. For men and women combined, the adjusted odds ratio was 1.49 (95 percent confidence interval, 0.84 to 2.64; P=0.17) for the association between the use of a product containing phenylpropanolamine and the risk of a hemorrhagic stroke, 1.23 (95 percent confidence interval, 0.68 to 2.24; P=0.49) for the association with the use of cough or cold remedies that contained phenylpropanolamine, and 15.92 (95 percent confidence interval, 1.38 to 184.13; P=0.03) for the association with the use of appetite suppressants that contained phenylpropanolamine. An analysis in men showed no increased risk of a hemorrhagic stroke in association with the use of cough or cold remedies containing phenylpropanolamine. No men reported the use of appetite suppressants. CONCLUSIONS: The results suggest that phenylpropanolamine in appetite suppressants, and possibly in cough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.

Adolescent↗
PubMed2000

DNA double-strand break repair in cell-free extracts from Ku80-deficient cells: implications for Ku serving as an alignment factor in non-homologous DNA end joining.

Non-homologous DNA end joining (NHEJ) is considered the major pathway of double-strand break (DSB) repair in mammalian cells and depends, among other things, on the DNA end-binding Ku70/80 hetero-dimer. To investigate the function of Ku in NHEJ we have compared the ability of cell-free extracts from wild-type CHO-K1 cells, Ku80-deficient xrs6 cells and Ku80-cDNA-complemented xrs6 cells (xrs6-Ku80) to rejoin different types of DSB in vitro. While the two Ku80-proficient extracts were highly efficient and accurate in rejoining all types of DNA ends, the xrs6 extract displayed strongly decreased NHEJ efficiency and accuracy. The lack of accuracy is most evident in non-homologous terminus configurations containing 3'-overhangs that abut a 5'-overhang or blunt end. While the sequences of the 3'-overhangs are mostly preserved by fill-in DNA synthesis in the Ku80-proficient extracts, they are always completely lost in the xrs6 extract so that, instead, small deletions displaying microhomology patches at their breakpoints arise. In summary, our results are consistent with previous results from Ku-deficient yeast strains and indicate that Ku may serve as an alignment factor that not only increases NHEJ efficiency but also accuracy. Furthermore, a secondary NHEJ activity is present in the absence of Ku which is error-prone and possibly assisted by base pairing interactions.

Animals↗
PubMed2000

Transcranial Doppler ultrasonography: year 2000 update.

In this update, the main clinical applications of transcranial Doppler ultrasonography are reassessed. A specific format for technology assessment, personal experience, and an extensive review of the literature form the basis of the evaluation. The document is approved by the American Society of Neuroimaging and the Neurosonology Research Group of the World Federation of Neurology.

Brain Diseases↗
PubMed1999

Childhood obesity: addressing the issue.

Childhood obesity is a major health issue in pediatric practice. The old idea that "a chubby baby is a healthy baby" is not necessarily the case. Social stigmas and recidivism surrounding obesity make addressing families and their children difficult; however, with early intervention, treatment can be successful. Prevention of obesity with health maintenance surveillance and family-focused behavior modification is the foundation for a healthy lifestyle and may prove the most effective way of avoiding long-term obesity-related morbidity.

Adolescent↗
PubMed1998

Rejoining of DNA double-strand breaks in vitro by single-strand annealing.

Nonhomologous DNA end joining (NHEJ) is considered the major pathway of double-strand break (DSB) repair in vertebrate cells. Various studies indicated the existence of at least two different NHEJ pathways; one that joins DNA ends accurately and depends on Ku, a protein heterodimer that binds to DNA ends, and one that generates deletions and is independent of Ku. While the former pathway has been characterised in some detail, only little is known about the latter error-prone. We have partially purified such an NHEJ activity from extracts of Xenopus laevis eggs. End-joined junctions formed in the most extensively purified protein fraction displayed deletions containing short patches of sequence homology at their break points, a feature characteristic of single-strand annealing (SSA). Detailed biochemical characterisation revealed the presence of DNA ligase III, DNA polymerase epsilon, FEN-1 endonuclease, and exonuclease activities of 5'-3' and 3'-5' directionality. We show that these activities are able to correctly process proposed intermediates of SSA. Interestingly, neither Ku nor the associated DNA-dependent protein kinase were detected, indicating that the mechanism can dispense with Ku. Our findings provide evidence for the existence of an error-prone NHEJ pathway that creates deletions by microhomology-driven SSA.

Animals↗
PubMed1997

Transcranial Doppler ultrasound battery reliably identifies severe internal carotid artery stenosis.

