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R Sachs

Publications and source records attributed to R Sachs.

At least 19 recordsLinked to original sources
PubMed2005

Full-color painting reveals an excess of radiation-induced dicentrics involving homologous chromosomes.

PURPOSE: To determine the ratio of homologous to heterologous dicentric chromosomes induced in human cells by ionizing radiation. This ratio is influenced by, and thus potentially informative about, underlying DNA damage/repair/misrepair processes and also the geometry of individual chromosome domains within the interphase nucleus. MATERIALS AND METHODS: 24-color mFISH (multiplex fluorescent in situ hybridization) was used to determine the ratio of 1-color (homologous) to 2-color (heterologous) dicentrics produced in human lymphocytes or fibroblasts by gamma-rays, alpha particles, or iron ions at various doses. Assuming that randomness independent of homology holds, the expected homologue:heterologue ratio for diploid human male cells is approximately 0.024, as shown by deriving a formula applicable to simple interchanges and then extending the result, via Monte Carlo simulation, to the general situation where complex aberrations are also considered. RESULTS AND CONCLUSIONS: There was a substantial excess of homologous dicentrics, with probability of occurrence by chance less than 0.02 for each of the three radiations and only about 10(-8) for all the data combined. Overall, approximately 18 homologous dicentrics were expected but 47 were found, including 11 involving chromosome 1. Observed excesses were similar for both sparsely and densely ionizing radiations. Geometric proximity of homologues is a possible explanation for the overabundance; in that case more extensive statistics should eventually uncover a linear energy transfer (LET) dependence. An alternative possibility, not ruled out by the present data, is homology-dependent misrepair.

Cell Culture Techniques↗
PubMed2004

Analysis of alpha-particle induced chromosome aberrations in human lymphocytes, using pan-centromeric and pan-telomeric probes.

PURPOSE: The aim of the present study has been the evaluation of the incomplete chromosome aberrations induced after alpha-particle irradiation by the simultaneous detection of all centromeres and telomeres present in human lymphocytes. Moreover, a study on the lengths of the different acentric fragments is presented. MATERIALS AND METHODS: Attached lymphocytes were irradiated at doses of 0.2, 0.5, 0.7 and 1 Gy using a 241Am source. Flourescent in-situ hybridization (FISH) techniques were applied using pan-centromeric and pan-telomeric probes. All abnormal cells were digitalised and analysed using a Cytovision FISH workstation. The description of all abnormalities observed, and the length of the acentric fragments was recorded. RESULTS: A total of 378 incomplete chromosomes plus incomplete acentrics was found. Cases with more than 92 telomeres were not detected. The ratio between total incomplete elements and multicentrics was 1.00. The total number of acentric (ace) fragments was 822; 57% of them were complete fragments ace (+,+), 26% incomplete fragments ace (+,-), and 17% interstitial fragments ace(-,-); the mean relative lengths were 2.91 +/- 0.06, 1.91 +/- 0.07 and 1.63 +/- 0.07, respectively. In all three cases a secondary peak in the length distribution was found, corresponding to a relative length between 3.5 and 4. CONCLUSION: The percentage of incomplete rejoinings is higher after alpha-particle exposure than that described previously for low-linear energy transfer (LET) radiation exposures. The results seem to indicate that compared to low-LET radiation, after alpha-particle exposure centromere-containing elements are more likely to be repaired.Many interstitial fragments are large linear forms that cannot be considered as non-distinguishable acentric rings.

Alpha Particles↗
PubMed2004

Chromosome spatial clustering inferred from radiogenic aberrations.

