Biomedical subjects
Publications and source records attributed to M O'Brien.
A tendon forms an integral part of musculotendinous unit. It transmits the tensions generated in muscles to bone. Tendons are stronger than muscles and are able to withstand larger forces. Tendons are subject to both tensile and high compressive forces.
After maturation tendons undergo many biochemical, cellular, mechanical and pathological changes that bring about a general decline in the structure and function of the tendon. This decline in the aging tendon is characterized by a reduced ability to adapt to environmental stress and loss of tissue homeostasis. The tendon's adaptability to these changes will decide the rate and the success of treatment of a tendon injury. This review examines these changes and also looks at how we can curtail their progression through exercise and lifestyle modification.
We examined whether chronic stimulation of red and white rat muscles increased the concentrations of the monocarboxylate transporter MCT1. Red and white tibialis anterior (RTA and WTA, respectively) and extensor digitorum longus (EDL) muscles were chronically stimulated via the peroneal nerve for 7 days. Stimulated and contralateral control muscles were examined for MCT1 content, L-lactate uptake, lactate dehydrogenase (LDH) isoforms, and muscle fiber composition. MCT1 was 1.5 times greater in stimulated RTA, 3 times greater in stimulated WTA, and 1.9 times greater in stimulated EDL compared with respective control muscles (P < 0.05). L-Lactate uptake increased in all stimulated muscles (P < 0.05), and this was highly correlated with the increase in MCT1 (r = 0.96). The heart-type LDH (H-LDH) subunits also increased in all stimulated muscles (P < 0.05). The H-LDH subunits correlated highly with MCT1 in the muscles (r = 0.83). There was no change in muscle-type LDH subunits (P > 0.05). There were negligible alterations in muscle fiber composition in the stimulated muscles, suggesting that the increase in MCT1 was independent of changes in muscle fiber composition. These studies are the first to demonstrate that chronic muscle contraction increases MCT1 concentrations in both red and white skeletal muscles.
PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin, and methotrexate (FAMTX) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS: Two hundred seventy-four patients with adenocarcinoma or undifferentiated carcinoma were randomized and analyzed for survival, tumor response, toxicity, and quality of life (QL). RESULTS: The overall response rate was 45% (95% confidence interval [CI], 36% to 54%) with ECF and 21% (95% CI, 13% to 29%) with FAMTX (P = .0002). Toxicity was tolerable and there were only three toxic deaths. The FAMTX regimen caused more hematologic toxicity and serious infections, but ECF caused more emesis and alopecia. The median survival duration was 8.9 months with ECF and 5.7 months with FAMTX (P = .0009); at 1 year, 36% (95% CI, 27% to 45%) of ECF and 21% (95% CI, 14% to 29%) of FAMTX patients were alive. The median failure-free survival duration was 7.4 months with ECF and 3.4 months with FAMTX (P = .00006). The global QL scores were better for ECF at 24 weeks, but the remaining QL data showed no differences between either arm of the study. Hospital-based cost analysis on a subset of patients was similar for each arm and translated into an increment cost of $975 per life-year gained. CONCLUSION: The ECF regimen results in a survival and response advantage, tolerable toxicity, better QL and cost-effectiveness compared with FAMTX chemotherapy. This regimen should now be considered the standard treatment for advanced esophagogastric cancer.