BACKGROUND AND PURPOSE: There is a clinical imperative for noninvasive tests for carotid disease that have high sensitivity. Previous studies have shown that transcranial Doppler ultrasound (TCD) can identify intracranial collateral flow patterns and other hemodynamic consequences of carotid occlusion. We hypothesized that a battery of such TCD findings would have a greater sensitivity than any one TCD finding alone and would have clinical utility in identifying carotid disease. METHODS: We determined the prevalence of seven TCD findings in patients with various degrees of carotid stenosis as measured by a blinded observer on 138 cerebral angiograms. We further determined the sensitivity and specificity of any one finding or any single abnormality in the TCD battery (the combination of all seven findings) for identifying severe (> or = 70%) carotid stenosis by angiography. RESULTS: The following four individual TCD findings were associated (P < .001) with > or = 70% carotid stenosis on cerebral angiography: ophthalmic and anterior cerebral artery flow reversal and low middle cerebral artery flow acceleration and pulsatility. The presence of any single abnormality in the TCD battery had a similar association (P < .001) with > or = 70% carotid stenosis. The individual TCD findings had sensitivities of 3% to 83% and specificities of 60% to 100% for identifying > or = 70% carotid stenosis. The TCD battery had a sensitivity of 95% and specificity of 42% for identifying > or = 70% carotid stenosis. CONCLUSIONS: A battery of TCD findings that can be routinely measured reliably identified patients with > or = 70% angiographic internal carotid artery stenosis with high sensitivity.

Carotid Artery, Internal↗
PubMed1996

A novel nuclease activity from Xenopus laevis releases short oligomers from 5'-ends of double- and single-stranded DNA.

BACKGROUND: Double-strand breaks in chromosomal DNA of eucaryotic cells are assumed to be repaired by mechanisms of illegitimate recombination capable of direct rejoining of the broken ends. Cell-free extracts of Xenopus laevis eggs efficiently perform these end joining reactions with any pair of noncomplementary DNA termini whose single-stranded 5'- or 3'-overhangs do not exceed a length of approximately 10 nt. RESULTS: Using hairpin-shaped oligonucleotides that allow the construction of double-strand break termini with 5'- or 3'-overhangs of defined length and sequence we show that 5'-overhangs of more than 9-10 nt are exonucleolytically resected in the extract to produce shorter 5'-overhangs that can be metabolized in the end joining reaction. 5'-recessed ends in double-stranded DNA with 3'-overhangs of more than 2nt as well as the 5'-ends of single-stranded DNA also serve as substrates for the exonuclease activity. In all cases, oligomers of about 10 nt are released from the 5'-ends. CONCLUSIONS: We describe here a novel 5'-exonuclease activity present in eggs from Xenopus laevis that reproducibly removes decameric oligonucleotides from 5'-ends of double- and single-stranded DNA. A possible function of this unusual activity is discussed in the context of homologous and illegitimate genetic recombination processes.

Animals↗
PubMed1996

The evaluation of symptomatic carotid artery disease. A survey of specialty practices in Rhode Island.

Severe, symptomatic carotid artery disease is most often diagnosed by conventional cerebral angiography. Noninvasive tests are commonly used to identify candidates for angiography and endarterectomy. The purpose of this study, a mail and telephone survey of academic and community neurologists, neurosurgeons, and vascular surgeons in Rhode Island in 1994, was to determine which noninvasive tests physicians used to evaluate these patients and how the test results were used to select patients for angiography. One hundred (86%) of a possible 116 responses were collected. Seventy-six percent of physicians chose carotid duplex ultrasound as the first diagnostic test, a percentage significantly higher than that for any other test (p < 0.0001). Fourteen percent chose angiography without a prior screening test; 3% chose magnetic resonance angiography (MRA) prior to angiography, 6% chose carotid duplex ultrasound plus MRA prior to angiography, and 1% chose MRA without angiography. The specific noninvasive test results required for angiography referral were surprisingly variable, both within and across the three physician specialties. Vascular surgeons and neurosurgeons were more likely to choose angiography without prior screening tests than were neurologists. In conclusion, the majority of specialty physicians in the state of Rhode Island chose carotid ultrasound as the screening test of choice for the evaluation of a potential endarterectomy candidate. Few responding physicians chose MRA in combination with carotid duplex ultrasound prior to angiography, or MRA prior to angiography or MRA alone. Awareness of the actual practice patterns of specialists may lead to programs of education for physicians to improve practice and patient outcome through more refined use of diagnostic tests prior to angiography or endarterectomy.

Carotid Artery Diseases↗
PubMed1996

Performance of carotid ultrasound in evaluating candidates for carotid endarterectomy is optimized by an approach based on clinical outcome rather than accuracy.

