Parenting measurement, normativeness, and associations with child outcomes: Comparing evidence from four non-Western cultures.

This study compared parenting across four non-Western cultures to test cross-cultural commonality and specificity principles in three aspects: measurement properties, parenting normativeness, and their associations with child outcomes. Both mothers and fathers (N = 1509 dyads) with preschool-aged children (M = 5.00 years; 48% girls) from urban areas of four countries (Malaysia, N = 372; China, N = 441; Turkey, N = 402; and Japan, N = 294) reported on four parenting constructs (authoritative, authoritarian, group harmony socialization, and intrusive control) and their sub-dimensions using modified culturally relevant measures. Teachers reported on children's internalizing, externalizing, and prosocial behaviors. The commonality principle was supported by two sets of findings: (1) full measurement invariance was established for most parenting constructs and sub-dimensions, except that intrusive control only reached partial scalar invariance, and (2) no variations were found in associations between parenting and any child outcomes across cultures or parent gender at the construct level for all four parenting constructs and at the sub-dimensional level for authoritarian and intrusive control sub-dimensions. The specificity principle was supported by the other two sets of findings: (1) cross-cultural differences in parenting normativeness did not follow the pattern of economic development but yielded culture-specific patterns, and (2) at the sub-dimensional level, the authoritative parenting and group harmony socialization sub-dimensions were differently associated with child outcomes across cultures and/or parent gender. The findings suggested that examining specific dimensions rather than broad parenting constructs is necessary to reflect cultural specificities and nuances. Our study provided a culturally-invariant instrument and a three-step guide for future parenting research to examine cross-cultural commonalities/specificities. RESEARCH HIGHLIGHTS: This is the first study to use an instrument with measurement invariance across multiple non-Western cultures to examine the commonality and specificity principles in parenting. Measurement invariance was achieved across cultures for authoritative and authoritarian parenting, group harmony socialization, intrusive control, and their sub-dimensions, supporting the commonality principle. Cross-cultural differences in parenting normativeness did not follow the pattern of economic development but yielded culture-specific patterns, supporting the specificity principle. Both commonalities and specificities were manifested in associations between parenting and child outcomes across cultures.

Risk factors for blood transfusion after shoulder arthroplasty.

AIMS: Currently, there is little information about the need for peri-operative blood transfusion in patients undergoing shoulder arthroplasty. The purpose of this study was to identify the rate of transfusion and its predisposing factors, and to establish a blood conservation strategy. METHODS: We identified all patients who had undergone shoulder arthroplasty at our hospital between 1 January 2011 and 31 December 2013. The rate of transfusion was determined from the patient's records. While there were exceptions, patients typically underwent transfusion if they had a level of haemoglobin of < 7.5 g/dl if asymptomatic, < 9.0 g/dl if they had a significant cardiac history or symptoms of dizziness or light headedness. Multivariable regression analysis was undertaken to identify predictors of transfusion. High- and low-risk cohorts for transfusion were identified from a receiver operating characteristic (ROC) curve. RESULTS: Of 1174 shoulder arthroplasties performed on 1081 patients, 53 cases (4.5%) required transfusion post-operatively. Predictors of blood transfusion were a lower pre-operative haematocrit (p < 0.001) and shoulder arthroplasty undertaken for post-traumatic arthritis (p < 0.001). ROC analysis identified pre-operative haematocrit of 39.6% as a 90% sensitivity cut-off for transfusion. In total 48 of the 436 (11%) shoulder arthroplasties with a pre-operative haematocrit < 39.6% needed transfusion compared with five of the 738 (0.70%) shoulder arthroplasties with a haematocrit above this level. DISCUSSION: We found that transfusion was needed less frequently than previously described for shoulder arthroplasty. Patients with a pre-operative haematocrit < 39.6% should be advised that there is an increased risk for blood transfusion, while those with a haematocrit above this level are unlikely to require transfusion. TAKE HOME MESSAGE: The rate of transfusion after shoulder arthroplasty is under 5%, and those with a pre-operative haematocrit greater than or equal to 39.6% have a very low likelihood (< 1%) of requiring a transfusion.

