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Biomedical subjects

R D Snyder

Publications and source records attributed to R D Snyder.

At least 37 records · Page 2Linked to original sources
PubMed1998

Can apoptosis in benign proliferative lesions predict risk of cancer development?

The presence of benign proliferative lesions is a risk factor for the development of cancer. However, only a subset of individuals presenting with benign lesions goes on to develop cancer. It is a major challenge of cancer research to identify those individuals at increased risk for this neoplastic progression. It has been suggested that individuals with inherent genomic instability may have a predisposition for cancer development. The hypothesis is presented that this genetic instability could be quantified through the analysis of apoptosis in biopsies of benign lesions. It is further conjectured that genetic damage-dependent apoptosis might serve as a prognostic indicator to identify individuals at increased risk for cancer.

Animals↗
PubMed1998

A review and investigation into the mechanistic basis of the genotoxicity of antihistamines.

The genotoxicity of twenty one clinically used (or discontinued) antihistamines is reviewed. New results are also presented from an evaluation of selected antihistamines in the V79 in vitro micronucleus assay. For two antihistamines, no genotoxicity data is available. Of the remaining nineteen, nine have been reported as positive and one equivocal in at least one genotoxicity assay despite the fact that none possess structural alerts for genotoxicity. Ethidium displacement and bleomycin amplification studies in V79 cells indicate that nine of these ten antihistamines are capable of intercalative DNA binding. Further, nine of the ten positive compounds, but none of the tested compounds which also intercalate but are reported to be negative in gene-tox assays (e.g. triprolidine, chlorcyclizine, clemastine), possess a dimethylamino substituent suggesting the requirement for this cationic function in the genotoxicity. It is proposed that the apparent genotoxicity of antihistamines and possibly many other pharmaceuticals derives from a hitherto unappreciated propensity of these drugs for stabilized intercalative DNA binding. It is further proposed that the bleomycin amplification assay may provide a widely applicable means for assessing functional intercalative drug/DNA interaction in intact mammalian cells.

Animals↗
PubMed1998

Quality of life decisions at the beginning of life: ethical considerations.

The burdens of life with treatment may outweigh the benefits. Under which set of circumstances and to what extent a neonate should receive medical intervention is a difficult ethical issue involving principles and cultural aspects which may be in conflict. The nature of the disease, the risks involved in treatment or non-treatment, the degree to which therapy will extend life, the discomfort associated with therapy, the anticipated quality of life, the wishes of surrogates, and national cultural mores are the important considerations in determination of the neonate's best interest in order to arrive at ethically defensible decisions. These decisions are not necessarily cross-culturally uniform.

Congenital Abnormalities↗
PubMed1997

Evaluation of positive controls for the in vitro unscheduled DNA synthesis assay using hepatocytes from induced (Aroclor 1254) and uninduced male cynomolgus monkey.

We have evaluated the use of four different positive control compounds for assessing UDS in monkey hepatocytes and have found three of these, methylmethanesulfonate, benzo[a]pyrene, and dimethylbenz[a]anthracene, to produce strong positive responses in vitro. Dimethylnitrosamine induced only weak responses. We also report that the strength of the response induced by procarcinogens was not enhanced in hepatocytes taken from Aroclor 1254-pretreated monkeys, even though substantial induction of cytochrome P450 enzymes was demonstrated in these cells. These studies raise the question of the utility of employing an in vivo induction system to enhance the monkey UDS assay.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Olfaction in migraine.

Olfactory thresholds for acetone and vanillin and the unpleasantness rating of concentrated acetone were measured in 20 migraine sufferers and 21 controls. The olfactory threshold for vanillin was lower in migraine sufferers than in controls. In addition, patients who reported that odours frequently seemed stronger during attacks of migraine were able to detect acetone at a lower concentration than most other patients. No differences were found between migraine sufferers and controls for ratings of the unpleasantness of concentrated acetone. These findings suggest that hyperacuity to odours persists between episodes of migraine. Sensitivity to odours could contribute to the migraine predisposition.

Acetone↗
PubMed1997

An analysis of the outcomes of treatment of small cell lung cancer in the elderly.

BACKGROUND: Many cases of small cell lung cancer will occur in the elderly population but optimal management of the disease in this age group remains uncertain. AIMS: To evaluate treatment of small cell lung cancer in the elderly in Australia and to compare treatment received and outcomes with those of younger patients. To draw insights from these observations into the optimal management of small cell lung cancer in the elderly. METHODS: A retrospective review of treatment charts and case notes for 51 elderly patients and 102 younger patients was undertaken. RESULTS: Elderly patients had similar baseline parameters with respect to disease stage and performance status. Elderly patients were mostly treated uniformly with combination chemotherapy, but suffered more dose reductions than younger patients. Benefits of chemotherapy were seen even in patients with poor performance status. Despite the dose reductions, response rates and survival times for elderly patients were usually similar to younger patients. CONCLUSIONS: Combination chemotherapy is beneficial to elderly patients with small cell lung cancer. Optimal therapy for the elderly may be different from that for younger patients and should be defined through prospective randomised clinical trials.