BACKGROUND AND PURPOSE: The best method of selecting endarterectomy candidates for cerebral angiography is controversial. Carotid duplex ultrasound (CDUS) is widely used, but its performance varies across institutions. The clinical utility of CDUS could be improved with test criteria based on patient outcome rather than test accuracy. METHODS: In 155 carotid bifurcations studied by CDUS and cerebral angiography, the degree of angiographic stenosis was measured by a reader, blinded to CDUS, using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method. We calculated accuracy, sensitivity, and specificity for predicting > or = 70% angiographic carotid stenosis of different peak systolic frequencies (PSF) measured by CDUS and generated a receiver operator characteristic (ROC) curve. We used NASCET outcome data and published data on angiographic complications to define relative "costs" of false-positive and false-negative CDUS, and we determined the point on the ROC curve representing the CDUS criterion with the highest clinical utility. We compared projected morbidity and mortality rates for 1000 hypothetical endarterectomy candidates resulting from the use of the most accurate CDUS criterion versus the CDUS criterion with the highest clinical utility by ROC analysis. RESULTS: While PSF > or = 8 kHz had the highest CDUS accuracy (93%), its projected stroke and death rate due to CDUS error was 10.4/1000. On the other hand, PSF > or = 7 kHz, defined by ROC analysis to have the highest clinical utility, had a lower morbidity and mortality rate of 6.8/1000. CONCLUSIONS: The use of ROC analysis and available outcome data can improve the performance of CDUS in selecting endarterectomy candidates for cerebral angiography.

Algorithms↗
PubMed1996

Mechanisms of nonhomologous DNA end-joining in frogs, mice and men.

DNA end-joining, a process related to illegitimate recombination and capable of rejoining unrelated pairs of DNA ends in the absence of sequence homology, is considered the major pathway of double-strand break (DSB) repair in mammalian cells. Whole cell and nuclear extracts from three human and one mouse cell line were investigated for their capacities to promote nonhomologous DNA end-joining and their relative activities of DNA-PK, a mammalian DNA end-binding protein complex implicated in DSB-repair. The levels of DNA end-joining and the spectra of junctions of the human systems were identical with the ones of a previously described cell-free joining system derived from Xenopus laevis eggs. Due to the presence of potent 3'-5'-exonuclease activities the mouse system displayed decreased levels of DNA end-joining and larger fractions of junctions containing deletions but otherwise the basic mechanisms of junction formation appeared to be identical with the Xenopus system. DNA-PK activity was found to be equally low in the Xenopus and the mouse system but 4- to 6-fold increased in the human systems. Our results suggest that the mechanisms of DNA end-joining may be modulated by the level of exonuclease activities and/or DNA end-protecting factors but are otherwise highly conserved in vertebrate cells.

Animals↗
PubMed1996

Carotid stenosis. A neurologist's perspective.

The initial step performed by neurologists in the evaluation of patients with potential carotid disease is to establish whether patients have had carotid territory symptoms. Symptoms are most often believed to be caused by emboli passing onto the cerebral circulation. Despite some limitations, conventional angiography remains the gold standard test to evaluate the carotid bifurcation. Because of the costs and risks of angiography, some combination of carotid duplex ultrasonography and MR angiography is chosen to select patients for angiography. Future research will focus on markers other than percent stenosis to assess stroke risk and treatments, such as angioplasty and stenting, for carotid lesions.

Angioplasty↗
PubMed1995

Cerebrovascular disease with antiphospholipid antibodies: immune mechanisms, significance, and therapeutic options.

There has been a recent, dramatic surge in interest in antiphospholipid antibodies and associated clinical disorders, especially focal ischemic cerebrovascular disease. Antiphospholipid antibodies are a heterogeneous group of antibodies with varying specificities. Coagulation assays will detect lupus anticoagulants while enzyme-linked immunosorbent assays detect anticardiolipin antibodies. There are numerous potential links between antiphospholipid antibodies and coagulation disorders, including interaction of antiphospholipid antibodies and a cofactor, beta 2-glycoprotein I, which itself is involved in coagulation mechanisms. While the specific mechanism of antiphospholipid antibody-related coagulopathy is unknown, it is clear that antiphospholipid antibodies are associated with an immune-mediated prothrombotic state. Patients with the highest titers of IgG antiphospholipid antibodies have a relatively high risk of recurrent thrombotic events, especially stroke, deep venous thrombosis, and spontaneous abortion. Because of limited controlled, prospective data, current therapy remains empiric and directed at coagulation mechanisms, immune mechanisms, or both.

Adrenal Cortex Hormones↗
PubMed1995

Healing of rickets during vitamin D therapy despite defective vitamin D receptors in two siblings with vitamin D-dependent rickets type II.

We report the healing of severe rickets despite hypocalcemia in two siblings with absent vitamin D receptors; long periods of treatment with excessive doses of vitamin D led to relative hypoparathyroidism and a return to normal of calcium metabolism during calcitriol treatment. This finding suggests that some other regulating factor may substitute for the defective vitamin D receptor.

Dose-Response Relationship, Drug↗