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Biomedical subjects

J E Lowe

Publications and source records attributed to J E Lowe.

At least 19 recordsLinked to original sources
PubMed2003

Effects of selenium compounds on induction of DNA damage by broadband ultraviolet radiation in human keratinocytes.

Background Ultraviolet radiation (UVR), a ubiquitous environmental genotoxin for the skin, produces DNA damage. The trace element selenium induces synthesis of the glutathione peroxidase and thioredoxin reductase enzyme families. These selenoenzymes detoxify a range of toxic compounds generated by free radicals. Objectives To assess the effects of pretreatment of primary human keratinocytes with selenium on UVR-induced DNA damage. Methods Cells were irradiated with UVR from FS-20 lamps and were subjected to comet assay. Results Comet tail length due to UVR-induced T4 endonuclease V-sensitive sites (caused by cyclopyrimidine dimers, CPDs) increased to 35 +/- 4.5 microm (mean +/- SD) immediately after irradiation (time 0 h, 100%). After 4 h, 68% of the damage remained and after 24 h, 23% of the damage was still present. Treatment with up to 200 nmol L-1 selenomethionine or 50 nmol L-1 sodium selenite had no effect on CPD formation or rates of repair, or on the number of excision repair sites as measured by cytosine arabino furanoside and hydroxyurea treatment. However, selenite and selenomethionine protected against oxidative damage to DNA as measured by formation of formamidopyrimidine (FaPy) glycosylase-sensitive sites, which are indicative of 8-hydroxy-2-deoxyguanosine photoproduct formation. In this assay, irradiation of keratinocytes increased mean +/- SD glycosylase-specific comet tail length from 5 +/- 1.5 microm to 19 +/- 3.3 microm. Preincubation for 18 h with 50 nmol L-1 selenite abolished the UVR-induced increase in comet length. Preincubation with 200 nmol L-1 selenomethionine was similarly protective. Conclusions Selenite and selenomethionine protect keratinocytes from UVR-induced oxidative damage, but not from formation of UVR-induced excision repair sites.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Sustained angina relief 5 years after transmyocardial laser revascularization with a CO(2) laser.

BACKGROUND: Although transmyocardial laser revascularization (TMR) has provided symptomatic relief of angina over the short term, the long-term efficacy of the procedure is unknown. Angina symptoms as assessed independently by angina class and the Seattle Angina Questionnaire (SAQ) were prospectively collected up to 7 years after TMR. METHODS: Seventy-eight patients with severe angina not amenable to conventional revascularization were treated with a CO(2) laser. Their mean age was 61+/-10 years at the time of treatment. Preoperatively, 66% had unstable angina, 73% had had >/=1 myocardial infarction, 93% had undergone >/=1 CABG, 42% had >/=1 PTCA, 76% were in angina class IV, and 24% were in angina class III. Their average pre-TMR angina class was 3.7+/-0.4. RESULTS: After an average of 5 years (and up to 7 years) of follow-up, the average angina class was significantly improved to 1.6+/-1 (P=0.0001). This was unchanged from the 1.5+/-1 average angina class at 1 year postoperatively (P=NS). There was a marked redistribution according to angina class, with 81% of the patients in class II or better, and 17% of the patients had no angina 5 years after TMR. A decrease of >/=2 angina classes was considered significant, and by this criterion, 68% of the patients had successful long-term angina relief. The angina class results were further confirmed with the SAQ; 5-year SAQ scores revealed an average improvement of 170% over the baseline results. CONCLUSIONS: The long-term efficacy of TMR persists for >/=5 years. TMR with CO(2) laser as sole therapy for severe disabling angina provides significant long-term angina relief.

Adult↗
PubMed2001

Oxidative DNA damage induced by high glucose and its suppression in human umbilical vein endothelial cells.

