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Biomedical subjects

A J Ryan

Publications and source records attributed to A J Ryan.

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

Intracranial injuries resulting from boxing.

A review of the available records indicates that there have been a substantial number of fatalities in primarily professional but also amateur boxers due to intracranial injuries sustained in the ring in comparison to the numbers of boxers at risk. The number of such fatalities has decreased steadily in recent years owing to different measures taken by boxing authorities to decrease the physical hazards in the ring and to improve monitoring of boxers during bouts by referees and physicians. The considerable concern about the long-term effects of repeated brain injury as the result of boxing in producing chronic encephalopathy is adequately justified by the many studies of live boxers and pathologic examinations of brains of former boxers made and recorded over the years since 1952. These indicate clearly a significant relationship between the numbers of bouts fought and the presence and severity of chronic encephalopathy.

Athletic Injuries↗
PubMed1998

Effect of hypohydration on gastric emptying and intestinal absorption during exercise.

Dehydration and hyperthermia may impair gastric emptying (GE) during exercise; the effect of these alterations on intestinal water flux (WF) is unknown. Thus the purpose of this study was to determine the effect of hypohydration ( approximately 2.7% body weight) on GE and WF of a water placebo (WP) during cycling exercise (85 min, 65% maximal oxygen uptake) in a cool environment (22 degrees C) and to also compare GE and WF of three carbohydrate-electrolyte solutions (CES) while the subjects were hypohydrated. GE and WF were determined simultaneously by a nasogastric tube placed in the gastric antrum and via a multilumen tube that spanned the duodenum and the first 25 cm of jejunum. Hypohydration was attained 12-16 h before experiments by low-intensity exercise in a hot (45 degrees C), humid (relative humidity 50%) environment. Seven healthy subjects (age 26.7 +/- 1.7 yr, maximal oxygen uptake 55.9 +/- 8.2 ml . kg-1 . min-1) ingested either WP or a 6% (330 mosmol), 8% (400 mosmol), or a 9% (590 mosmol) CES the morning following hypohydration. For comparison, subjects ingested WP after a euhydration protocol. Solutions ( approximately 2.0 liters total) were ingested as a large bolus (4.6 ml/kg body wt) 5 min before exercise and as small serial feedings (2.3 ml/kg body wt) every 10 min of exercise. Average GE rates were not different among conditions (P > 0.05). Mean (+/-SE) values for WF were also similar (P > 0.05) for the euhydration (15.3 +/- 1.7 ml . cm-1 . h-1) and hypohydration (18.3 +/- 2.6 ml . cm-1 . h-1) experiments. During exercise after hypohydration, water absorption was greater (P < 0.05) with ingestion of WP (18.3 +/- 2. 6) and the 6% CES (16.5 +/- 3.7), compared with the 8% CES (6.9 +/- 1.5) and the 9% CES (1.8 +/- 1.7). Mean values for final core temperature (38.6 +/- 0.1 degrees C), heart rate (152 +/- 1 beats/min), and change in plasma volume (-5.7 +/- 0.7%) were similar among experimental trials. We conclude that 1) hypohydration to approximately 3% body weight does not impair GE or fluid absorption during moderate exercise when ingesting WP, and 2) hyperosmolality (>400 mosmol) reduced WF in the proximal intestine.

Adult↗
PubMed1997

A correlation between residual DNA double-strand breaks and clonogenic measurements of radiosensitivity in fibroblasts from preradiotherapy cervix cancer patients.

