Right ventricular regional wall curvedness and area strain in patients with repaired tetralogy of Fallot

A quantitative understanding of right ventricular (RV) remodeling in repaired tetralogy of Fallot (rTOF) is crucial for patient management. The objective of this study is to quantify the regional curvatures and area strain based on three-dimensional (3-D) reconstructions of the RV using cardiac magnetic resonance imaging (MRI). Fourteen (14) rTOF patients and nine (9) normal subjects underwent cardiac MRI scan. 3-D RV endocardial surface models were reconstructed from manually delineated contours and correspondence between end-diastole (ED) and end systole (ES) was determined. Regional curvedness (C) and surface area at ED and ES were calculated as well as the area strain. The RV shape and deformation in rTOF patients differed from normal subjects in several respects. Firstly, the curvedness at ED (mean for 13 segments, 0.030 ± 0.0076 vs. 0.029 ± 0.0065 mm(-1); P < 0.05) and ES (mean for 13 segments, 0.040 ± 0.012 vs. 0.034 ± 0.0072 mm(-1); P < 0.001) was decreased by chronic pulmonary regurgitation. Secondly, the surface area increased significantly at ED (mean for 13 segments, 982 ± 192 vs. 1,397 ± 387 mm(2); P < 0.001) and ES (mean for 13 segments, 576 ± 130 vs. 1,012 ± 302 mm(2); P < 0.001). In particular, rTOF patients had significantly larger surface area than that in normal subjects in the free wall but not for the septal wall. Thirdly, area strain was significantly decreased (mean for 13 segments, 56 ± 6 vs. 34 ± 7%; P < 0.0001) in rTOF patients. Fourthly, there were increases in surface area at ED (5,726 ± 969 vs. 6,605 ± 1,122 mm(2); P < 0.05) and ES (4,280 ± 758 vs. 5,569 ± 1,112 mm(2); P < 0.01) and decrease in area strain (29 ± 8 vs. 18 ± 8%; P < 0.001) for RV outflow tract. These findings suggest significant geometric and strain differences between rTOF and normal subjects that may help guide therapeutic treatment.     

Using in vivo Cine and 3D multi-contrast MRI to determine human atherosclerotic carotid artery material properties and circumferential shrinkage rate and their impact on stress/strain predictions

In vivo magnetic resonance image (MRI)-based computational models have been introduced to calculate atherosclerotic plaque stress and strain conditions for possible rupture predictions. However, patient-specific vessel material properties are lacking in those models, which affects the accuracy of their stress/strain predictions. A noninvasive approach of combining in vivo Cine MRI, multicontrast 3D MRI, and computational modeling was introduced to quantify patient-specific carotid artery material properties and the circumferential shrinkage rate between vessel in vivo and zero-pressure geometries. In vivo Cine and 3D multicontrast MRI carotid plaque data were acquired from 12 patients after informed consent. For each patient, one nearly-circular slice and an iterative procedure were used to quantify parameter values in the modified Mooney-Rivlin model for the vessel and the vessel circumferential shrinkage rate. A sample artery slice with and without a lipid core and three material parameter sets representing stiff, median, and soft materials from our patient data were used to demonstrate the effect of material stiffness and circumferential shrinkage process on stress/strain predictions. Parameter values of the Mooney-Rivlin models for the 12 patients were quantified. The effective Young's modulus (YM, unit: kPa) values varied from 137 (soft), 431 (median), to 1435 (stiff), and corresponding circumferential shrinkages were 32%, 12.6%, and 6%, respectively. Using the sample slice without the lipid core, the maximum plaque stress values (unit: kPa) from the soft and median materials were 153.3 and 96.2, which are 67.7% and 5% higher than that (91.4) from the stiff material, while the maximum plaque strain values from the soft and median materials were 0.71 and 0.293, which are about 700% and 230% higher than that (0.089) from the stiff material, respectively. Without circumferential shrinkages, the maximum plaque stress values (unit: kPa) from the soft, median, and stiff models were inflated to 330.7, 159.2, and 103.6, which were 116%, 65%, and 13% higher than those from models with proper shrinkage. The effective Young's modulus from the 12 human carotid arteries studied varied from 137 kPa to 1435 kPa. The vessel circumferential shrinkage to the zero-pressure condition varied from 6% to 32%. The inclusion of proper shrinkage in models based on in vivo geometry is necessary to avoid over-estimating the stresses and strains by up 100%. Material stiffness had a greater impact on strain (up to 700%) than on stress (up to 70%) predictions. Accurate patient-specific material properties and circumferential shrinkage could considerably improve the accuracy of in vivo MRI-based computational stress/strain predictions.     

Micromechanics of the fibrosa and the ventricularis in aortic valve leaflets.