In order to investigate the mechanism of the production of oxidative DNA damage by hyperglycemia, we measured formamidopyrimidine N-glycosylase (FPG)-sensitive sites by the comet assay in human umbilical vein endothelial cells (HUVECs) cultured under various conditions including high glucose. Mean values of FPG-sensitive sites were higher in HUVECs cultured for 5 days in high glucose (45 mM) compared with normal glucose (5mM) medium (P<0.001). FPG-sensitive sites increased in a time-dependent manner under high glucose treatment (3 days: P<0.05, 5 days: P<0.001), whereas L-glucose, which is taken up poorly into the cells, gave a slight increase in FPG-sensitive sites (P<0.05). Flow cytometric analysis using 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, di(acetoxymethyl ester) showed that incubation with L-glucose produced more reactive oxygen species than incubation with D-glucose. However, these increases were slight (1.22- and 1.12-folds, respectively). Incubation of HUVECs with aminoguanidine (100 microM) or pyridoxamine (1mM), which are inhibitors of glycation, decreased the levels of FPG-sensitive sites (P<0.001). However, these inhibitors did not suppress the intracellular generation of reactive oxygen species induced by high glucose. These results indicate that FPG-sensitive sites induced by high glucose are not due to intracellular reactive oxygen species. In order to clarify what caused the induction of FPG-sensitive sites, we investigated the effect of glyoxal and 3-deoxyglucosone (3-DG) on the induction of FPG-sensitive sites and the intracellular production of reactive oxygen species in HUVECs. Glyoxal and 3-DG at a concentration of 100 microg/ml induced FPG-sensitive sites (P<0.001, P<0.01, respectively). In contrast, glyoxal did not generate reactive oxygen species inside HUVECs. The results shown in this study suggest that glyoxal formed intracellularly or extracellularly during high glucose treatment might induce FPG-sensitive sites by a mechanism not involving reactive oxygen species.

Binding Sites↗
PubMed2001

Is chronically dysfunctional yet viable myocardium distal to a severe coronary stenosis hypoperfused?

BACKGROUND: Controversy exists regarding the perfusion status of chronically dysfunctional yet viable myocardium. Studies investigating the pathophysiology of this condition have reached different conclusions, with some suggesting that myocardial blood flow (MBF) in these regions is normal at rest with regional dysfunction resulting from repetitive stress-induced ischemia (stunned myocardium), whereas others have proposed that MBF is chronically reduced at rest (hibernating myocardium). However, adequately powered experimental studies investigating this question in an appropriate animal model using clinically available techniques have not been performed. Based on the mixed results of prior studies, we hypothesized that these chronically dysfunctional yet viable regions may actually represent a mixture of hibernation and stunning. Consequently, the purpose of this study was to quantitatively determine the distribution of MBF in left ventricular regions with chronically impaired resting function but preserved viability in a large population of animals with single-vessel coronary stenosis in an attempt to further elucidate the mechanism(s) responsible for chronic, reversible myocardial dysfunction. METHODS: Fifty-two adult mini-swine with 90% proximal left circumflex (LCx) stenosis underwent dynamic positron emission tomography (PET) with 13N-ammonia and 18F-fluorodeoxyglucose and dobutamine stress echocardiography (DSE) (5 to 40 microg/kg/min) 1 month after stenosis creation. Values of MBF and FDG uptake by PET and wall motion score index (WMSI) by DSE were compared using a standard 16-segment model. RESULTS: Of 312 possible LCx segments seen on PET, 303 (97.1%) were visualized by DSE. Of the 303 LCx segments, 279 (92.1%) had rest dysfunction (WMSI > or = 2) by DSE. One hundred eighty-two segments (60.1%) had decreased (< 85% reference) MBF at rest with preserved to increased (> 60% reference) FDG uptake and were classified as hibernating. Ninety-two segments (30.4%) had preserved MBF (> or = 85% reference) and were classified as stunned. Five segments (1.7%) with reduced (< or = 60% reference) FDG uptake by PET and akinesis or dyskinesis at rest (WMSI > or = 3) and no contractile reserve were considered infarcted. Hibernating segments had significantly higher FDG uptake at rest (360.7+/-48.3 vs 212.3+/-17.7% septal values; p < 0.001) than stunned segments consistent with greater resting ischemia. Likewise, mean rest WMSI was also worse in hibernating versus stunned segments (2.35+/-0.04 vs 2.13+/-0.04; p < 0.001). There was no difference in the percentage of hibernating versus stunned segments exhibiting contractile reserve during dobutamine infusion (55.5 vs 63.7%; p = 0.4), indicating similar degrees of viability. CONCLUSIONS: Myocardial hibernation and stunning appear to frequently coexist in regions served by a stenotic coronary vessel. Hibernating regions appear to have greater resting ischemia based on higher values of FDG uptake and greater resting dysfunction. Reversible left ventricular dysfunction in the setting of chronic coronary artery disease is likely due to a combination of these two mechanisms.