PURPOSE: To determine the maximum-tolerated dose (MTD) of all-trans-retinoic acid (ATRA) administered on an intermittent oral schedule with interferon-alpha2a (IFN-alpha2a) in children with refractory cancer, and whether the marked reduction in plasma ATRA concentrations observed with chronic daily oral dosing could be circumvented with an intermittent dosing schedule. PATIENTS AND METHODS: Thirty-three children with refractory cancer (stratified by age, < or = 12 and > 12 years) were treated with ATRA 3 consecutive days per week and IFN-alpha2a 3 x 10(6) U/m2 5 consecutive days per week, both repeated weekly. The starting dose of ATRA was 60 mg/m2/d divided into three doses, with planned escalations to 90 and 120 mg/m2/d. Because severe headaches have been noted to occur on the initial day of ATRA administration, only two of three doses of ATRA were administered on day 1 of each week. RESULTS: Pseudotumor cerebri or dose-limiting headache was observed in two of five patients older than 12 years treated at the 120-mg/m2/d dose level and in one of six < or = 12 years at the 90-mg/m2/d level. Other non-dose-limiting toxicities of ATRA included reversible elevations in hepatic transaminases and triglycerides, dry skin, cheilitis, and nausea/vomiting. One child with recurrent neuroblastoma had an objective response of 6 months' duration, and one with recurrent Wilms' tumor had histologic maturation of multiple tumors. This intermittent schedule allowed for exposure to relatively high plasma concentrations of ATRA on a repetitive basis. Following 30-mg/m2 doses, the ATRA area under the concentration-time curve (AUC) decreased from 96 +/- 14 micromol/L/min on day 1 to 26 +/- 24 micromol/L/min by day 3 of drug administration, but on day 1 of the fourth consecutive week of therapy, the AUC averaged 110 +/- 16 micromol/L/min. The recommended pediatric phase II dose of ATRA administered on this schedule is 90 mg/m2/d. CONCLUSION: An intermittent schedule of ATRA administration appears to circumvent the low plasma drug exposure that is a result of the sustained upregulation of metabolism when this drug is administered on a chronic daily schedule. Based on the results of this trial, a phase II trial of ATRA/IFN-alpha2a in neuroblastoma and Wilms' tumor using this schedule is in progress.
PURPOSE: A phase I trial of docetaxel was performed to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities, and the incidence and severity of other toxicities in children with refractory solid tumors. PATIENTS AND METHODS: Forty-four children received 103 courses of docetaxel administered as a 1-hour intravenous infusion every 21 days. Doses ranged from 55 to 150 mg/m2, MTD was defined in heavily pretreated and less heavily pretreated (< or = 2 prior chemotherapy regimens, no prior bone marrow transplantation [BMT], and no radiation to the spine, skull, ribs, or pelvic bones) patients. RESULTS: Dose-related neutropenia was the primary dose-limiting toxicity. The MTD in the heavily pretreated patient group was 65 mg/m2, but the less heavily pretreated patients tolerated a significantly higher dose of docetaxel (maximum-tolerated dose, 125 mg/m2). Neutropenia and constitutional symptoms consisting of malaise, myalgias, and anorexia were the dose-limiting toxicities at 150 mg/m2 in the less heavily pretreated patients. Thrombocytopenia was not prominent, even in patients who experienced dose-limiting neutropenia. Common nonhematologic toxicities of docetaxel included skin rashes, mucositis, and mild elevations of serum transaminases. Neuropathy was uncommon. Peripheral edema and weight gain were observed in two of five patients who received more than three cycles of docetaxel. A complete response (CR) was observed in one patient with rhabdomyosarcoma, a partial response (PR) in one patient with peripheral primitive neuroectodermal tumor (PPNET), and a minimal response (MR) in two patients with PPNET. Three of the four responding patients were treated at doses > or = 100 mg/m2. CONCLUSION: The recommended phase II dose of docetaxel administered as a 1-hour intravenous infusion in children with solid tumors in 125 mg/m2. Because neutropenia was the dose-limiting toxicity and thrombocytopenia was mild, further escalation of the dose should be attempted with granulocyte colony-stimulating factor (G-CSF) support.