The elastic response of aortic valve cusps is a summation of its fibrous components. To investigate the micromechanical function of valve leaflet constituents, we separated the fibrosa and the ventricularis from fresh and glutaraldehyde-fixed leaflets and tested them individually. The ventricularis was stiffer circumferentially than radially (7.41 kPa vs 3.68 kPa, p less than 0.00001) and was more extensible radially (62.7% vs 21.8% strain to high modulus phase, p less than 0.00001). The fibrosa was also stiffer circumferentially than radially (13.02 kPa vs 4.65 kPa, p less than 0.0008), but had uniform extensibility. Glutaraldehyde fixation did not affect the circumferential elastic modulus of the fibrosa, but reduced its radial modulus from 4.65 kPa to 2.32 kPa (p less than 0.0078). The elastic modulus of the ventricularis remained unchanged. Fixation also reduced the extensibility of the ventricularis circumferentially (from 21.8% to 15.2% strain, p less than 0.018), but not radially, and increased the radial extensibility of the fibrosa from 27.7% to 46.1% (p less than 0.0048). These data show that while the ventricularis contains a large amount of elastin, the amount of radially oriented collagen is similar to that of the fibrosa. The fibrosa, by itself, has the same extensibility in both directions (about 23% strain), but can extend much more radially when connected to the rest of the leaflet because it is attached to the ventricularis in a highly folded configuration. The two layers therefore complement each other during aortic valve function, and become detrimentally altered by fixation in glutaraldehyde.     

Evaluation of several economical computational methods for geometry optimization of phosphorus acid derivatives

Several economical methods for geometry optimisation, applicable to larger molecules, have been evaluated for phosphorus acid derivatives. MP2/cc-pVDZ and B3LYP/6-31+G(d) geometry optimizations are used as reference points, results from geometry optimizations for other methods and their subsequent single point energy calculations are compared to these references. The geometries from HF/MIDI! optimizations were close to those of the references and subsequent single point energies with B3LYP/6-31+G(d,p) or EDF1/6-31+G(d) gave a mean average deviation (MAD) of less than 0.5 kcal mol-1 from those obtained with the reference geometries.     

EVALUATION OF SEVERAL ECONOMICAL COMPUTATIONAL METHODS FOR GEOMETRY OPTIMISATION OF PHOSPHORUS ACID DERIVATIVES

Several economical methods for geometry optimisation, applicable to larger molecules, have been evaluated for phosphorus acid derivatives. MP2/cc-pVDZ and B3LYP/6-31+G(d) geometry optimisations are used as reference points, results from geometry optimisations for other methods and their subsequent single point energy calculations are compared to these references. The geometries from HF/MIDI! optimisations were close to those of the references and subsequent single point energies with B3LYP/6-31+G(d,p) or EDF1/6-31+G(d) gave a mean average deviation (MAD) of less than 0.5 kcal mol^?1 from those obtained with the reference geometries.     

Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia

Murine models and association studies in eating disorder (ED) patients have shown a role for the brain-derived neurotrophic factor (BDNF) in eating behavior. Some studies have shown association of BDNF -270C/T single-nucleotide polymorphism (SNP) with bulimia nervosa (BN), while BDNF Val66Met variant has been shown to be associated with both BN and anorexia nervosa (AN). To further test the role of this neurotrophin in humans, we screened 36 SNPs in the BDNF gene and tested for their association with ED and plasma BDNF levels as a quantitative trait. We performed a family-based association study in 106 ED nuclear families and analyzed BDNF blood levels in 110 ED patients and in 50 sib pairs discordant for ED. The rs7124442T/rs11030102C/rs11030119G haplotype was found associated with high BDNF levels (mean BDNF TCG haplotype carriers = 43.6 ng/ml vs. mean others 23.0 ng/ml, P = 0.016) and BN (Z = 2.64; P recessive = 0.008), and the rs7934165A/270T haplotype was associated with AN (Z =-2.64; P additive = 0.008). The comparison of BDNF levels in 50 ED discordant sib pairs showed elevated plasma BDNF levels for the ED group (mean controls = 41.0 vs. mean ED = 52.7; P = 0.004). Our data strongly suggest that altered BDNF levels modulated by BDNF gene variability are associated with the susceptibility to ED, providing physiological evidence that BDNF plays a role in the development of AN and BN, and strongly arguing for its involvement in eating behavior and body weight regulation.     