Animals↗
PubMed2001

Contrasting effects of an ultraviolet B and an ultraviolet A tanning lamp on interleukin-6, tumour necrosis factor-alpha and intercellular adhesion molecule-1 expression.

BACKGROUND: Recent studies have demonstrated that a tanning lamp emitting predominantly ultraviolet (UV) A induces significant yields of the type of potentially mutagenic DNA damage that are associated with the onset of skin cancer (i.e. cyclobutane pyrimidine dimers). UV-induced immunosuppression is also an important event leading to skin cancer. OBJECTIVES: To the modulation of key immunological molecules following exposure to a broad-spectrum UVB lamp and a predominantly UVA-emitting tanning lamp using model in vitro systems. METHODS: We compared secretion and mRNA expression of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha in normal human epidermal keratinocytes, and interferon (IFN)-gamma-induced intracellular adhesion molecule (ICAM)-1 in normal human fibroblasts irradiated in vitro with a broad-spectrum UVB lamp or with a Philips 'Performance' tanning lamp. RESULTS: With broad-spectrum UVB irradiation, upregulation of IL-6 and TNF-alpha mRNA was detected 6 h after irradiation, and a dose-dependent increase of cytokines in the supernatants of irradiated cells was found 24 h after irradiation. In contrast, there was no cytokine secretion and little evidence for mRNA upregulation following exposure to a tanning lamp. When cells were exposed first to broad-spectrum UVB, then the tanning lamp, UVB-induced cytokine secretion was inhibited, although mRNA levels were upregulated to a level close to that observed with UVB alone. By using a Schott WG 320 nm filter to attenuate the level of UVB relative to UVA emitted by the tanning lamp, the inhibition of cytokine secretion was shown to be associated with UVA exposure. Both UV sources inhibited IFN-gamma-induced ICAM-1 mRNA expression in a dose-dependent fashion. By using a Schott WG 335 nm filter, inhibition of ICAM-1 mRNA expression by the tanning lamp was shown to be associated with UVB exposure. CONCLUSIONS: These results suggest that UV sources emitting different levels of UVA and UVB have differential effects on the modulation of different immunoregulatory molecules, and indicate that there are potential interactions between these wavelengths.

Beauty Culture↗
PubMed2001

Comparison of survival after mitral valve replacement with biologic and mechanical valves in 1139 patients.

OBJECTIVE: We sought to compare 10-year survival in patients after mitral valve replacement with biologic or mechanical valve prostheses. METHODS: Retrospective survival analysis was performed on data from 1139 consecutive patients older than 18 years of age undergoing mitral valve replacement with Carpentier-Edwards (n = 495; Baxter Healthcare Corp, Irvine, Calif) or St Jude Medical (n = 644; St Jude Medical, Inc, St Paul, Minn) prostheses. RESULTS: The 10-year survival was not statistically different between the patients receiving Carpentier-Edwards valves and those receiving St Jude Medical valves (P =.16). Adjusted survival estimates at 2, 5, and 10 years were 82% +/- 2% (95% confidence intervals, 79%-85%), 69% +/- 2% (95% confidence intervals, 64%-73%), and 42% +/- 3% (95% confidence intervals, 37%-48%), respectively, for the Carpentier-Edwards group and 83% +/- 2% (95% confidence intervals, 80%-86%), 72% +/- 2% (95% confidence intervals, 69%-76%), and 51% +/- 3% (95% confidence intervals, 45%-58%), respectively, for the St Jude Medical group. Predictors of worse survival after mitral valve replacement are older age, lower ejection fraction, presence of class IV congestive heart failure, coronary artery disease, renal disease, smoking history, hypertension, concurrent other valve surgery, and redo heart surgery. CONCLUSION: Choice of biologic or mechanical prosthesis does not significantly affect long-term patient survival after mitral valve replacement.

Age Factors↗
PubMed2000

Early postoperative changes in regional systolic and diastolic left ventricular function after transmyocardial laser revascularization: a comparison of holmium:YAG and CO2 lasers.