PURPOSE: To study the relationship between residual DNA damage and clonogenic measurements of radiosensitivity in fibroblasts from pretreatment cervix cancer patients. METHODS AND MATERIALS: Early passage vaginal fibroblasts from nine preradiotherapy cervix cancer patients and two radiosensitive skin fibroblast cell strains were studied. Cell survival was measured by clonogenic assay following both high and low dose rate irradiation. Residual DNA damage was measured using pulsed-field gel electrophoresis (PFGE) after irradiating radiolabeled, plateau-phase cells at 37 degrees C and allowing 24 h for repair. DNA damage was expressed both in terms of the residual damage slope (fitted to data from 60 to 150 Gy) and the fraction of activity released (FAR) following 150 Gy. RESULTS: The surviving fraction at 2 Gy (SF2) values after high dose rate irradiation for the vaginal fibroblasts ranged from 0.15 to 0.32 (a 2.2-fold difference). When the two radiosensitive cell strains were included, residual damage, expressed as the residual damage slope, correlated with alpha (r = 0.82, p = 0.002), D bar (r = -0.91, p < 0.001) and SF2 (p = -0.79, p = 0.004), and when the vaginal fibroblasts alone were studied, the residual damage slope again correlated with clonogenic survival, although less strongly [alpha (r = 0.66, p = 0.053), D bar (r = -0.83, p = 0.006), and SF2 (r = -0.63, p = 0.07)]. Within the group of vaginal fibroblasts there was a 4.0-fold difference in residual DNA damage slope. When residual damage was expressed as FAR at 150 Gy, then for all cell strains the correlations were alpha: r = 0.78, p = 0.004, D bar: r = -0.86, p = 0.001, and SF2: r = -0.78, p = 0.004, and for the vaginal fibroblast strains alone the correlations were alpha: r = 0.60, p = 0.088, D bar: r = -0.75, p = 0.02, and SF2: r = 0.62, p = 0.077. CONCLUSION: This study confirms previous findings that residual DNA damage correlates with clonogenic survival in fibroblasts. In addition, it demonstrates a correlation for fibroblasts from pretreatment cervix cancer patients demonstrating a relatively small range of SF2 values.

Cell Survival↗
PubMed1997

SYBR Green I staining of pulsed field agarose gels is a sensitive and inexpensive way of quantitating DNA double-strand breaks in mammalian cells.

Pulsed field gel electrophoresis (PFGE) is widely used to measure DNA double strand breaks (dsb). The DNA of cultured cells can be prelabelled with radioactivity, which helps greatly in detection and quantitation of DNA dsb. However, this approach cannot be used with non-cycling cells from biopsy material. We describe a method which uses SYBR Green I to stain DNA in dried agarose gels. DNA is detected and analysed using readily available camera equipment and image analysis software. This method is as sensitive as [3H]thymidine prelabelling of cells and allows DNA dsb to be measured simply and economically in non-cycling cells.

Animals↗
PubMed1997

Upper limit for intestinal absorption of a dilute glucose solution in men at rest.

We studied gastric and intestinal function by gastric intubation/intestinal perfusion in six healthy male volunteers to evaluate optimal use of a 6% glucose-electrolyte (GES) solution. Gastric volume, residual volume, emptying rate, and secretion were measured for an initial 763 +/- 19 ml gastric load of GES and at the beginning and end of four additional gastric loads (2.2 ml.kg-1; approximately 180 ml) given at 10-min intervals. The relatively high gastric (713 +/- 58 ml) and residual (507 +/- 26 ml) volumes maintained a high gastric emptying rate (19.5 +/- 1.4 ml.min-1). Composition of the GES emptied into the duodenum was also measured in this first experiment. In a second experiment, this modified solution was infused (triple lumen tube) into the duodenum at a rate equal to gastric emptying rate, or at 38 or 77% greater rates. Absorption of water (11.3-12.9 ml.h-1.cm-1) and glucose 4.3-5.6 mmol.h-1.cm-1) were similar at all perfusion rates during the second experiment. We conclude that duodenojejunal segmental absorption rates of water and glucose produced by a rapid, sustained gastric emptying rate cannot be increased by delivering a greater load of glucose and water by intestinal perfusion.

Adult↗
PubMed1997

Effect of running intensity on intestinal permeability.