The economics of using prophylactic antibiotic-loaded bone cement in total knee replacement.

The rate of peri-prosthetic infection following total joint replacement continues to rise, and attempts to curb this trend have included the use of antibiotic-loaded bone cement at the time of primary surgery. We have investigated the clinical- and cost-effectiveness of the use of antibiotic-loaded cement for primary total knee replacement (TKR) by comparing the rate of infection in 3048 TKRs performed without loaded cement over a three-year period versus the incidence of infection after 4830 TKRs performed with tobramycin-loaded cement over a later period of time of a similar duration. In order to adjust for confounding factors, the rate of infection in 3347 and 4702 uncemented total hip replacements (THR) performed during the same time periods, respectively, was also examined. There were no significant differences in the characteristics of the patients in the different cohorts. The absolute rate of infection increased when antibiotic-loaded cement was used in TKR. However, this rate of increase was less than the rate of increase in infection following uncemented THR during the same period. If the rise in the rate of infection observed in THR were extrapolated to the TKR cohort, 18 additional cases of infection would have been expected to occur in the cohort receiving antibiotic-loaded cement, compared with the number observed. Depending on the type of antibiotic-loaded cement that is used, its cost in all primary TKRs ranges between USD $2112.72 and USD $112 606.67 per case of infection that is prevented.

Management of impending necrosis associated with soft tissue filler injections.

BACKGROUND: As the number of soft tissue filler injections increases, the number of adverse events associated with injection may rise. Impending necrosis represents a serious complication that, if not treated correctly and timely, may have grave consequences. OBJECTIVE: We describe a protocol utilizing hyaluronidase, nitroglycerin paste, aspirin, antacid and a topical oxygen therapy that may be used to treat impending necrosis subsequent to injection with soft tissue fillers. CONCLUSION: We have successfully treated nine post-filler injection adverse events involving impending necrosis or necrosis following both hyaluronic acid and calcium hydroxylapatite injections using our protocol.

Is coronary computed tomography angiography a resource sparing strategy in the risk stratification and evaluation of acute chest pain? Results of a randomized controlled trial.

OBJECTIVES: Annually, almost 6 million U.S. citizens are evaluated for acute chest pain syndromes (ACPSs), and billions of dollars in resources are utilized. A large part of the resource utilization results from precautionary hospitalizations that occur because care providers are unable to exclude the presence of coronary artery disease (CAD) as the underlying cause of ACPSs. The purpose of this study was to examine whether the addition of coronary computerized tomography angiography (CCTA) to the concurrent standard care (SC) during an index emergency department (ED) visit could lower resource utilization when evaluating for the presence of CAD. METHODS: Sixty participants were assigned randomly to SC or SC + CCTA groups. Participants were interviewed at the index ED visit and at 90 days. Data collected included demographics, perceptions of the value of accessing health care, and clinical outcomes. Resource utilization included services received from both the primary in-network and the primary out-of-network providers. The prospectively defined primary endpoint was the total amount of resources utilized over a 90-day follow-up period when adding CCTA to the SC risk stratification in ACPSs. RESULTS: The mean (± standard deviation [SD]) for total resources utilized at 90 days for in-network plus out-of-network services was less for the participants in the SC + CCTA group ($10,134; SD ±$14,239) versus the SC-only group ($16,579; SD ±$19,148; p = 0.144), as was the median for the SC + CCTA ($4,288) versus SC only ($12,148; p = 0.652; median difference = -$1,291; 95% confidence interval [CI] = -$12,219 to $1,100; p = 0.652). Among the 60 total study patients, only 19 had an established diagnosis of CAD at 90 days. However, 18 (95%) of these diagnosed participants were in the SC + CCTA group. In addition, there were fewer hospital readmissions in the SC + CCTA group (6 of 30 [20%] vs. 16 of 30 [53%]; difference in proportions = -33%; 95% CI = -56% to -10%; p = 0.007). CONCLUSIONS: Adding CCTA to the current ED risk stratification of ACPSs resulted in no difference in the quantity of resources utilized, but an increased diagnosis of CAD, and significantly less recidivism and rehospitalization over a 90-day follow-up period.