OBJECTIVES: The purpose of this study was to determine the short-term effects of transmyocardial laser revascularization (TMR) on regional left ventricular systolic and diastolic function, myocardial blood flow (MBF) and myocardial water content (MWC). BACKGROUND: Clinical studies of TMR have noted a significant incidence of cardiac complications in the early postoperative period. However, the early post-treatment effects of laser therapy on the myocardium and their potential contribution to postoperative cardiac morbidity are unknown. METHODS: Swine underwent holmium:yttrium-aluminum-garnet (holmium:YAG) (n = 12) or carbon dioxide (CO2) (n = 12) laser TMR. Regional systolic function for the lased and nonlased regions was quantitated using preload recruitable work area (PRWA) and regional diastolic function with the ventricular stiffness constant alpha. RESULTS: Preload recruitable work area was significantly decreased in the lased regions both 1 (59.8+/-13.0% of baseline, p = 0.02) and 6 h (64.2+/-9.4% of baseline, p = 0.02) after holmium:YAG TMR. This decreased PRWA was associated with a significant reduction in MBF to the lased regions (13.2% reduction at 1 h, p = 0.02; 18.4% decrease at 6 h post-TMR, p = 0.01). These changes were not seen after CO2 laser TMR. A significant increase in MWC (1.4+/-0.3% increase with holmium:YAG, p = 0.004; 1+/-0.2% increase with CO2, p = 0.002) and alpha (217.4+/-44.2% of baseline 6 h post-holmium:YAG TMR, p = 0.05; 206+/-36.7% of baseline 6 h post-CO2 TMR, p = 0.03) was seen after TMR with both lasers. CONCLUSIONS: In the early postoperative setting, impaired regional systolic function in association with regional ischemia is seen after TMR with a holmium:YAG laser. Both holmium:YAG and CO2 lasers are associated with increased MWC and impaired diastolic relaxation in the lased regions. These changes may explain the significant incidence of early postoperative cardiac morbidity. The impact of these findings on anginal relief and long-term outcome are not known.

Animals↗
PubMed2000

UV damage causes uncontrolled DNA breakage in cells from patients with combined features of XP-D and Cockayne syndrome.

Nucleotide excision repair (NER) removes damage from DNA in a tightly regulated multiprotein process. Defects in NER result in three different human disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS). Two cases with the combined features of XP and CS have been assigned to the XP-D complementation group. Despite their extreme UV sensitivity, these cells appeared to incise their DNA as efficiently as normal cells in response to UV damage. These incisions were, however, uncoupled from the rest of the repair process. Using cell-free extracts, we were unable to detect any incision activity in the neighbourhood of the damage. When irradiated plasmids were introduced into unirradiated XP-D/CS cells, the ectopically introduced damage triggered the induction of breaks in the undamaged genomic DNA. XP-D/CS cells thus have a unique response to sensing UV damage, which results in the introduction of breaks into the DNA at sites distant from the damage. We propose that it is these spurious breaks that are responsible for the extreme UV sensitivity of these cells.

Base Pairing↗
PubMed2000

The cancer-free phenotype in trichothiodystrophy is unrelated to its repair defect.

The DNA repair-deficient genetic disorders xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) can both result from mutations in the XPD gene, the sites of the mutations differing between the two disorders. The hallmarks of XP are multiple pigmentation changes in the skin and a greatly elevated frequency of skin cancers, characteristics that are not seen in TTD. XP-D and most TTD patients have reduced levels of DNA repair, but some recent reports have suggested that the repair deficiencies in TTD cells are milder than in XP-D cells. We reported recently that inhibition of intracellular adhesion molecule-1 (ICAM-1) expression by UVB irradiation was similar in normal and TTD cells but increased in XP-D cells, suggesting a correlation between ICAM-1 inhibition and cancer proneness. In the first part of the current work, we have extended these studies and found several other examples, including XP-G and Cockayne syndrome cells, in which increased ICAM-1 inhibition correlated with cancer proneness. However, we also discovered that a subset of TTD cells, in which arg112 in the NH2-terminal region of the XPD protein is mutated to histidine, had an ICAM-1 response similar to that of XP-D cells. In the second part of the work, we have shown that TTD cells with this specific NH2-terminal mutation are more sensitive to UV irradiation than other TTDs, most of which are mutated in the COOH-terminal region, and are indistinguishable from XP-D cells in cell killing, incision breaks, and repair of cyclobutane pyrimidine dimers. Because the clinical phenotypes of these patients do not obviously differ from those of TTDs with mutations at other sites, we conclude that the lack of skin abnormalities in TTD is independent of the defective cellular responses to UV. It is likely to result from a transcriptional defect, which prevents the skin abnormalities from being expressed.