Immunohistochemical evaluation of pRb2/p130, VEGF, EZH2, p53, p16, p21waf-1, p27, and PCNA in Barrett's esophagus

Control of the G1/S-phase transition as well as angiogenic switch are two of the most studied mechanisms in cancer. The current study examined the correlation between the immunohistochemical expression of pRb2/p130, VEGF, EZH2, p53, p16, p21waf-1, p27, and PCNA in Barrett's esophagus (BE). Overall, p53 showed a much higher expression in BE patients (up to 50%) than in controls (1-10%) (P < 0.005). Also p21 showed a downregulation in BE when compared to normal esophagus (70% of cells vs. 65%), but the difference did not show any statistical significance (P = 0.45). pRb2/p130 was detected in 80% of cells in normal controls, but showed positive in only 20% of cells in BE biopsies. Additionally, Rb2/p130 expression was inversely correlated to that of VEGF, EZH2, and PCNA (P < 0.0001, P = 0.0032, P < 0.001, respectively). p27 stained more intensely and in a widespread manner (70%) cells in normal esophageal tissues but about only 30% in BE samples (P < 0.001). Lastly, in accordance with other reports, we also found p16 expressed by immunohistochemistry at high levels in normal controls and at low levels in BE (P < 0.001). In conclusion, p16, p21, p27, and p53 staining confirmed previously published data. Interestingly, pRb2/p130 expression was found significantly decreased in metaplastic epithelium compared to normal controls and showed significant inverse correlation with the expression of other markers, such as VEGF, EZH2, and PCNA. These data, taken together, indicate that these molecular events occurring in Barrett's metaplasia (BM) may represent one of the many steps taking place during esophageal malignant progression such as impairment of cell-cycle control, altered differentiation, and unbalanced angiogenesis.     

Utilization of raw or heat-treated starch fed in liquid diet to pre-ruminants. 1. Calves.

Five 7-day-old Frisian bull calves, raised in Israel received twice a day a mixture of 40 g of soybean concentrate (65% protein) and 80 g of one of the following carbohydrates: glucose (G), expanded (heat-treated) (ES) or untreated (US) corn starch. In the afternoon the calves received in addition 400 g of milk replacer. Until weaning at experimental day 25, ES calves showed better growth and food utilization than their counterparts. Daily weight gain for the entire growing period up to slaughter was higher for the starch than for the glucose-fed group (P less than 0.05 for ES vs G). Heat treatment of starch increased its in vitro availability to amylase and its in vivo digestibility. Bypass of the rumen was complete in all G calves. In the ES and US groups, partial diversion of the liquid feed into the rumen was evident. The G group showed hyperglycemia after meals, while almost no increase in blood glucose level was observed after soy-starch meals (either US or ES).     

Left ventricular rupture threshold during the healing phase after myocardial infarction in the dog

The mechanical resistance of the infarcted left ventricle to rupture, or rupture threshold, was measured by the balloon technique 1-42 days after left anterior descending coronary artery ligation in 70 dogs: 26 without infarction (18 sham, 8 with ligation) and 44 with infarction. Rupture threshold in noninfarcted hearts was higher than in infarcted hearts (1168 +/- 165 (SD) vs. 754 +/- 223 mmHg (1 mmHg = 133.32 Pa), p less than 0.001) and did not change over 6 weeks. In contrast, rupture threshold in infarcted hearts decreased (p less than or equal to 0.05) after 14 days, the average value for 21-42 days being less than that for 1-14 days: 577 +/- 140 vs. 867 +/- 191 mmHg, p less than 0.001. Passive left ventricular stiffness in infarcted hearts was higher than for noninfarcted hearts throughout the 6 weeks during early filling (11.1 +/- 3.9 vs. 7.1 +/- 1.4 mmHg/mL, p less than 0.001) but decreased (p less than or equal to 0.05) after 14 days during the prerupture phase (11.3 +/- 5.3 vs. 6.2 +/- 3.0 mmHg/mL, p less than 0.005). Between 7 and 42 days, the infarct zone showed marked increase in hydroxyproline (10.0 +/- 2.0 vs. 48.8 +/- 19.7 mg/g dry weight, p less than 0.001), shrinkage (infarct size, 25 +/- 9 vs. 9 +/- 5% of the left ventricle, p less than 0.005), and thinning (infarct to normal wall thickness ratio, 0.83 +/- 0.11 vs. 0.51 +/- 0.09, p less than 0.001) but little further stretching (expansion index or the ratio of lengths of infarcted and noninfarcted segments, 1.14 +/- 0.10 vs. 1.28 +/- 0.17, p less than 0.2). A mild decrease (p less than 0.05) in left atrial pressure and increase (p less than 0.05) in diastolic area and fractional change in area (two-dimensional echocardiography) were detected at 6 weeks. The late decrease in rupture threshold and prerupture stiffness of the infarcted left ventricle and thinning of the scar suggest a late decrease in mechanical strength and resistance of the infarcted left ventricle to distension.     