Enhanced intestinal permeability has been associated with gastrointestinal disorders in long-distance runners. The primary purpose of this study was to evaluate the effect of running intensity on small intestinal permeability by using the lactulose and rhamnose differential urinary excretion test. Secondary purposes included assessing the relationship between small intestinal permeability and gastrointestinal symptoms and evaluating gastric damage by using sucrose as a probe. Six healthy volunteers [5 men, 1 woman; age = 30 +/- 2 yr; peak O2 uptake (VO2peak) = 57.7 +/- 2.1 ml.kg-1.min-1] rested or performed treadmill exercise at 40, 60, or 80% VO2peak for 60 min in a moderate environment (22 degrees C, 50% relative humidity). At 30 min into rest or exercise, the permeability test solution (5 g sucrose, 5 g lactulose, 2 g rhamnose in 50 ml water, approximately 800 mosM) was ingested. Urinary excretion rates (6 h) of the lactulose-to-rhamnose ratio were used to assess small intestinal permeability, and concentrations of each probe were determined by using high-performance liquid chromatography. Running at 80% VO2peak increased (P < 0.05) small intestinal permeability compared with rest, 40, and 60% VO2peak with mean values expressed as percent recovery of ingested dose of 0.107 +/- 0.021 (SE), 0.048 +/- 0.009, 0.056 +/- 0.005, and 0.064 +/- 0.010%, respectively. Increases in small intestinal permeability did not result in a higher prevalence of gastrointestinal symptoms, and urinary recovery of sucrose did not reflect increased gastric permeability. The significance and mechanisms involved in increased small intestinal permeability after high-intensity running merit further investigation.

Adult↗
PubMed1996

Dominant genetic instability and sensitivity to DNA damaging agents in a mammalian cell line.

An SV40 transformed Indian muntjac cell line (SVM) has been shown to be hypersensitive to cell killing by a wide range of DNA damaging agents. Evidence points to defects in DNA replication and DNA recombination resulting in chromosome instability both spontaneously and following exposure to DNA damaging agents. We have generated proliferating hybrids between SVM and a spontaneously transformed Indian muntjac cell line (DM). Study of these hybrids indicates that the SVM phenotype acts in a genetically dominant manner and is associated with the expression of SV40 large T antigen. We propose that transformation and immortalization of Indian muntjac fibroblasts by SV40 virus can lead to a set of persistent changes in gene expression that result in chromosome instability and increased sensitivity to DNA damaging agents. Genes involved in these processes are likely to be of great importance as chromosome instability can play a central role in cancer development.

Alkylating Agents↗
PubMed1996

Gastrointestinal permeability following aspirin intake and prolonged running.

We sought to evaluate the effects of exercise and aspirin on gastroduodenal and intestinal permeability. Seven volunteers (age = 29 +/- 3 yr, VO2max = 56.8 +/- 4.1 ml.kg-1.min-1) rested or performed treadmill exercise (60 min at approximately 68% VO2max), with or without aspirin ingestion. Placebo (glucose) or aspirin (1.3 g) was taken the night before and prior to rest or exercise (total 2.6 g). A permeability test solution (approximately 1300 mOsm.kg-1), containing 10 g lactulose (L), 5 g mannitol (M), and 10 g sucrose (S), was ingested prior to rest or exercise. Urinary excretion rates (6.h-1), expressed as a percentage of ingested dose, were used to quantify intestinal (L/M ratio) or gastroduodenal (S) permeability. Ingestion of aspirin before running increased (P < 0.05) intestinal permeability compared to placebo+running and placebo+rest, but not compared to aspirin+rest; mean (+/-SE) values for the L/M ratio were 0.248 +/- 0.046, 0.029 +/- 0.012, 0.012 +/- 0.004, and 0.104 +/- 0.057, respectively. Gastroduodenal permeability following aspirin+running (3.25 +/- 1.21%) was also elevated (P < 0.05) compared to placebo+running (0.43 +/- 0.15%) and placebo+rest (0.24 +/- 0.11%), but not compared to aspirin+rest (0.66 +/- 0.27%). Neither running nor aspirin ingestion was associated with gastrointestinal (GI) complaints. Thus, GI permeability while running can be markedly elevated by aspirin ingestion.

Adult↗
PubMed1995

Real-time simultaneous wide- and small-angle fibre diffraction.