PURPOSE: Methotrexate nephrotoxicity can lead to delayed methotrexate elimination and the development of life-threatening toxicity, which may not be preventable with the standard rescue agent leucovorin. In preclinical studies, we previously demonstrated that carboxypetidase-G2 (CPDG2) rapidly hydrolyzes methotrexate to nontoxic metabolites. A protocol for the compassionate use of CPDG2 in patients who develop nephrotoxicity while receiving high-dose methotrexate was therefore developed. The pharmacologic and clinical outcome of CPDG2 rescue administered with thymidine and leucovorin in 20 patients is presented here. METHODS: Patients with high-dose methotrexate-induced renal dysfunction received one to three doses of CPDG2, 50 U/kg body weight intravenously (i.v.), thymidine 8 g/m2/d by continuous i.v. infusion, and standard pharmacokinetically guided leucovorin rescue. Plasma concentrations of methotrexate and its inactive metabolite 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) were measured before and after CPDG2 using high-pressure liquid chromatography (HPLC). Tolerance of CPDG2 and thymidine, development of methotrexate toxicities, and recovery of renal function were monitored. RESULTS: Twenty patients who received high-dose methotrexate for osteosarcoma (n = 11), lymphoid cancers (n = 8), and gastric cancer (n = 1) developed nephrotoxicity (median serum creatinine, 3.2 mg/dL) and elevated plasma methotrexate concentrations (median, 201 mumol/L at hour 46). CPDG2 and thymidine rescue was well tolerated and resulted in a rapid 95.6% to 99.6% reduction in the plasma methotrexate concentration. Methotrexate-related toxicity was mild to moderate. Serum creatinine returned to normal values at a median of 22 days. CONCLUSION: CPDG2, thymidine, and leucovorin rescue was highly effective in 20 patients at high risk for developing life-threatening methotrexate toxicity after the onset of methotrexate-induced nephrotoxicity and delayed methotrexate excretion.
The meniscofemoral ligaments (MFL) of the knee have both functional and clinical importance, but have been poorly described. We examined 42 human cadaver knees: there was at least one MFL in every joint and both ligaments were present in 27. The anterior MFL was present in the knees in all 18 males and in 17 of the 24 females. The posterior MFL was present in 16 males and 22 females. Measurement of the ligaments showed that they were of significant size. The mean midpoint width for the anterior MFL was 5.09 +/- 1.41 mm in males and 2.99 +/- 1.29 mm in females. The mean width of the posterior MFL was 5.48 +/- 2.13 mm in males and 3.79 +/- 2.56 mm in females. The average length of the anterior MFL was 27.09 +/- 2.15 mm in males and 24.38 +/- 3.39 mm in females, and the posterior MFL was 31.13 +/- 2.54 mm and 27.59 +/- 3.74 mm, respectively. There were anatomical variations in 16 (38%) knees (62.5% female, 37.5% male), more commonly in the posterior ligament. We conclude that the meniscofemoral ligaments are anatomically and probably functionally important structures in the human knee.
Squash is a moderate to high intensity sport which demands specific fitness. Squash at any level places a high demand on the aerobic system for energy delivery during play and recovery. In addition, the sport requires bursts of intense, anaerobic physical activity involving the lactic anaerobic energy system. Players must possess appropriate levels of local muscular endurance, strength, power, flexibility and speed, combined with agility, balance and co-ordination. Irrespective of the standard of play, aerobic fitness training and specific anaerobic training should be undertaken by all who play or intend to play squash. Aerobic fitness for the individual who is new to the game and has little training background can be improved using low intensity continuous running. Training sessions and matches should be preceded by warm-up and flexibility exercises which may reduce the chance of injury and enhance readiness to perform. Despite squash being an indoor sport, it is likely that play in hot and humid weather may generate significant thermal loads with the associated elevations in heart rate. Fluid losses of 2 L/min and rectal temperatures of 39 degrees C may occur, thereby increasing the cardiovascular stress of participation and the risk of heat illness. Sudden death and other manifestations of heart disease can occur in squash, therefore advice regarding the safe participation for those with, or who have the potential to develop disease appears essential. For those under 40 years of age who are well and have no known heart disease, medical clearance is not mandatory prior to taking up squash; for such individuals, regular medical monitoring may be unnecessary. For healthy individuals older than 40 years of age irrespective of health status, but particularly for those with coronary disease or relevant risk factors, a medical checkup is recommended prior to, and at least annually after taking up squash. Healthy individuals older than 40 years of age with one or more risk factors require a medical checkup prior to commencing squash for the first time and at regular intervals (every 2 years) thereafter. These individuals should also have a medically supervised exercise test. Those individuals older than 40 years of age who have a known history of heart disease, most commonly coronary artery disease, may play squash if it is demonstrated that, on examination or following therapy or surgery, they can exercise safely to a high workload. Most eye injuries which occur in squash are related to eye/ball and eye/racquet contact. The incidence of injury is very low but such injuries may be totally preventable. Ideally, all players should wear protective eye apparatus. The "ideal' protective apparatus should comply with the Australian/New Zealand Standard for eye protectors for racquet sports. It should be recognised at the outset that there is a paucity of specific data regarding squash and pregnancy. Most women with normal pregnancies may continue to exercise and play squash particularly in the early stages of pregnancy but should notify their physician of their intention to do so. Musculo-skeletal injuries to the lower limb dominate most studies and common injuries include sprains and strains to the back and ankles. Of particular interest is the development of degenerative hip disease in elite squash players necessitating retirement or curtailment of activity in the third decade. Dealing with injuries and illness that are attributed to squash requires an approach based on prevention as well as on appropriate injury management.