Long-term outcomes of injection laryngoplasty in patients with potentially recoverable vocal fold paralysis.

OBJECTIVES/HYPOTHESIS: Injection laryngoplasty (IL) is a temporary intervention for unilateral vocal fold paralysis (UVFP). IL is often performed in patients with a potentially recoverable recurrent laryngeal nerve insult while awaiting spontaneous recovery, compensation, or definitive intervention. This study investigates the long-term outcomes of subjects treated with an IL. STUDY DESIGN: Restrospective chart review. METHODS: A single-institution, retrospective review was performed from January 2004 to July 2008; subjects with potentially recoverable UVFP who underwent an IL were included. RESULTS: The following etiologies were noted for the 42 subjects included: idiopathic in 13 (31%), iatrogenic in 25 (60%), infectious in two (5%), traumatic in one (2%), and stroke in one (2%). Ten subjects (24%) had full recovery of their paralysis, four (10%) partially recovered movement with adequate recovery of voice, 16 (40%) had no recovery of motion but compensation with adequate recovery of voice, 12 (29%) required further definitive intervention in the form of laryngeal framework surgery. Voice-related quality of life scores improved for all patients surveyed after IL and improved more for those who ultimately recovered or compensated. CONCLUSIONS: The majority of subjects with potentially recoverable UVFP recover vocal fold motion and/or adequate voice after IL without permanent intervention.

Comparison of outcomes and complications between awake and asleep injection laryngoplasty: a case-control study.

OBJECTIVES/HYPOTHESIS: To compare clinical outcomes and complication rates in patients undergoing injection laryngoplasty (IL) under local versus general anesthesia. STUDY DESIGN: Retrospective case-control review METHODS: Charts of 141 consecutive patients undergoing IL were reviewed. Subjects who underwent IL with local anesthesia were grouped as experimental cases. Subjects who underwent IL with general anesthesia were grouped as controls. The voice-related quality of life (VRQOL) measure was employed to determine outcomes before and after IL. All undesirable events resulting from an IL were recorded as complications. RESULTS: One hundred sixty-six ILs were performed in 141 patients (83 males, mean age = 58.9 years). Unilateral vocal fold immobility was diagnosed in 60.9%. One hundred five (63.3%) ILs were performed under local anesthesia, and 61 were performed under general anesthesia. Pre- and postinjection VRQOL data was available for 78 ILs (50 cases, 28 controls). Average VRQOL in the awake patient improved by 25.05 points, whereas average VRQOL in the asleep patient improved by 20.81 points (P = .42). There were 24 complications (14.5% of all injections), which included 19.1% of cases and 6.6% of controls (odds ratio = 2.9). Six ILs had to be aborted. All complications were minor and self-limited. CONCLUSIONS: Both awake and asleep IL offer comparable VRQOL results. Although having the benefit of avoiding general anesthesia, IL in the awake patient has a slightly higher complication rate.

A Comparative Study of Arm-Restraint Methodology: Differential Effects of Mother and Stranger Restrainers on Infants' Distress Reactivity at 6 and 9 Months of Age.

This study examined both differential patterns and the stability of infants' (N = 70) distress reactivity across mother and stranger arm-restraint conditions when infants were 6 and 9 months of age. Reactivity measures included observational variables for the rise, intensity, and duration of infant distress as well as motor activities associated with escape behaviors. Correlation analyses revealed that infant behaviors during arm restraint were modestly stable across conditions and over time; however, mean comparisons also showed that infants' distress responses appear to be sensitive to protocol parameters (whether restrainer is mother or stranger). At 6 months of age, infants cried more during maternal restraint than with strangers and exhibited escape behaviors more frequently with mothers. Findings further indicate that infants' distress reactivity undergoes developmental alterations from 6 to 9 months of age, with infants crying more quickly, reaching peak intensity of distress faster, and displaying more distress at 9 months compared to 6 months. These changes in infants' reactivity were particularly accentuated during maternal compared to stranger restraint conditions at 9 months of age.