A combination of two independent imaging area-detector systems controlled by a single data-acquisition system, provides a powerful system for X-ray diffraction studies of time-resolved phenomena over a wide q range, in samples with intrinsic or induced structural orientation. With this system we have observed a transient, tensile-stress-induced, orthorhombic-to-monoclinic transition in high-density polyethylene.

Journal Article↗
PubMed1995

Testosterone, growth hormone and IGF-I responses to acute and chronic resistive exercise in men aged 55-70 years.

We investigated the responses of serum testosterone (T) and human growth hormone (hGH) concentrations to a bout of heavy resistive exercise and the responses of T, hGH, and insulin-like growth factor I (IGF-I) to a 16 wk progressive resistive training program in 13 men (60 +/- 4 yrs). Body composition via hydrostatic weighing and muscle strength using a 3 repetition maximum (3RM) test on 6 variable resistance exercise machines were assessed before and after the training program. Fasting blood samples were drawn on 2 consecutive days prior to training and again on 2 consecutive days after the last day of exercise. Blood was also drawn immediately before and approximately 10 min after a single exercise session during the first wk of training, and after an exercise session of the same relative resistance during the last wk of training. The training program resulted in a 37% increase in upper body strength and a 39% increase in lower body strength (both p < 0.01). Lean body mass increased significantly (61.8 +/- 2.1 vs 63.7 +/- 7.8 kg; p < 0.001) while % fat decreased (26.5 +/- 1.5 vs 24.9 +/- 6.0%; p < 0.01) as a result of training. Serum T concentration was unchanged, but GH increased approximately 18-fold in response to a single bout of resistive exercise before (0.24 +/- 0.08 vs 4.60 +/- 1.35 mg/l) and after (0.26 +/- 0.06 vs 4.66 +/- 1.46 mg/l; p < 0.01) training. Baseline serum concentrations of T, hGH, and IGF-I were unaffected by the training program. We conclude that an acute bout of resistive exercise causes a substantial hGH response in older men, but 16 wks of progressive resistive training does not affect baseline concentrations of the anabolic hormones.

Aged↗
PubMed1995

Tissue-specific HSP70 response in animals undergoing heat stress.

Heatstroke is a multisystem disorder that can result in death. Activities that increase the rate of heat storage predispose an organism to thermal injury. Using a 72-kDa heat shock protein (HSP72) as a marker of thermal injury, we determined 1) which organs synthesize HSP in animals after hyperthermia and 2) whether a high heating rate (HHR) resulted in more HSP72 than a low heating rate (LHR). Rats were assigned to either control, HHR (0.166 degrees C/min), or LHR (0.045 degrees C/min) groups. Heat exposure ended when colonic temperature (Tc) reached 42 degrees C. Total time in the heat and thermal load (measured as the time an animal maintained a Tc > 40.4 degrees C) were significantly lower in HHR compared with LHR animals. Hyperthermia resulted in a tissue-specific increase in HSP72 in the liver, small intestine, and kidney, but not in the brain or quadriceps muscles. In addition, HHR animals showed significantly greater accumulation of HSP72 in the liver compared with animals in the LHR group. Thus HSP72 synthesis is tissue specific at high physiological temperatures and may identify a critical target tissue susceptible to early thermal damage.

Animals↗
PubMed1995

Responses of rat mesenteric arteries to norepinephrine during exposure to heat stress and acidosis.