Age Factors↗
PubMed1996

The Melbourne Family Grief Study, I: Perceptions of family functioning in bereavement.

OBJECTIVE: The aim of this study was to identify patterns of family functioning in adult families after the death of a parent. METHOD: One hundred fifteen families completed measures of family functioning, grief, psychological state, and social adjustment 6 weeks (time 1), 6 months (time 2), and 13 months (time 3) after the death of a parent (a total of 670 individual responses). Cluster analytic methods were applied to develop a typology of perceptions of family functioning during bereavement. RESULTS: Five types of families emerged from dimensions of cohesiveness, conflict, and expressiveness on the Family Environment Scale. Thirty-six percent of the families were considered supportive because of their high cohesiveness, and another 23% resolved conflict effectively. Two types were dysfunctional: hostile families, distinguished by high conflict, low cohesiveness, and poor expressiveness, and sullen families, who had more moderate limitations in these three areas; they declined in frequency from 30% at time 1 to 15% at time 3. The remaining type (26%), termed intermediate, exhibited midrange cohesiveness, low control, and low achievement orientation. The typology at time 1 predicted typologies at time 2 and time 3. There were no age or gender differences among the family types, but offspring, as compared with spouses, were overrepresented in the hostile families. CONCLUSIONS: Family types can be identified, allowing at-risk families to be helped to prevent complications of grief. Screening with the family relationship index of the Family Environment Scale would facilitate such a family-centered approach.

Adaptation, Psychological↗
PubMed1996

The Melbourne Family Grief Study, II: Psychosocial morbidity and grief in bereaved families.

OBJECTIVE: The aim of this study was to describe the intensity of grief, the psychosocial morbidity, and the coping patterns in members of families classified according to a typology of family functioning comprising supportive, conflict-resolving, intermediate, sullen, and hostile classes. METHOD: One hundred fifteen families were assessed longitudinally 6 weeks (time 1), 6 months (time 2), and 13 months (time 3) after the death of a parent (constituting 670 individual responses) on measures of grief intensity, psychological state, social adjustment, and family coping. A previously described typology of perceptions of family functioning was applied. Repeated measures multivariate analysis of variance based on both individuals and families and post hoc comparisons of significant results were undertaken. RESULTS: Sullen families displayed the most intense grief and the most severe psychosocial morbidity. Well-functioning families (supportive and conflict-resolving) resolved their grief and adjusted more adaptively than their dysfunctional counterparts (intermediate, sullen, and hostile families). There were no cluster-by-time interactions. The clusters accounted for 15.7% of the variance in depression (Beck Depression Inventory) and 27.9% of the variance in social functioning (Social Adjustment Scale). Well-functioning families used more family coping strategies (Family Crisis Oriented Personal Evaluation Scales). CONCLUSIONS: More intense grief and greater psychosocial morbidity are found in sullen, hostile, and intermediate bereaved families than in the more adaptive supportive and conflict-resolving types. At-risk families are identifiable and could be treated preventively to reduce morbidity.

Adaptation, Psychological↗
PubMed1996

Apparent inhibition of apoptosis by polyamines and aminothiols in DNA fragmentation assays is artifactual.

We report that, in commonly used DNA fragmentation assays, polyamines and the radioprotective aminothiol WR1065 artifactually depress the degree of spontaneous or induced cellular apoptosis in two distinct ways. Firstly, in assays utilizing Hoechst 33258 dye to measure apoptotic DNA, both amines quench the fluorescence of low affinity dye/DNA binding resulting in preferential underestimation of DNA in the apoptotic DNA fraction and a resultant underestimation of the extent of DNA fragmentation. Secondly, these amines can cause aggregation and condensation of apoptotic DNA, causing anomalous sedimentation under conditions universally employed to separate apoptotic from intact DNA in cell lysates. This anomalous sedimentation of apoptotic DNA leads to underestimation of fragmentation in fluorescence assays as well as in agarose gel assays. We demonstrate that manipulation of the ionic strength of the lysis buffer or lowering the dye concentration ameliorates the effects of dye quenching in the Hoechst assay. Alternatively, this effect is alleviated by substituting DAPI for Hoechst in this assay. Inclusion of a polyanion to the lysis buffer antagonizes the condensation and anomalous sedimentation of apoptotic DNA observed regardless of which dye is used in the assay. These studies call into question the validity of previously reported studies suggesting that polyamines and the radioprotective aminothiol, WR1065, inherently suppress the apoptotic process and underline the need to consider alternative endpoints of apoptosis such as morphology in order to assess effects on cellular apoptosis of exogenously added agents, particularly di- or polycations.