Preoperative disease severity at sites of subsequent skull base defects after endoscopic sinus surgery.

BACKGROUND: Skull base (SB) injury is a known complication of endoscopic sinus surgery (ESS). Risk factors for SB injury include poor visualization, low-lying SB, and SB asymmetry. Anecdotal evidence indicates that many SB defects occur in areas with minimal mucosal disease adjacent to the SB. We evaluated preoperative computed tomography (CT) scans to determine the degree of mucosal disease present at the site of subsequent SB defects caused by ESS. METHODS: Retrospective review of patients with SB injury as a result of ESS. Preoperative and postoperative CT films were reviewed for extent of overall sinus disease and disease at the site of the subsequent SB defect and presence of risk factors for SB injury. RESULTS: Preoperative and postoperative CT scans were obtained for 22 patients with 23 defects, who underwent 21 primary and 1 revision ESS. Fifteen (65%) patients had no disease, 2 (9%) patients had minimal disease, and 6 (26%) patients had complete opacification at the site of subsequent SB injury. SB defects occurred in the ethmoid roof (15 patients, 65%), lateral lamella (5 patients, 22%), cribriform plate (2 patients, 9%), and sphenoid sinus (1 patient, 4%). Risk factors for SB injury were only identified in 6 patients. CONCLUSION: SB injuries resulting from ESS occurred in SB regions with minimal or no mucosal disease in over two-thirds of cases. Explanations for this may include thinner bone and mucosa in areas without chronic disease that is easier to injure and less resistance to dissection in minimally diseased areas. Caution should always be exercised in ESS, but especially in minimally diseased areas.

Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group.

BACKGROUND: We report the findings from the first large, double-blind, placebo-controlled study conducted to evaluate the efficacy and safety of risperidone in the treatment of psychotic and behavioral symptoms in institutionalized elderly patients with dementia. METHOD: 625 patients (67.8% women; mean age = 82.7 years) with DSM-IV diagnoses of Alzheimer's disease (73%), vascular dementia (15%), or mixed dementia (12%) and significant psychotic and behavioral symptoms were included. Each patient was randomly assigned to receive placebo or 0.5 mg/day, 1 mg/day, or 2 mg/day of risperidone for 12 weeks. The primary outcome measure was the Behavioral Pathology in Alzheimer's Disease rating scale (BEHAVE-AD). RESULTS: The study was completed by 70% of the patients. Baseline Functional Assessment Staging scores were 6 or 7 in more than 95% of the patients, indicating severe dementia. At endpoint, significantly greater reductions in BEHAVE-AD total scores and psychosis and aggressiveness subscale scores were seen in patients receiving 1 and 2 mg/day of risperidone than in placebo patients (p = .005 and p < .001, respectively). At week 12, 0.5 mg/day of risperidone was superior to placebo in reducing BEHAVE-AD aggression scores (p = .02). More adverse events were reported by patients receiving 2 mg/day of risperidone than 1 mg/day. The most common dose-related adverse events were extrapyramidal symptoms, somnolence, and mild peripheral edema. The frequency of extrapyramidal symptoms in patients receiving 1 mg/day of risperidone was not significantly greater than in placebo patients. CONCLUSION: Risperidone significantly improved symptoms of psychosis and aggressive behavior in patients with severe dementia. Results show that 1 mg/day of risperidone is an appropriate dose for most elderly patients with dementia.

Cisapride 20 mg b.i.d. provides symptomatic relief of heartburn and related symptoms of chronic mild to moderate gastroesophageal reflux disease. CIS-USA-52 Investigator Group.