PURPOSE: Analysing chromosome aberrations induced by low linear energy transfer (LET) radiation in order to characterize systematic spatial clustering among the 22 human autosomes in human lymphocytes and to compare their relative participation in interchanges. MATERIALS AND METHODS: A multicolour fluorescence in situ hybridization (mFISH) data set, specifying colour junctions in metaphases of human peripheral blood lymphocytes 72 h after in vitro exposure to low LET radiation, was analysed separately and in combination with previously published results. Monte Carlo computer simulations and mathematical modelling guided data analysis. RESULTS AND CONCLUSIONS: Statistical tests on aberration data confirmed two clusters of chromosomes, [1, 16, 17, 19, 22] and [13, 14, 15, 21, 22], as having their members being on average closer to each other than randomness would predict. The first set has been reported previously to be near the centre of the interphase nucleus and to be formed mainly by gene-rich chromosomes, while the second set comprises the nucleolus chromosomes. The results suggest a possible interplay between chromosome positioning and transcription. A number of other clusters suggested in the literature were not confirmed and considerable randomness of chromosome-chromosome juxtapositions was present. In addition, and consistent with previous results, it was found that chromosome participation in interchanges is approximately proportional to the two-thirds power of the DNA content.

Chromosome Aberrations↗
PubMed2002

Integrated care pathways: outcome from inpatient rehabilitation following nontraumatic spinal cord lesion.

BACKGROUND: Integrated care pathways (ICPs) map the predicted course of an episode of patient care. They detail the expected interventions during the episode and document departures from the expected pathway (variance). This study describes the use of an ICP to audit the rehabilitation of patients with nontraumatic spinal cord injury admitted between 1997 and 1999. METHODS: The ICPs and outcomes of 85 patients with nontraumatic spinal cord injury admitted to the Neurorehabilitation Unit at the National Hospital for Neurology and Neurosurgery, Queen Square, London were analysed. Data extracted included diagnosis, level of the lesion and duration of stay. The numbers and categories of goals and the rates of goal achievement were extracted and the variance patterns analysed. RESULTS: An average of 28 patients were admitted each year. The level of disability on admission and the duration of stay decreased over the three-year period, while the average patient age increased from 48 to 54 years. None of these changes were statistically significant. On average each patient had three new goals set each week. Ninety per cent of all goals were achieved; this was not dependent on the category of goal. Sixteen patients (19%) accounted for 58% of all nonachieved goals. These patients tended to have acute-onset disability. The number of variances fell from 15 to 7 over the three-year period. CONCLUSIONS: The pathway enables monitoring of the rehabilitation process. As the Unit becomes more experienced there is a trend to shorter, more focused admissions with fewer variances. Specific groups of patients with particular needs can be identified. Future patients benefit from closure of the 'audit loop' and the implementation of clinical change based on information obtained from the ICP.

Analysis of Variance↗
PubMed2001

Testicular metastasis from ileal carcinoid: report of a case.

PURPOSE: This report presents a patient with testicular metastasis from an ileal carcinoid. METHODS: This was a retrospective case review with literature review. RESULTS: The patient underwent right orchiectomy for a solid mass. Pathology revealed carcinoid tumor. Octreotide scan showed increased concentration in the right lower quadrant of the abdomen. Computerized tomography results were negative. Colonoscopy with biopsy revealed carcinoid of the terminal ileum. The patient underwent an elective resection of the terminal ileum and the right colon. Pathology revealed carcinoid tumor with vascular and lymphatic invasion present, and eight lymph nodes were positive. The patient had adjuvant treatment with octreotide. CONCLUSION: Carcinoid tumors have been reported to metastasize to numerous areas. This is the first report of testicular metastasis from ileal carcinoid. Primary carcinoids of the testicle have been reported also. The clinician should be aware of this rare metastatic event. When pathology reveals carcinoid of the testicle, metastatic disease should be excluded before the tumor is identified as primary.

Antineoplastic Agents, Hormonal↗
PubMed2001

Large-mutation spectra induced at hemizygous loci by low-LET radiation: evidence for intrachromosomal proximity effects.