Journal Article↗
PubMed1996

End of life decisions at the beginning of life.

Modern neonatal intensive care technology enhances the ability to maintain vulnerable newborns. In some circumstances survival may be insufficient justification for care. "End of life" strategies, originally applicable to adults, are being considered for newborns. Unresolved ethical issues in the care of these newborns involve multiple considerations. Concern occurs regarding patient-centered beneficence, non-maleficence, distributive justice, futility, legal rights of infants, and autonomy. The benefits to a newborn of treatment may fail to overcome the burdens of subsequent life. Under what circumstances a newborn loses the right to have life prolonged becomes a difficult ethical issue. With time and debate the proper response will become implemented.

Decision Making↗
PubMed1995

In vivo administration of dichloroacetic acid suppresses spontaneous apoptosis in murine hepatocytes.

Spontaneous apoptosis in hepatocytes of male B6C3F1 mice that received dichloroacetic acid (DCA) in their drinking water for 5-30 days (28-58 days of life) was examined as part of ongoing studies to determine the molecular basis of the hepatocarcinogenicity of this nongenotoxic water chlorination by-product. DCA at 0.5 and 5.0 g/liter, significantly reduced apoptosis relative to untreated controls in a dose-dependent fashion. Regression analysis indicated that apoptosis declined over the 30-day period in the livers of control, age-paired animals receiving no drug. Animals receiving low-dose DCA exhibited a similar, although quantitatively depressed, trend line, whereas animals receiving high-dose DCA showed maximal depression of apoptosis at 5 days, which was sustained throughout the course of the 30-day period. These studies suggest that DCA has the ability to down-regulate apoptosis in murine liver. When taken together with previous data demonstrating DCA-dependent decrease in labeling index in these same livers, these data further support the hypothesis that the carcinogenic mechanism of DCA may involve suppression of the ability of the liver to remove initiated cells by apoptosis rather than by induction of selective proliferation of initiated cells.

Animals↗
PubMed1995

Phase II study of high dose epirubicin in combination with cyclophosphamide in patients with advanced breast cancer.

BACKGROUND: Combination chemotherapy for metastatic breast cancer will palliate symptoms in the majority of patients but only a small percentage will have prolonged survival. Higher doses of doxorubicin lead to increased response rates in breast cancer and early studies have shown that epirubicin could be tolerated in higher doses with less relative toxicity than doxorubicin. AIMS: This study was initiated to assess the dose of epirubicin that could be tolerated by escalating its dose while maintaining a fixed dose of cyclophosphamide. Simultaneously tumour response rate, spectrum of toxicities, duration of response and overall survival in patients with metastatic breast cancer were assessed. METHODS: Patients with metastatic breast cancer commenced chemotherapy with a starting dose of epirubicin of 120 milligram per metre squared (mg/m2) and cyclophosphamide 600 mg/m2. The dose of epirubicin was to be escalated or reduced depending on toxicity. RESULTS: Forty female patients were entered into this study and three patients withdrew because of toxicity. Overall tumour response rate was 75% with 27.5% of patients obtaining a complete response. Median time to progressive disease was 35 weeks and median overall survival was 48 weeks, with median survival for complete responders being 103 weeks. Thirty-one (77%) patients completed five or more courses of treatment. Haematological toxicity was the main side effect and 70% of patients required a dose reduction. No patients were eligible for a dose escalation. One patient died as a consequence of neutropenic sepsis. Four (10%) patients had treatment ceased because of decrease in left ventricular ejection fraction and one patient died as a consequence of heart failure. Four patients remain alive. CONCLUSIONS: High dose epirubicin combined with cyclophosphamide is an effective treatment regimen for metastatic breast cancer obtaining higher overall response rates with increased percentage complete responses compared to conventional dose chemotherapy. Although toxicity was increased, high dose chemotherapy was well tolerated and mortality associated with treatment was not increased. No dose escalations of epirubicin were possible and a dose of 90 mg/m2 of epirubicin would be the maximum dose when used in combination with cyclophosphamide. Further trials are required to determine the influence of this high dose therapy on survival duration and whether comparable benefits can be achieved with shorter durations of therapy.

Adenocarcinoma↗
PubMed1995

The effect of five prosthetic feet on the gait and loading of the sound limb in dysvascular below-knee amputees.