Although mercaptopurine is the thiopurine antimetabolite predominantly used in the treatment of childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is more potent than mercaptopurine in in vitro cytotoxicity studies in human leukemic cell lines and leukemic cells from patients with ALL. We conducted a pediatric Phase I trial of TG administered as a continuous i.v. infusion (CIV). A pharmacokinetically guided dose escalation was performed to define the dose rate of TG required to achieve a steady-state plasma concentration (Css) exceeding the target concentration of 1 microM, and then the maximum tolerated duration of infusion of TG at this dose rate was defined. Eighteen patients (median age, 18 years; range, 4-25 years) with refractory malignancies (16 solid tumors and 2 ALL) were enrolled in this study. The starting dose rate of 10 mg/m2/h administered for 24 h achieved an average Css of 0.9 microM (range, 0.7-1.2 microM). Therefore, the dose rate was escalated to 20 mg/m2/h, which achieved an average Css of 4.1 microM (range, 1. 0-8.3 microM). This disproportionate increase in the Css of TG suggested a capacity-limited (saturable) elimination process, and a pharmacokinetic model incorporating two compartments with capacity-limited elimination from the central compartment was developed to describe the disposition of TG. The TG clearances (derived from model parameters) at the 10- and 20-mg/m2/h dose rates were 987 and 608 ml/min/m2, respectively. Dose-limiting myelosuppression (absolute granulocyte count < 500/mm3 and platelet count < 25,000/mm3) was observed in two of three patients treated with a dose rate of 20 mg/m2/h administered for 36 h. Administration of CIV of TG at 20 mg/m2/h for 24 h was well tolerated in nine patients. Nonhematological toxicities included nonneutropenic infections and mild, reversible changes in hepatic function tests. The recommended dose rate and duration for CIV of TG is 20 mg/m2/h for 24 h.
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The aim of this study was to examine the effects of chronic low frequency stimulation on the lactate transport across the plasma membrane of the tibialis anterior (TA) muscle of the rat. Stimulating electrodes were implanted on either side of the peroneal nerve in one hindlimb. Chronic stimulation (10 Hz, 50 microsecond bursts, 24h/day) commenced 7 days after surgery, and were continued for 7 days. Animals were then left for 24 h, and thereafter muscles were obtained. Cytochrome C-oxidase activity was increased 1.9-fold in the stimulated TA compared to the control TA (p < 0.05). Lactate transport (zero-trans) was measured in giant sarcolemmal vesicles obtained from the chronically stimulated TA and the control TA. At each of the concentrations used in these studies a significant increase in lactate transport was observed; 2.8-fold increase at 1 mM lactate p < 0.05); 2-fold increases at both 30 mM and 50 mM lactate p < 0.05). These studies have shown that lactate transport capacity is markedly increased in response to chronic muscle contraction.
The anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) has been shown previously to form adducts preferentially within internucleosomal or linker DNA rather than to DNA within the nucleosome. To determine whether other "open" regions of chromatin have an increased affinity for cisplatin, adduct formation within specific chromatin domains was analyzed. There was a significant increase in cisplatin-DNA adduct formation for DNA associated with the nuclear matrix (NM) compared with other chromatin domains and total unfractionated DNA. In contrast, treatment of the same cells with trans-diamminedichloroplatinum(II) (transplatin) did not result in preferential adduct formation. These findings led to the hypothesis that it might be possible to alter DNA to make it a more favorable target for cisplatin. The effect of arginine butyrate on cisplatin-DNA adduct formation was analyzed in human cancer cells. The combination of arginine butyrate and cisplatin resulted in a concentration-responsive increase in cisplatin-DNA adduct formation in PC-3 cells and an overall increase in cisplatin-DNA adduct formation in three other human cancer cell lines. The same combination also resulted in a significant increase in drug-induced cytotoxicity at a low concentration of cisplatin. These results suggest that chromatin configuration can affect cisplatin adduct formation.
OBJECTIVES: To document the types of firearms associated with firearm fatalities, and to determine the availability of information on firearm characteristics in existing data sources. DESIGN: Review of police, medical examiner, and crime laboratory records for all firearm homicides and review of medical examiner records for all suicides and unintentional and undetermined firearm fatalities. SETTING: City of Milwaukee, Wis, from 1990 through 1994. POPULATION: A total of 175 firearm suicides and 524 firearm homicides. MAIN OUTCOME MEASURES: Source of data; circumstances and means of death; host demographic characteristics; firearm make, model, caliber, barrel length, and serial number. RESULTS: Handguns accounted for 468 (89%) of 524 firearm homicides and 124 (71%) of 175 firearm suicides. Handguns of .25 caliber accounted for 14% (n = 63) of 438 firearm homicides and 12% (n = 15) of all firearm suicides in which caliber was known. The Raven MP-25 was the single most commonly identified firearm and accounted for 10% (n = 15) of 153 handgun homicide cases and 7% (n = 7) of the 76 suicide cases in which the manufacturer of the firearm was identified. From all data sources combined, information on firearm type was available in 681 (97%) of 699 cases, caliber/gauge in 636 cases (91%), manufacturer/model in 309 cases (44%), and serial number in 276 cases (40%). CONCLUSIONS: Inexpensive, short-barreled .25-caliber handguns were the most common weapon type associated with firearm homicides and suicides in Milwaukee during 1990 through 1994. Product-specific information is a crucial part of planning appropriate injury countermeasures for firearms. In combination, police, crime laboratory, and medical examiner data can supply this information with modest changes in data collection procedures.
This paper is a review of the current status of technology for mammalian oocyte growth and development in vitro. It compares and contrasts the characteristics of the various culture systems that have been devised for the culture of either isolated preantral follicles or the oocyte-granulosa cell complexes form preantral follicles. The advantages and disadvantages of these various systems are discussed. Endpoints for the evaluation of oocyte development in vitro, including oocyte maturation and embryogenesis, are described. Considerations for the improvement of the culture systems are also presented. These include discussions of the possible effects of apoptosis and inappropriate differentiation of oocyte-associated granulosa cells on oocyte development. Finally, the potential applications of the technology for oocyte growth and development in vitro are discussed. For example, studies of oocyte development in vitro could help to identify specific molecules produced during oocyte development that are essential for normal early embryogenesis and perhaps recognize defects leading to infertility or abnormalities in embryonic development. Moreover, the culture systems may provide the methods necessary to enlarge the populations of valuable agricultural, pharmaceutical product-producing, and endangered animals, and to rescue the oocytes of women about to undergo clinical procedures that place oocytes at risk.