A mathematical model is used to analyze mutant spectra for large mutations induced by low-LET radiation. The model equations are based mainly on two-break misrejoining that leads to deletions or translocations. It is assumed, as a working hypothesis, that the initial damage induced by low-LET radiation is located randomly in the genome. Specifically, we analyzed data for two hemizygous loci: CD59- mutants, mainly very large-scale deletions (>3 Mbp), in human-hamster hybrid cells, and data from the literature on those HPRT- mutants which involve at least deletion of the whole gene, and often of additional flanking markers (approximately 50-kbp to approximately 4.4-Mbp deletions). For five data sets, we estimated f, the probability that two given breaks on the same chromosome will misrejoin to make a deletion, as a function of the separation between the breaks. We found that f is larger for nearby breaks than for breaks that are more widely separated; i.e., there is a "proximity effect". For acute irradiation, the values of f determined from the data are consistent with the corresponding break misrejoining parameters found previously in quantitative modeling of chromosome aberrations. The value of f was somewhat smaller for protracted irradiation than for acute irradiation at a given total dose; i.e., the mutation data show a decrease that was smaller than expected for dose protraction by fractionation or low dose rate.

Animals↗
PubMed2001

Impairment of coronary microvascular dilation in response to cold pressor--induced sympathetic stimulation in type 2 diabetic patients with abnormal stress thallium imaging.

Coronary microcirculation dysfunction may be associated with myocardial perfusion defects on thallium imaging in diabetic patients without coronary artery stenosis. Microvascular coronary adaptation to increased myocardial oxygen demand in response to sympathetic stimulation evoked by the cold pressor test was examined in 22 type 2 diabetic patients with thallium imaging defects and in 15 control subjects. Both the diabetic patients and control subjects had angiographically normal coronary arteries and no other risk factors. Despite a similar increase in the rate-pressure product in the two groups (22.6 +/- 12.4% in diabetic patients and 31.8 +/- 8.2% in control subjects, NS), coronary blood flow increase in the left anterior descending artery (mean flow velocity measured by intracoronary Doppler multiplied by the cross-sectional area measured by digital angiography) was significantly lower in diabetic patients than in control subjects (14.7 +/- 19.8 vs. 75.5 +/- 13.5%, respectively; P = 0.0001). In addition, when there was a positive correlation between the two parameters in control subjects (r = 0.651, P < 0.01), there was no relationship in diabetic patients (r = 0.054). In conclusion, vasodilation of the coronary microcirculation in response to sympathetic stimulation evoked by the cold pressor test is impaired in type 2 diabetic patients without epicardial artery lesions. This microvascular impairment during sympathetic stimulation may explain exercise-induced myocardial perfusion abnormalities observed in these patients and may impair microcirculatory coronary vasodilation during current life stress episodes such as exercise, mental stress, or cold exposition.

Blood Flow Velocity↗
PubMed2001

[Inhibition of iron-catalyzed oxidative reactions restores mathcing between coronary blood flow and myocardial metabolic demand in type 2 diabetes].

In diabetes, endothelium-dependent dilation of large and small coronary arteries is impaired, which results in a mismatch between myocardial metabolic demand and coronary blood flow. It has been proved that deferoxamine, an iron chelator that inhibits Fenton and Haber-Weiss reactions, restores a normal response to cold pressor test and flow increase in angiographically normal epicardial coronary arteries of diabetic patients. This result suggests that nitric oxide could be inactivated by reactive oxygen species. The aim of this study was to assess the effects of deferoxamine on coronary microcirculation vasomotion when myocardial oxygen demand is increased by sympathetic stimulation elicited by cold pressor test in type 2 diabetic patients. In 17 patients with angiographically normal coronary arteries and without any other coronary risk factors, coronary blood flow has been measured using quantitative angiography and intracoronary Doppler at baseline and during a cold pressor test, before and after intravenous administration of 500 mg deferoxamine. Increase in rate-pressure product, an estimate of myocardial metabolic demand, was similar before and after deferoxamine (+21.1 +/- 8.7% vs +20.5 +/- 8.9%, respectively), but coronary blood flow increase was significantly higher after deferoxamine (+6.3 +/- 12.9% vs +31.8 +/- 16.7%, respectively, p < 0.001), and coronary resistance was increased before deferoxamine and decreased after (+14.8 +/- 21.9% vs -7.9 +/- 10.9%, respectively, p < 0.001). Moreover, before deferoxamine, the negative correlation between coronary blood flow and rate-pressure product changes before deferoxamine (R = 0.518, P < 0.05) was turned in a positive relationship after deferoxamine (r = 0.546, p < 0.05). In conclusion, in type 2 diabetic patients, endothelium-dependent dilation of the coronary microcirculation is restored when iron-catalysed oxidative reactions are inhibited by deferoxamine, which restores the normal matching between myocardial oxygen demand and coronary blood flow.