The purpose of this study was to determine the effects of prosthetic foot design on the vertical ground reaction forces experienced by the sound and amputated limbs in a group of persons with dysvascular below-knee amputations. Stride characteristics, joint motion, and ground reaction forces were recorded simultaneously during a self-selected free walking velocity in seven subjects wearing five different prosthetic feet (SACH, Flex-Foot, Carbon Copy II, Seattle, Quantum). Subjects used each foot for one month prior to testing. Results indicated that the sound limb was exposed to higher vertical ground reaction forces than normal despite a reduced walking velocity. Use of the Flex-Foot resulted in the lowest sound limb vertical forces, which appears to be related to its large arc of dorsiflexion motion. In addition, there was increased loading response knee flexion of the sound limb indicating an attempt by these subjects to modulate floor impact. These results suggest that the intact lower extremity is susceptible to excessive floor impact, and that prosthetic foot design can have an effect on the magnitude of the vertical forces experienced by the limb.

Aged↗
PubMed1994

Effects of metal treatment on DNA repair in polyamine-depleted HeLa cells with special reference to nickel.

Human cells depleted of the naturally occurring polyamines putrescine, spermidine, and spermine exhibit altered chromatin structure and marked deficiencies in DNA replicative and repair processes. Similar effects have been observed following treatment of normal mammalian cells with various heavy metal salts. In an attempt to better understand how metals interfere with normal DNA metabolic processes, a series of studies was carried out in which the toxicity and repair-inhibitory properties of various metals were evaluated in polyamine-depleted HeLa cells. Cytotoxicity of copper, zinc, magnesium, and cadmium was not altered in cells carrying lower polyamine pools. However, the sensitivity to nickel was markedly increased upon polyamine depletion, a condition that was readily reversed by polyamine supplementation. Nucleoid sedimentation analysis indicated that a greater amount of nickel-induced DNA damage occurred in polyamine-depleted cells than in normal cells, possibly serving as the basis for the increased sensitivity. Both polyamine depletion and nickel treatment result in decreased repair of DNA strand breaks and decreased cloning efficiency following X-ray and ultraviolet irradiation. Nickel treatment of polyamine-depleted cells resulted in synergistic sensitivity to both radiation treatments. None of the other metals tested enhanced X-ray or ultraviolet sensitivity of polyamine-depleted cells. Analysis of retarded repair sites following ultraviolet irradiation indicated those sites to be nonligatable in polyamine-depleted and nickel-treated cells, suggesting a block in the normal gap-sealing process.

DNA Repair↗
PubMed1994

Effect of 2'-deoxy-2'-(fluoromethylene) cytidine on the ultraviolet and X-ray sensitivity of HeLa cells.

The effects of treatment of HeLa cells with the antitumor nucleoside analog 2'-deoxy-2'-(fluoromethylene) cytidine (FMdC) on ultraviolet and X-ray sensitivity were examined. A 1-h pretreatment with FMdC increased cellular sensitivity to both X-rays and ultraviolet irradiation as determined by survival curve analysis. Increased sensitivity to killing was accompanied by a clear reduction in the rate and extent of X-ray-induced DNA strand break repair and in the closure of excision repair-dependent DNA breaks following ultraviolet irradiation. These studies demonstrate that FMdC treatment compromises the repair of both ionizing ("short-patch") and nonionizing ("long-patch") DNA damage. The mechanism by which this is likely to occur is discussed. Based on these findings, it is likely that FMdC, in addition to possessing inherent antitumor activity, might provide additional antineoplastic benefit when administered in combination therapies with radiation.

DNA Damage↗
PubMed1994

Radiosensitivity of polyamine-depleted HeLa cells and modulation by the aminothiol WR-1065.

The radiosensitivity of cultured HeLa cells was increased upon depletion of the natural cellular polyamines putrescine, spermidine and spermine through treatment of cultures with inhibitors of polyamine biosynthesis. This increased radiosensitivity was manifested as a decrease in the D0 and by the absence of a shoulder in the survival curves. However, our previous studies have shown that the initial yield of X-ray-induced DNA damage did not appear to be elevated in polyamine-depleted cells. In addition, polyamine-depleted cells exhibited markedly altered X-ray-induced changes in the distribution of cells in the phases of the cell cycle characterized by increased time of onset and lengthened duration of G2-phase delay. Addition of polyamines to cultures for short periods prior to irradiation restored normal radioresistance and reversed the anomalous features of the G2-phase delay profile. Polyamine supplementation experiments as well as studies in which combinations of inhibitors were employed to modulate specific polyamine levels suggest that spermidine may play a primary role in governing cellular radioresponsiveness. The radioprotective aminothiol WR-1065 protected normal and polyamine-depleted cells to a proportionately similar extent (protection factor of 2.4 and 2.8, respectively) but had no apparent ability to restore the shoulder or alter the G2-phase delay markedly in polyamine-depleted cells. The findings reported here extend our previous observations that polyamine depletion results in a compromised ability to respond to X irradiation and suggest that a defect in repair and/or the G2-phase delay response may be the determining factors.

Cell Survival↗