Cell Line↗
PubMed2000

An experimental model of chronic myocardial hibernation.

BACKGROUND: Hibernating myocardium describes persistently impaired ventricular function at rest caused by reduced coronary blood flow. However, a realistic animal model reproducing this chronic ischemic state does not exist. The purpose of this study was to explore whether chronic low-flow hibernation could be produced in swine. METHODS: Miniswine underwent 90% stenosis of the left circumflex coronary artery. Positron emission tomography and dobutamine stress echocardiography were performed 3 and 30 days (n = 6) or 14 days (n = 4) after occlusion to evaluate myocardial blood flow and viability. Triphenyl tetrazolium chloride assessed percent infarction. Electron microscopy was used to identify cellular changes characteristic of hibernating myocardium. RESULTS: Positron emission tomography (13N-labeled-ammonia) 3 days after occlusion demonstrated a significant reduction in myocardial blood flow in the left circumflex distribution. This reduced flow was accompanied by increased glucose use (18F-fluorodeoxyglucose), which is consistent with hibernating myocardium. Thirty days after occlusion, positron emission tomography demonstrated persistent low flow with increased glucose use in the left circumflex distribution. Dobutamine stress echocardiography 3 days after occlusion demonstrated severe hypocontractility at rest in the left circumflex region. Regional wall motion improved with low-dose dobutamine followed by deterioration at higher doses (biphasic response), findings consistent with hibernating myocardium. The results of dobutamine stress echocardiography were unchanged 30 days after occlusion. Triphenyl tetrazolium chloride staining (n = 6) revealed a mean of 8% +/- 2% infarction of the area-at-risk localized to the endocardial surface. Electron microscopy (n = 4) 14 days after occlusion demonstrated loss of contractile elements and large areas of glycogen accumulation within viable cardiomyocytes, also characteristic of hibernating myocardium. CONCLUSIONS: Chronic low-flow myocardial hibernation can be reproduced in an animal model after partial coronary occlusion. This model may prove useful in the study of the mechanisms underlying hibernating myocardium and the use of therapies designed to improve blood flow to the heart.

Animals↗
PubMed2000

Induction of angiogenesis after TMR: a comparison of holmium: YAG, CO2, and excimer lasers.

BACKGROUND: Transmyocardial laser revascularization (TMR) is an emerging treatment for end-stage coronary artery disease. A variety of lasers are currently available to perform the procedure, although their relative efficacy is unknown. The purpose of this study was to compare changes in myocardial blood flow and function 6 months after TMR with holmium:yttrium-aluminum-garnet (holmium:YAG), carbon dioxide (CO2), and xenon chloride excimer lasers in a model of chronic ischemia. METHODS: Miniswine underwent subtotal (90%) left circumflex coronary stenosis. Baseline positron emission tomography and dobutamine stress echocardiography were performed to document hibernating myocardium in the left circumflex coronary artery distribution. Animals were then randomized to sham redo-thoracotomy (n = 5) or TMR using a holmium:YAG (n = 5), CO2 (n = 5) or excimer (n = 5) laser. Six months postoperatively, the positron emission tomography and dobutamine stress echocardiography studies were repeated and the animals sacrificed. RESULTS: In animals undergoing TMR with holmium: YAG and CO2 lasers, a significant improvement in myocardial blood flow to the lased left circumflex regions was seen. No significant change in myocardial blood flow was seen in sham- or excimer-lased animals. There was a significant improvement in regional stress function of the lased segments 6 months postoperatively in animals undergoing holmium:YAG and CO2 laser TMR that was consistent with a reduction in ischemia. There was no change in wall motion in sham- or excimer-lased animals. Significantly greater neovascularization was observed in the holmium:YAG and CO2 lased regions than with either the sham procedure or excimer TMR. CONCLUSIONS: Transmyocardial laser revascularization with either holmium:YAG or CO2 laser improves myocardial blood flow and contractile reserve in lased regions 6 months postoperatively. These changes were not seen following excimer TMR or sham thoracotomy, suggesting that differences in laser energy or wavelength or both may be important in the induction of angiogenesis.