Adult↗
PubMed2000

[Dysfunction of the coronary microcirculation in type 2 diabetic patients].

A failure of coronary blood flow to increase during cold pressor test has been shown in patients with coronary atherosclerosis and impaired metabolic coronary vasodilatation in response to atrial pacing has been demonstrated in diabetic patients without significant epicardial artery stenoses. This study was designed to evaluate coronary microvascular adaptation to increased myocardial oxygen demand in response to sympathetic stimulation in diabetic patients with angiographically normal coronary arteries. Microvascular coronary adaptation to increased myocardial oxygen demand due to sympathetic stimulation evoked by the cold pressor test has been examined in 22 type 2 diabetic patients and in 15 control subjects with angiographically normal coronary arteries and no other risk factors. Coronary blood flow was calculated by measuring mean flow velocity in left anterior descending coronary artery by intracoronary Doppler and cross sectional area of the artery by digital angiography. Results show that despite a similar increase in rate-pressure product in the 2 groups (+22.6 +/- 12.4% in diabetic patients and +31.8 +/- 8.2% in control subjects, NS), coronary blood flow increase in left anterior descending artery was significantly lower in diabetic patients than in control subjects (+14.7 +/- 19.8% vs +75.5 +/- 13.5%, respectively, p = 0.0001). In addition, when there was a positive correlation between the 2 parameters in control subjects (R = 0.651, p < 0.01), there was no relationship in diabetic patients (R = 0.054). In conclusion, this study demonstrates that vasodilatation of coronary microcirculation in response to sympathetic stimulation evoked by cold pressor test is impaired in type 2 diabetic patients without epicardial artery lesions. This microvascular impairment during sympathetic stimulation may explain exercise-induced myocardial perfusion abnormalities observed in these patients and may impair microcirculatory coronary vasodilatation during current life stress episodes such as exercise, mental stress or cold exposure.

Adaptation, Physiological↗
PubMed1999

Vascular surgical society of great britain and ireland: integrated care pathways for vascular surgery

BACKGROUND: Integrated care pathways (ICPs) represent a multidisciplinary approach to clinical patient care. METHODS: A 1-year prospective trial of the use of ICPs for elective vascular surgical procedures was undertaken. A multidisciplinary group constructed ICPs for patients admitted for open repair of abdominal aortic aneurysm, carotid endarterectomy or femoropopliteal bypass grafting. Patient management followed ICPs on a daily basis with signatures required to confirm that each action had been taken. Variances from the ICPs were carefully recorded. Audit of variance data allowed subsequent revision of the ICPs and hence provision of the best possible nursing and clinical practice. METHODS: A total of 33 patients were entered into the study; 16 had a femoropopliteal bypass graft, eight carotid endarterectomy and nine open repair of an abdominal aortic aneurysm. ICPs were well received by patients and staff. They improved communication, promoted an appreciation of each health group's role in patient care, increased nursing autonomy, reduced calls to junior medical staff, improved patient education and confidence, and caused a marked reduction in length of hospital stay. Overall, patients were discharged 13 per cent earlier after open abdominal aortic aneurysm repair, 22 per cent earlier after carotid endarterectomy and 38 per cent earlier after femoropopliteal bypass grafting. CONCLUSION: ICPs have clear benefits. They improve overall clinical efficiency and enhance clinical governance. Successful use of ICPs depends upon 'clinical champions' and effective project management. Sufficient resources and training are essential.

Journal Article↗
PubMed1999

Integrated care pathways for vascular surgery.