Both cardiovascular abnormalities and metabolic acidosis can be prominent in heat stroke and may contribute to morbidity and mortality in heat stroke victims. Thus the effects of heat stress and/or low pH on the responses of rat mesenteric arteries (approximately 300 microns) to norepinephrine (NE; 10(-8)-10(-5) M) and acetylcholine (ACh; 10(-5) M) were examined. Arteries (5-7/group) were isolated, cannulated with micro-pippettes, placed under constant intraluminal pressure (50 mmHg), and then examined during 60-min exposures to either 1) 37, 42, or 43 degrees C or 2) 37 or 42 degrees C under conditions of low pH (pH = 7.0 by addition of 1 N HCl). Contractile responses to NE remained unaltered during exposure to 42 and 43 degrees C. When arteries were returned from that elevated temperature back to 37 degrees C for 30 min, enhanced (P < 0.05) contractile responses to NE were observed. Exposure to low pH depressed contractile responses to NE to a similar extent in arteries tested at 37 or 42 degrees C. Dilations to ACh were not altered by exposure to 42 degrees C, regardless of pH conditions, but were progressively reduced during the 43 degrees C (P = 0.09) exposure. Arteries exposed to NE demonstrated vasomotion. The NE-induced vasomotion, while maintained at 37 degrees C, was reduced (P < 0.05) by exposure to 43 degrees C. In conclusion, the contractile response to NE in mesenteric arteries was not altered by heat stress per se (up to 43 degrees C) but was depressed by low pH. The latter response was not potentiated by heat stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Different fates of camptothecin-induced replication fork-associated double-strand DNA breaks in mammalian cells.

The S phase cytotoxicity of camptothecin (CPT) requires both the formation of a covalent topoisomerase I-DNA complex and ongoing DNA replication. The interaction of DNA synthesis and the drug-induced complexes results in the production of DNA double-strand breaks (DSBs) concentrated in replicating DNA. These DSBs are likely to be extremely cytotoxic lesions and are likely to account for the S phase specificity of CPT. Here we show that a brief exposure to CPT results in replication-associated DSBs and, once formed, the fate of these DNA DSBs is different in human and Chinese hamster cell lines. In hamster CHO-KI, even at supra-lethal concentrations, CPT-induced DSBs in nascent DNA disappear within 5 h of drug removal. Those CHO-KI cells in S phase during treatment with toxic doses of CPT arrive at mitosis within 18 h, with potentially lethal chromatid aberrations. In human cells, CPT-induced DSBs are long lived, and are still detectable at least 24 h after drug removal. After toxic doses of CPT to S phase human cells, mitosis does not occur within 72 h of drug removal and there is an extended, perhaps permanent, cycle arrest in S/G2, possibly due to the presence of unrepaired DNA DSBs. These data, and the greater sensitivity of hamster than human cells to low doses of CPT, suggests that, besides the generation of replication fork-associated DNA DSBs, subsequent processing/repair of these lesions may modulate the sensitivity of cells to this important anti-tumour drug.

Animals↗
PubMed1994

Heat stress does not sensitize rats to the toxic effects of bacterial lipopolysaccharide.

To determine whether heat stress sensitizes rats to lipopolysaccharide (LPS), four groups were examined: saline, LPS, heat stressed+saline, and heat stressed+LPS treated rats. Saline or LPS (Escherichia coli, 5 mg.kg-1 body weight, i.v.) was given after exposure to heat and at the same time of day for nonheated rats. Survival was monitored for 24 or 48 h; samples of liver and small intestine were obtained at 24 h for histological analysis. Thermal responses were similar (P > 0.05) for the heat stressed saline and LPS treated rats: mean values for maximum colon temperature were 43.0 +/- 0.1 and 42.9 +/- 0.1 degrees C, respectively. Mortality was similar for rats exposed to heat stress+saline (11%, 2/19) and heat stress+LPS (32%, 6/19). No lethality was observed in nonheated rats given saline or LPS. Tissue damage was similar in heat stress+saline and heat stress+LPS treated rats. Liver showed mild to severe degrees of coagulative necrosis while duodenum exhibited damage to the villous tips. These findings show that severe heat stress does not markedly sensitize the rat to the lethal activity of LPS.

Analysis of Variance↗
PubMed1993

Hypersensitivity of Cockayne's syndrome cells to camptothecin is associated with the generation of abnormally high levels of double strand breaks in nascent DNA.