BACKGROUND AND PURPOSE: The erythematous response of human skin to radiotherapy has proven useful for testing the predictions of the linear quadratic (LQ) model in terms of fractionation sensitivity and repair half time. No formal investigation of the response of human skin to doses less than 2 Gy per fraction has occurred. This study aims to test the validity of the LQ model for human skin at doses ranging from 0.4 to 5.2 Gy per fraction. MATERIALS AND METHODS: Complete erythema reaction profiles were obtained using reflectance spectrophotometry in two patient populations: 65 patients treated palliatively with 5, 10, 12 and 20 daily treatment fractions (varying thicknesses of bolus, various body sites) and 52 patients undergoing prostatic irradiation for localised carcinoma of the prostate (no bolus, 30-32 fractions). RESULTS AND CONCLUSIONS: Gender, age, site and prior sun exposure influence pre- and post-treatment erythema values independently of dose administered. Out-of-field effects were also noted. The linear quadratic model significantly underpredicted peak erythema values at doses less than 1.5 Gy per fraction. This suggests that either the conventional linear quadratic model does not apply for low doses per fraction in human skin or that erythema is not exclusively initiated by radiation damage to the basal layer. The data are potentially explained by an induced repair model.
Using a prospectively acquired database of 290 patients with advanced gastric adenocarcinoma, the prognostic significance of serum levels of carcinoembryonic antigen (CEA) (237 patients), alphafeto protein (AFP) (164 patients), beta-human chorionic gonadotrophin (beta HCG) (165 patients), CA19-9 (64 patients) and CA125 (104 patients) and tissue staining for C-erb B-2 (160 patients) and beta HCG (160 patients) was investigated. Serum was taken prior to 5-fluorouracil (5FU)-based chemotherapy and immunohistochemistry was performed on diagnostic specimens. In the univariate analysis, tumour markers of poor prognosis were CEA > or = 5 micrograms/l (P = 0.01; median survival (MS) 42 versus 35 weeks), serum beta HCG > or = 4 U/l (P = 0.02; MS 42 versus 25 weeks), CA125 > or = 35 U/ml (P = 0.03; MS 43 versus 31 weeks) and CA125 > or = 350 U/ml (P = 0.001; MS 42 versus 17 weeks). Other significant factors were poor performance status, the presence of metastases and poorly differentiated tumour histology. Tumours markers of poor prognosis in the multivariate analysis were serum beta HCG > or = 4 IU/l [hazard ratio (HR) 1.7; 95% confidence interval (CI) 2.8-1.1] and CA125 > or = 350 U/ml (HR 2.2; CI 4.2-1.2). There was a degree of subgroup variability in this model but, in general, other factors correlating with a poor survival were poor performance status, metastases and poorly differentiated tumour histology. This is the largest prognostic study of each tumour marker in advanced disease and demonstrates that serum beta HCG and CA125 in gastric cancer prior to chemotherapy do convey an independent poor prognosis which may reflect not just tumour burden but aggressive biology.
BACKGROUND: Balloon dilation or sphincteroplasty is emerging as a potentially safe and effective alternative to sphincterotomy in the management of bile duct stones. However, concerns related to the possible development of fibrosis or papillary stenosis led us to investigate the acute and long-term effects of balloon sphincteroplasty on papillary structure. METHODS: Sixteen pigs (45 to 50 kg) underwent transduodenal cannulation of the bile duct while under general anesthesia. Balloon sphincteroplasty was performed in 10 pigs to a diameter of 8 mm at a pressure of 10 atm. Sphincterotomy was carried out in 3 pigs while 2 other untreated pigs acted as controls. Eleven animals were sacrificed at intervals from 15 to 120 minutes after balloon sphincteroplasty or sphincterotomy. The remaining 5 animals were sacrificed between 6 and 12 weeks later. Histologic sections through the papilla were assessed for evidence of morphologic changes. RESULTS: When compared with controls, sections taken 15 to 120 minutes after balloon sphincteroplasty showed a progressive increase in acute inflammation extending transmurally. Intramucosal, but no transmural, hemorrhage was noted. No architectural distortion or smooth muscle disruption was observed in contrast to the transmural hemorrhage, smooth muscle disruption, and mucosal necrosis seen following sphincterotomy. After 6 to 12 weeks, mild chronic inflammation with follicular hyperplasia was present but no smooth muscle disruption or fibrosis was observed. CONCLUSION: Balloon sphincteroplasty causes an acute transmural inflammatory response and chronic follicular hyperplasia but is not associated with fibrosis or altered papillary architecture.