OBJECTIVES: a trial of the use of integrated care pathways (ICPs) for elective vascular surgical procedures. DESIGN: a 12-month prospective study, following a multi-disciplinary group construction of current "best practice" ICPs, with changes in practice only occurring following careful audit of results. MATERIALS: patients admitted to a single vascular unit for "open" repair of abdominal aortic aneurysm, carotid endarterectomy or femoropopliteal bypass grafting. METHODS: patients followed ICPs on a daily basis with signatures required to confirm that action had been taken and careful recording of variances from the ICPs. Audit of variance data allowed changes in the ICPs and, hence, provision of the best possible nursing and clinical practice. RESULTS: ICPs were well received by patients and staff. They improved communication, promoted an appreciation of each health group's role in patient care, increased nursing autonomy, reduced calls to junior medical staff, improved patient education and confidence and caused a marked reduction in hospital "length of stay". CONCLUSIONS: ICPs have clear benefits. This study realises that benefits might be maximal for high throughput, high-cost procedures. Successful use of ICPs depends upon "clinical champions" and effective project management. Sufficient resource and training are essential.

Aortic Aneurysm, Abdominal↗
PubMed1998

Coronary artery responses to physiological stimuli are improved by deferoxamine but not by L-arginine in non-insulin-dependent diabetic patients with angiographically normal coronary arteries and no other risk factors.

BACKGROUND: Acetylcholine produces coronary artery (CA) constriction in diabetic patients, suggesting an impairment of endothelium-dependent dilation. In diabetes, multiple metabolic abnormalities may inactivate nitric oxide through oxygen free radical production. METHODS AND RESULTS: To examine the mechanism of this abnormal response, two physiological tests (ie, a cold pressor test [CPT] and coronary flow increase induced by an injection of 10 mg papaverine [PAP] in the distal left anterior descending CA) were performed before and after either intravenous L-arginine (625 mg/min x 10 minutes) or intravenous deferoxamine (50 mg/min x 10 minutes) in 22 normotensive nonsmoking diabetic patients with angiographically normal CAs and normal cholesterol. Coronary surface areas were measured with quantitative angiography. Before the administration of L-arginine or deferoxamine, CPT induced CA constriction in both groups (-14 +/- 10% and -15 +/- 11%, respectively; each P<.001), and PAP injection in distal LAD did not modify significantly proximal LAD dimensions. In the 10 diabetic patients receiving L-arginine, responses to CPT and PAP were not modified. Conversely, in the 12 patients receiving deferoxamine, CA dilated in response to the two tests (+10 +/- 9% after CPT and +22 +/- 7% after PAP, each P<.001). Intracoronary isosorbide dinitrate, an endothelium-independent dilator, produced similar dilation in the two groups (+47 +/- 19% and +41 +/- 15%, respectively; each P<.001). CONCLUSIONS: This study shows that (1) responses of angiographically normal CAs to CPT and to flow increase are impaired in diabetic patients; (2) abnormal responses are not improved by L-arginine, suggesting that a deficit in substrate for nitric oxide synthesis is not involved; and (3) deferoxamine restores a vasodilator response to the two tests, suggesting that inactivation of NO by oxygen species might be partly responsible for the impairment of CA dilation in diabetic patients.

Adult↗
PubMed1994

Singular perturbation theory applied to Markov models for DNA damage caused by ionizing radiation.

The induction of DNA double strand breaks by ionizing radiation, and enzymatic double strand break repair or misrepair, are modeled as continuous time Markov chains. Systems of partial differential equations for appropriate probability generating functions are solved by singular perturbation theory with scaling. The zero-th order singular perturbation result coincides with a model recently suggested in a biological literature. Higher order terms correct for various effects including "overkill". The results are applicable to both sparsely ionizing and densely ionizing radiation.

Animals↗
PubMed1993

Corneal complications associated with the use of crack cocaine.