Aluminum↗
PubMed2000

Efficacy of the internal mammary artery in combined aortic valve replacement-coronary artery bypass grafting.

BACKGROUND: While internal mammary artery (IMA) use predicts improved survival after coronary bypass grafting (CABG), it remains unknown whether patients undergoing concomitant aortic valve replacement (AVR) realize a similar benefit. METHODS: All patients at a single teaching institution, undergoing combined AVR-CABG, which included a graft to the left anterior descending coronary artery (LAD) from 1984 to 1994 (n = 227) were examined retrospectively. RESULTS: Patients receiving an IMA graft (yesIMA, n = 135) and patients receiving only saphenous vein grafts (nonIMA, n = 92) were not different in their presenting symptoms, or in their incidence of preoperative risk factors. The patients with IMA were more likely to be male, have a later year of operation, be younger, and have a greater body surface. Morbidity was not different between groups. IMA use did not affect 30-day mortality. Long-term actuarial survival was greater in the group with IMA (63% +/- 7% vs 42% +/- 6% at 5 years, p < 0.01). A multivariate Cox proportional hazards model demonstrated that use of an IMA graft improved survival, while recent myocardial infarction, diabetes, earlier year of operation, and lower ejection fraction diminished long-term survival. The relative risk of IMA grafting was 0.570. CONCLUSIONS: Within the limits of a retrospective analysis, patients in a modern era of cardiac operation, who undergo combined AVR-CABG, do not suffer increased morbidity from IMA use, and may realize a survival benefit from use of the IMA as a conduit for bypass of the LAD coronary artery.

Aged↗
PubMed2000

Ultraviolet-B-induced apoptosis and cytokine release in xeroderma pigmentosum keratinocytes.

We have assessed the ability of xeroderma pigmentosum and normal keratinocytes grown out from skin biopsies to undergo apoptosis after irradiation with ultraviolet B. Keratinocytes have been studied from xeroderma pigmentosum complementation groups A (three biopsies), C (three biopsies), D (one biopsy), xeroderma pigmentosum variant (two biopsies), and Cockayne syndrome (one biopsy). The three xeroderma pigmentosum group A and the xeroderma pigmentosum group D samples were at least six times more sensitive than normal cells to ultraviolet B-induced apoptosis. The xeroderma pigmentosum variant samples showed intermediate susceptibility. Xeroderma pigmentosum group C samples proved heterogeneous: one showed high sensitivity to apoptosis, whereas two showed near normal susceptibility. The Cockayne syndrome sample showed the high susceptibility of xeroderma pigmentosum groups A and D only at a higher fluence. These results suggest that the relationships between repair deficiency, apoptosis, and susceptibility to skin cancer are not straightforward. Ultraviolet B-induced skin cancer is also thought to be due in part to ultraviolet B-induced impairment of immune responses. The release of the inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha from cultured xeroderma pigmentosum keratinocytes tended to occur at lower fluences than in normals, but was less extensive, and was more readily inhibited at higher fluences of ultraviolet B.

Apoptosis↗
PubMed2000

Apoptosis and cytokine release induced by ionizing or ultraviolet B radiation in primary and immortalized human keratinocytes.

We have compared the induction of apoptosis and cytokine release by UVB and gamma-radiation in primary (untransformed) and in two immortalized human epithelial/keratinocyte cell lines, HaCaT and KB (KB is now known to be a subline of the ubiquitous keratin-forming tumour cell line HeLa and we therefore designate it HeLa-KB). In both the primary and the immortalized cell lines apoptosis and release of the inflammatory cytokine interleukin-6 are induced rapidly following UVB irradiation. In contrast, only the immortalized cells undergo apoptosis and release interleukin-6 after gamma-irradiation and here the onset of apoptosis and cytokine release are delayed. The same distinction between primary and immortalized cells was observed when double-strand breaks were induced with the anticancer drug mitoxantrone, which stabilizes topoisomerase II-cleavable complexes. We suggest that immortalization may sensitize keratinocytes to the apoptogenic effect of ionizing radiation or mitoxantrone by deregulating normal cell cycle checkpoints. In both human keratinocytes and fibroblasts, cell killing, as assayed by loss of colony-forming ability, is not coupled to apoptosis. Immortalization increases resistance to gamma-radiation killing but sensitizes to apoptosis. In contrast, although immortalization also sensitizes to UVB-induced apoptosis, it does not affect UVB-induced cell killing. Apoptosis unambiguously indicates death at the single cell level but clonal cell survival integrates all the cellular and genetic processes which prevent or permit a scorable clone to develop.