OBJECTIVE: We evaluated the efficacy and safety of a twice-daily dosage regimen of cisapride 20 mg in relieving the symptoms of mild-moderate gastroesophageal reflux disease (GERD) in patients with moderate intensity heartburn and no history of erosive esophagitis. METHODS: After a 2-wk, single-blind, placebo run-in period, 398 patients who continued to experience moderate intensity heartburn were randomized to either placebo (n = 196) or cisapride 20 mg (n = 202) twice daily for 4 wk. RESULTS: Compared with placebo, cisapride significantly reduced scores for daytime and nighttime heartburn (p < 0.001), total regurgitation (p < 0.001), eructation (p = 0.04), and early satiety (p = 0.04). Cisapride 20 mg b.i.d. was also superior to placebo in reducing total use of rescue antacid medication (p < 0.001); reducing, in concordance analyses, daytime and nighttime heartburn with antacid usage (p < 0.001); increasing the percentage of heartburn-free days and antacid-free nights (p < 0.5); and increasing the percentage of patients self-rated as having minimal or better symptomatic improvement (p = 0.01). Cisapride 20 mg b.i.d. was well tolerated. The most common adverse event in the cisapride group was diarrhea, reported by 10% of patients, compared with an incidence of 4% in the placebo group. CONCLUSION: Cisapride 20 mg b.i.d. was shown to be effective and safe for the short-term treatment of daytime and nighttime heartburn and for other symptoms associated with mild-moderate GERD.

Pharmacokinetic profile of cisapride 20 mg after once- and twice-daily dosing.

Cisapride is a substituted piperidinyl benzamide. It is chemically related to metoclopramide but lacks the antidopaminergic properties of metoclopramide that affect the central nervous system and cause extrapyramidal side effects. Cisapride is indicated for the symptomatic treatment of patients with nocturnal heartburn due to gastroesophageal reflux disease. Based on extensive assessment of the drug's pharmacokinetic profile, the currently approved initial oral dosing regimen for cisapride is 10 mg QID. However, the pharmacokinetics of cisapride after oral administration of 20 mg BID have not been investigated. We present here findings from an open-label trial assessing the pharmacokinetics of cisapride 20-mg tablets after a single dose and at steady state (BID dosing). The results indicate that 20-mg BID and 10-mg QID regimens produce similar steady-state concentrations.

Ritanserin in the treatment of cocaine dependence.

Sixty-five cocaine-dependent subjects were enrolled into a 10-week randomized, double-blind study to determine the safety and efficacy of the serotonin-2 receptor antagonist, ritanserin (10 mg/day), in reducing cocaine consumption and craving. All subjects also participated in a structured intensive outpatient psychosocial program. Seventy-three percent of the participants completed the treatment program and follow-up. Subjects experienced a significant reduction in craving: 66.4% and 32.5% for the placebo and ritanserin groups, respectively. These reductions in craving were not paralleled by substantial decreases in cocaine use. Self-reported cocaine use was less frequent in the placebo group; paradoxically, blood levels of its metabolite, benzoylecgonine, were also higher although insignificantly so. Generally, ritanserin was well tolerated but significantly prolonged the QTc interval on the electrocardiogram. This outpatient program is effective at maintaining cocaine-dependent individuals in treatment and reducing craving. Ritanserin (10 mg/day) is not an efficacious adjunct to psychosocial treatment for cocaine dependence.

A clinical evaluation of risperidone in the treatment of schizophrenia: a 10-week, open-label, multicenter trial. ARCS Study Group. Assessment of Risperdal in a Clinical Setting.