BACKGROUND: A case series of patients with corneal complications associated with crack cocaine use is presented. Patients had infectious keratitis or sterile epithelial defects. METHODS: Entry criteria into this series included the presence of an infectious corneal ulcer or sterile epithelial defect after the patient used crack cocaine routinely. Patients were prospectively identified from July 1, 1989 to June 30, 1991. RESULTS: Fourteen patients with crack-related corneal problems were identified. In 10 patients with infectious corneal ulcers, both bacterial and fungal organisms were isolated, and patients were treated with appropriate antimicrobial therapy. The group of patients with sterile corneal epithelial defects were seen after they had rubbed their eyes vigorously after crack cocaine use. The epithelial defects were treated and healed without complication. CONCLUSION: Crack cocaine users appear to represent a unique subset of young patients predisposed to infectious keratitis and corneal epithelial defects. A number of hypotheses are offered to explain this effect. Both ophthalmologists and the general public should be aware of these severe corneal problems associated with the use of crack cocaine.

Adult↗
PubMed1993

Studies of metaphase and interphase chromosomes using fluorescence in situ hybridization.

Our measurements have bearing on the resolution with which maps can be constructed and abnormalities can be detected by studying the proximity of DNA sequences in metaphase and interphase chromosomes. The results of our analyses are summarized in Figure 8. Metaphase chromosomes are compacted sufficiently that it is impractical to order sequences separated by less than approximately 1 Mbp. In contrast, 100-kbp resolution can be obtained in interphase chromosomes. Distance measurements reveal that interphase chromatin behaves as a random polymer over distances up to 1-2 Mbp. At greater distances, higher order constraints, perhaps the dimensions of the individual chromosome domains, come into play. A caveat remains: Because the effect of the FISH procedure on native chromosome organization is not well understood, these conclusions may not be applicable to native chromatin. We have illustrated that FISH, with appropriately chosen probes, can supplement conventional cytogenetics in the study of chromosome abnormalities. The technique is increasingly being applied in research laboratories to detect and characterize chromosome abnormalities and point the way to the location of genes involved in human disease.

Chromosome Aberrations↗
PubMed1993

Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function.

Evidence is increasing for small-vessel disease and disturbance of endothelium-dependent vasodilation in diabetic patients. The aim of this study was to compare coronary circulation in 11 diabetic patients (6 type I and 5 type II) and 7 control subjects. All patients had normal left ventricular systolic function and angiographically normal coronary arteries. To evaluate the maximal area of coronary microcirculation, coronary vascular reserve was determined by intracoronary Doppler and a maximally vasodilating dose of intracoronary papaverine (peak-to-resting coronary flow velocity ratio). To assess coronary endothelial function responses to stepwise intracoronary infusion of acetylcholine (10(-8) to 10(-5) M coronary estimated concentrations) were analyzed on four different segments in each patient by quantitative angiography. Peak-to-resting coronary flow velocity ratio was lower in diabetic patients than in control subjects (3.9 +/- 0.9 and 5.0 +/- 0.7, respectively, P < 0.02). Acetylcholine did not produce any diameter change at 10(-8) and 10(-7) M, but a progressive diameter reduction was observed at 10(-6) and 10(-5) M (-8.0 +/- 15.2%, P < 0.02 and -24.0 +/- 13.6%, P < 0.001, respectively). In control subjects, a progressive diameter dilation was produced from 10(-8) to 10(-6) M acetylcholine (5.1 +/- 3.4, 12.1 +/- 7.0, and 16.4 +/- 7.3%, respectively, all P < 0.001), and a moderate reduction was observed at 10(-5) M (-4.9 +/- 7.5%, P < 0.02). In the two groups, all segments dilated similarly after intracoronary isosorbide dinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Estimating genomic distance from DNA sequence location in cell nuclei by a random walk model.

The folding of chromatin in interphase cell nuclei was studied by fluorescent in situ sequences chromatin according to a random walk model. This model provides the basis for calculating the spacing of sequences along the linear DNA molecule from interphase distance measurements. An interphase mapping strategy based on this model was tested with 13 probes from a 4-megabase pair (Mbp) region of chromosome 4 containing the Huntington disease locus. The results confirmed the locations of the probes and showed that the remaining gap in the published maps of this region is negligible in size. Interphase distance measurements should facilitate construction of chromosome maps with an average marker density of one per 100 kbp, approximately ten times greater than that achieved by hybridization to metaphase chromosome. achieved by hybridization to metaphase chromosomes.

Cell Nucleus↗