We report that fibroblasts from individuals with Cockayne's Syndrome (CS), an autosomal recessive disease exhibiting hypersensitivity to UV, are also hypersensitive to the killing action of camptothecin (CPT). In normal and CS cell lines the level of the protein-linked single strand DNA breaks (SSBs) induced by equal doses of CPT is similar, and these DNA breaks disappear within minutes of the removal of CPT. Thus, the toxicity of CPT does not correlate with the primary DNA lesions induced by the drug, and the hypersensitivity of CS cells cannot be explained by excessive topoisomerase I activity or by a defect in the enzyme ligation step. We have reported that CPT toxicity in normal cells is closely associated with the generation of double-strand DNA breaks (DSBs), predominantly at sites of DNA replication. The hypersensitivity of CS cells to CPT correlates closely with the much higher level of DSBs in nascent DNA than in normal cells. These DSBs are long-lived in all cells, but in CS many more (about 10-fold) remain 24 h after CPT removal and are presumably responsible for the higher frequency of chromosome aberrations in these cells. In CS as in normal cells aphidicolin prevents the generation of replication-related DSBs, suggesting that the movement of the DNA polymerase is necessary for the induction by CPT of the cytotoxic DSBs. Resistance to CPT and UV is restored to wild type in proliferating hybrids constructed between CS lines from two different complementation groups as is the abundance of replication-related DSBs. On the basis of this complementation we conclude that the UV and CPT sensitivities are distinct phenotypic traits arising from mutations in the CS A and B genes.

Aphidicolin↗
PubMed1993

Fine tuning of DNA repair in transcribed genes: mechanisms, prevalence and consequences.

Cells fine-tune their DNA repair, selecting some regions of the genome in preference to others. In the paradigm case, excision of UV-induced pyrimidine dimers in mammalian cells, repair is concentrated in transcribed genes, especially in the transcribed strand. This is due both to chromatin structure being looser in transcribing domains, allowing more rapid repair, and to repair enzymes being coupled to RNA polymerases stalled at damage sites; possibly other factors are also involved. Some repair-defective diseases may involve repair-transcription coupling: three candidate genes have been suggested. However, preferential excision of pyrimidine dimers is not uniformly linked to transcription. In mammals it varies with species, and with cell differentiation. In Drosophila embryo cells it is absent, and in yeast, the determining factor is nucleosome stability rather than transcription. Repair of other damage departs further from the paradigm, even in some UV-mimetic lesions. No selectivity is known for repair of the very frequent minor forms of base damage. And the most interesting consequence of selective repair, selective mutagenesis, normally occurs for UV-induced, but not for spontaneous mutations. The temptation to extrapolate from mammalian UV repair should be resisted.

Animals↗
PubMed1992

Characterisation and correction of a mammalian cell mutant defective in late step of base excision repair.

An Indian muntjac cell line, SVM, is unusually sensitive to cell killing induced by a range of alkylating agents. Cells transfected with the Escherichia coli ada gene or human genomic DNA have allowed the response of SVM to alkylating agents to be dissociated into two distinct components. Thus, in SVM, which expresses very low levels of alkyltransferase (AT), O6-alkylguanine appears to be the major cytotoxic, clastogenic, and recombinogenic lesion following exposure to agents such as methylnitrosourea (MNU). However, SVM is also very sensitive to agents such as dimethylsulfate (DMS), which produce only very low levels of O6-methylguanine damage. Sensitivity to DMS resides in an inability to complete base excision repair, with the appearance of persistent single-strand DNA breaks (SSBs), and does not appear to involve defects in glycosylase, apurinic/apyrimidinic endonuclease, or DNA ligase activities. Another, possibly related, phenotypic trait in SVM is its limited ability to ligate transfected linear plasmid DNA. Transfectants of SVM, harboring human DNA sequences, show a significant correction of DMS-induced cytotoxicity and clastogenicity and a reduction in the levels of DMS-induced DNA SSBs. The DMS-resistant transfectants have an increased ability to ligate linear plasmid DNA, and also express AT, making these lines resistant to alkylating agents such as MNU. These results suggest that cells possess a mechanism that regulates AT expression, plasmid break-joining ability, and certain aspects of base excision repair. Transfectants of SVM containing human DNA provide a means to isolate genes involved in a coordinate response to alkylation damage.

Alkylating Agents↗