Apoptosis↗
PubMed1999

Intermediate-term clinical outcome following transmyocardial laser revascularization in patients with refractory angina pectoris.

BACKGROUND: This study was conducted to examine the intermediate-term clinical outcomes in patients with refractory angina pectoris treated with transmyocardial laser revascularization (TMR) at our institution. TMR is an alternative surgical technique for the treatment of myocardial ischemia and angina pectoris not amenable to conventional percutaneous or surgical revascularization. Limited data exist evaluating the natural history and duration of clinical improvement in angina pectoris following TMR. METHODS AND RESULTS: Thirty-four patients with severe coronary artery disease unsuitable for treatment with standard revascularization techniques underwent TMR in myocardial regions determined to be ischemic by preoperative SPECT (201)Tl perfusion imaging following dipyridamole stress. Patients were assessed postoperatively at 3, 6, and 12 months for clinical outcomes including death, myocardial infarction, functional class of angina pectoris, and hospitalizations for unstable angina. Myocardial perfusion imaging by (201)Tl scintigraphy was also assessed at these temporal end points. Overall mortality at 1 year was 14.7% (n=5). Nonfatal myocardial infarction occurred in 3 patients (8.8%). Among the patients with complete 12-month follow-up (n =27), mean anginal class improved from 3.5+/-0. 5 pre-TMR to 2.8+/-0.7 and 2.5+/-0.7 at 3 and 6 months, respectively, and 2.8+/-0.9 at 12 months. Overall improvement in angina pectoris was sustained at 1 year by at least one functional class in 50% of patients. Mean hospitalizations per year for unstable angina declined from 2.4+/-1.6 pre-TMR to 1.7+/-2.0 post-TMR (P=0.01). There was no significant improvement in perfusion by SPECT (201)Tl imaging at any temporal end point post-TMR. CONCLUSIONS: Despite the lack of demonstrable improvement in perfusion by SPECT (201)Tl imaging, TMR improved the functional class of angina pectoris in patients with end stage coronary artery disease to a modest degree. Although the maximal benefit in symptoms occurred at 6 months post-TMR, mild sustained clinical improvement above baseline was evident in 50% of patients at 1 year.

Aged↗
PubMed1999

Metabolic changes in the normal and hypoxic neonatal myocardium.

Hypoxia is characterized by inadequate oxygen delivery to the myocardium with a resulting imbalance between oxygen demand and energy supply. Several adaptive mechanisms occur to preserve myocardial survival during hypoxia. These include both short- and long-term mechanisms, which serve to achieve a new balance between myocardial oxygen demand and energy production. Short-term adaptation includes downregulation of myocardial function along with upregulation of energy production via anaerobic glycolysis following an increase in glucose uptake and glycogen breakdown. Long-term adaptation includes genetic reprogramming of key glycolytic enzymes. Thus, the initial decline in high-energy phosphates following hypoxia is accompanied by a decrease in myocardial contractility and myocardial energy requirements are subsequently met by ATP supplied from anaerobic glycolysis. Thus, a downregulation in cardiac function and/or enhanced energy production via anaerobic glycolysis are the major mechanisms promoting myocardial survival during hypoxia. In contrast to the aforementioned metabolic changes occurring in adult myocardium, the effects of chronic hypoxia on neonatal myocardial metabolism remain undefined. Studies from our laboratory using a novel neonatal piglet model of chronic hypoxia have shown a shift in cardiac myocyte substrate utilization towards the newborn state with a preference for glucose utilization. We have also shown, using this same model, that chronically hypoxic neonatal hearts were more tolerant to ischemia than non-hypoxic hearts. This ischemic tolerance is likely due to adaptive metabolic changes in the chronically hypoxic hearts, such as increased anaerobic glycolysis and glycogen breakdown.

Adaptation, Physiological↗