The efficacy and safety of risperidone have previously been demonstrated in controlled clinical trials in hospitalized chronic schizophrenia patients who met strict research criteria. The present study was designed to evaluate the efficacy and safety of risperidone in a heterogeneous patient population. Patients were enrolled in the study if they had a diagnosis of schizophrenia (DSM-III-R) with or without acute exacerbation. Of the 945 patients from 158 psychiatric centers who entered this phase IV study, 558 completed the 10-week trial. During week 1, the dose of risperidone was titrated to 6 mg/day, maintained there for 1 week, and then adjusted over a 4-week period as clinically necessary; the dose was then fixed for the final 4-week period. The mean dose of risperidone at endpoint was 5.9 mg/day. Patients were evaluated at baseline and at weeks 2, 6, and 10, using Clinical Global Impression scale, Psychotic Symptoms Assessment scale, and Global Assessment of Functioning scale. Significant improvement in mean scores was found on each of these measures at endpoint. Comparable results were obtained at week 10 in treatment-resistant and non-treatment-resistant patients. Risperidone was generally well tolerated and the severity of extrapyramidal symptoms was significantly reduced at endpoint.

Ritanserin in the treatment of alcohol dependence--a multi-center clinical trial. Ritanserin Study Group.

Four hundred and twenty-three alcohol dependent subjects were enrolled into a 12-week randomized, double-blind, placebo-controlled study to determine the safety and efficacy of the 5-HT2 receptor antagonist, ritanserin (2.5 mg/day or 5 mg/day), in reducing alcohol intake and craving. All subjects received 1 week of single-blind placebo prior to randomization into the 11-week double-blind phase. Additionally, all subjects received weekly individual sessions of manual-guided cognitive-behavioral therapy. Comparing the single-blind period with endpoint, there was approximately a 23% reduction in drinks/day; 34% fall in the total number of drinking days/week; 22% decrease in drinks/drinking day; and a 37% diminution in alcohol craving for all treatment groups. All treatment groups experienced a beneficial clinical outcome as assessed by the Clinical Global Impression Scale. There was, however, no significant difference between treatment groups on any of these measures of alcohol drinking, craving, or clinical outcome. Subjects were of relatively high social functioning at baseline, and this did not change significantly during treatment. Treatment groups did not differ significantly on either medication compliance or reported adverse events. Ritanserin treatment was associated with a dose-related prolongation of subjects' QTc interval recording on the electrocardiogram. These results suggest that alcohol dependent subjects can show marked clinical improvement within a structured alcohol treatment program. These findings do not support an important role for ritanserin in the treatment of alcohol dependence.

Substantia nigra damage after fluorothyl-induced seizures in rats worsens after post-seizure recovery: no exacerbation with hyperglycaemia.

The substantia nigra pars reticularis (SNPR) of rats is highly susceptible to both seizure- and ischaemia-mediated damage. Hyperglycaemic exacerbation of brain damage similar to that observed after global brain ischaemia may also occur in rats with status epilepticus. We tested the hypotheses that hyperglycaemia exacerbates seizure-induced SNPR damage in rats and that SNPR lesions develop rapidly post-seizure. Halothane-anaesthetized, paralysed, and mechanically ventilated rats were prepared for haemodynamic and EEG monitoring. Halothane was discontinued, and mechanical ventilation on 30% oxygen/70% nitrous oxide was continued for 1 h. Three treatment groups (20 rats each) were studied: (1) control, lactated Ringer's solution; (2) equiosmolar control, 40% mannitol; and (3) hyperglycaemia, 50% dextrose. Infusions were started 5 min before seizures were induced with flurothyl 3% administered for either 45 (n = 10) or 75 (n = 10) min. Immediately after seizures, half of the animals underwent cerebral perfusion-fixation with formalin and half were allowed to recover for 2 h post-seizure and then perfused. Brain histology was assessed by light microscopy and scored 0-5 (0 = no damage) for the percentage of eosinophilic neurons and vacuolation in the SNPR. Glucose administration decreased the severity of SNPR damage in rats subjected to 75 min of seizures and 2 h recovery (pathology scores: control, eosinophilic neurons = 3.6, vacuolation = 4.0; hyperglycaemia, eosinophilic neurons = 3.0, vacuolation = 2.75; p < 0.05). SNPR damage was worse after 2 h of recovery (pathology scores: 0 h recovery, eosinophilic neurons = 0.9, vacuolation = 0.1; 2 h recovery, eosinophilic neurons = 3.9, vacuolation = 3.8; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol.

PURPOSE: This study was prepared to address two objectives: (a) to determine whether progressively higher total doses of hepatic irradiation can prolong survival in a selected population of patients with liver metastases; (b) to refine existing concepts of liver tolerance for fractionated external radiation employing a fraction size which might be appropriate in clinical protocols evaluating elective or adjuvant radiation of the liver. METHODS AND MATERIALS: One hundred seventy-three analyzable patients with computed tomography measurable liver metastases from primary cancers of the gastrointestinal tract were entered on a dose escalating protocol of twice daily hepatic irradiation employing fractions of 1.5 Gy separated by 4 hr or longer. Sequential groups of patients received 27 Gy, 30 Gy, and 33 Gy to the entire liver and were monitored for acute and late toxicities, survival, and cause of death. Dose escalation was implemented following survival of 10 patients at each dose level for a period of 6 months or longer without clinical or biochemical evidence of radiation hepatitis. RESULTS: The use of progressively larger total doses of radiation did not prolong median survival or decrease the frequency with which liver metastases were the cause of death. None of 122 patients entered at the 27 Gy and 30 Gy dose levels revealed clinical or biochemical evidence of radiation induced liver injury. Five of 51 patients entered at the 33 Gy level revealed clinical or biochemical evidence of late liver injury with an actuarial risk of severe (Grade 3) radiation hepatitis of 10.0% (+/- 7.3% S.E.) at 6 months, resulting in closure of the study to patient entry. CONCLUSION: The study design could not credibly establish a safe dose for hepatic irradiation, however, it did succeed in determining that 33 Gy in fractions of 1.5 Gy is unsafe, carrying a substantial risk of delayed radiation injury. The absence of apparent late liver injury at the 27 Gy and 30 Gy dose levels suggests that a prior clinical trial of adjuvant hepatic irradiation in patients with resected colon cancer may have employed an insufficient radiation dose (21 Gy) to fully test the question.

Expression of mammalian O6-alkylguanine-DNA alkyltransferase in a cell line sensitive to alkylating agents.

Chinese hamster ovary cells (CHO) were co-transfected with pSV2neo and sheared DNA from either a human cell line (HT29) expressing high levels of O6-alkylguanine-DNA alkyltransferase (AGT) or from a cell line (BE) deficient in this activity. Cells expressing the selectable marker were obtained by exposure to G418 and colonies resistant to alkylation damage isolated by growth in the presence of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). The number of colonies of cells expressing AGT activity arising after transfection with DNA from BE cells was similar to the number arising from cells exposed to HT29 DNA. Although the amount of AGT repair protein expressed in the transfectant colonies from this experiment was relatively low, these results indicate that repair of alkylation damage can be restored in AGT-deficient cells by transfection of human DNA from both repair-deficient and proficient cells. A separate transfection of CHOMG cells [a mutant of CHO cells resistant to the drug, methylglyoxal bis(guanylhydrazone) (MGBG)] with HT29 DNA and pSV2neo followed by selection of G418 and 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) resulted in three colonies with high AGT levels. These transfectants had different growth rates and expressed levels of the AGT protein between 230 and 300 fmol/mg protein. The transfectants were as resistant to the cytotoxic effects of BCNU, Clomesone, methylnitrosourea (MNU) and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) as HT29 cells which were much more resistant than the parental CHOMG cells. Pretreatment of transfectant cells with 0.4 mM O6-methylguanine for 24 h reduced AGT activity to 14% basal levels, which upon removal of the base increased to approximately 74% basal level within 8 h. The sensitivity to the cytotoxic effects of both the chloroethylating and methylating agents was enhanced by treatment with O6-methylguanine. In the same manner, the number of BCNU-induced DNA interstrand cross-links increased in transfectant cells pretreated with O6-methylguanine. These results provide further evidence that the formation of methyl or chloroethyl adducts at the O6-position contribute significantly to cell lethality.