An Observational Study on the Perceptive and Physiological Variables During a 10,000-m Race Walking Competition

ABSTRACT: Vernillo, G, Agnello, L, Drake, A, Padulo, J, Piacentini, MF, and Torre, AL. An observational study on the perceptive and physiological variables during a 10,000-m race walking competition. J Strength Cond Res 26(10): 2741-2747, 2012-In this study, we observed the variations on physiological and perceptual variables during a self-paced 10,000-m race walking (RW) event with the aim to trace a preliminary performance profile of the distance. In 14 male athletes, the heart rate (HR) was monitored continuously throughout the event. The rating of perceived exertion (RPE) was collected using the Borg's 6-20 RPE scale placed at each 1,000 m of an outdoor tartan track. Pacing data were retrieved from the official race results and presented as percent change compared with the first split time. The athletes spent 95.4% at 90-100% of the HRpeak, whereas the other work (4.6%) was negligible. During the race, a shift toward higher HR values was observed because % HRpeak increased by 3.6% in the last vs. the first 1,000-m sector (p = 0.002, effect size [ES] = 1.55 ± 0.68, large). The mean RPE reported by the athletes in the last 1,000 m was significantly higher than in the first 5 sectors (p < 0.02, ES = 1.93-2.96, large to very large). The mean percent change increased between the first 6 sectors and the last 1,000-m sector (p < 0.01, ES = 1.02-2.1, moderate to very large). The analysis of walking velocity at each 1,000-m sector suggested the adoption of a negative pacing. In conclusion, the RPE may be a valid marker of exercise intensity even in real settings. Match physiological and perceptual data with work rate are required to understand race-related regulatory processes. Pacing should be considered as a conscious behavior decided by the athletes based on the internal feedback during the race.     

The use of real-time monitoring during flywheel resistance training programmes: how can we measure eccentric overload? A systematic review and meta-analysis

This systematic review and meta-analysis aimed to analyse the technologies and main training variables used in the literature to monitor flywheel training devices in real time. In addition, as the main research question, we investigated how eccentric overload can be effectively monitored in relation to the training variable, flywheel shaft type device and the moment of inertia selected. The initial search resulted in 11,621 articles that were filtered to twenty-eight and seventeen articles that met the inclusion criteria for the systematic review and meta-analysis, respectively. The main technologies used included force sensors and rotary/linear encoders, mainly to monitor peak or mean force, power or speed. An eccentric overload was not always achieved using flywheel devices. The eccentric overload measurement was related to the main outcome selected. While mean force (p = 0.011, ES = -0.84) and mean power (p < 0.001, ES = -0.30) favoured the concentric phase, peak power (p < 0.001, ES = 0.78) and peak speed (p < 0.001, ES = 0.37) favoured the eccentric phase. In addition, the lower moments of inertia (i.e., from 0.01 to 0.2 kg·m²) and a cylindrical shaft type (i.e., vs conical pulley) showed higher possibilities to achieve eccentric overload. A wide variety of technologies can be used to monitor flywheel devices, but to achieve eccentric overload, a flywheel cylindrical shaft type with low moments of inertia is advised to be used.     

Expression of C-type natriuretic peptide and of its receptor NPR-B in normal and failing heart

C-type natriuretic peptide (CNP) was recently found in the myocardium, but possible insights into differences between atrium and ventricle production are so far lacking. Our aim was to evaluate, in an experimental model of pacing-induced heart failure (HF), plasma and tissue levels of CNP and mRNA expression of the peptide and of its specific receptor, NPR-B. Cardiac tissue was collected from male adult minipigs without (control, n=5) and with pacing-induced HF (n=5). Blood samples were collected at baseline and after pacing (10 min, 1, 2, 3 weeks). CNP in plasma and in cardiac extracts was determined by a radioimmunoassay, while the expression of mRNA by real time PCR. Compared to control, plasma CNP was increased after 1 week of pacing stress (36.9+/-10.4 pg/ml vs.16.7+/-1.1, p=0.013, mean+/-S.E.M.). As to myocardial extract, at baseline, CNP was found in all cardiac chambers and its content was 10-fold higher in atria than in ventricles (RA: 13.7+/-1.9 pg/mg protein; LA: 8.7+/-3.8; RV: 1.07+/-0.33; LV: 0.93+/-0.17). At 3 weeks of pacing, myocardial levels of CNP in left ventricle were higher than in controls (15.8+/-9.9 pg/mg protein vs. 0.9+/-0.17, p=0.01). CNP gene expression was observed in controls and at 3 weeks of pacing. NPR-B gene expression was found in all cardiac regions analyzed, and a down-regulation was observed in ventricles after HF. The co-localization of the CNP system and NPR-B suggests a possible role of CNP in HF and may prompt novel therapeutical strategies.     

Chest Compression Synchronized Ventilation versus Intermitted Positive Pressure Ventilation during Cardiopulmonary Resuscitation in a Pig Model

BackgroundGuidelines recommend mechanical ventilation with Intermitted Positive Pressure Ventilation (IPPV) during resuscitation. The influence of the novel ventilator mode Chest Compression Synchronized Ventilation (CCSV) on gas exchange and arterial blood pressure compared with IPPV was investigated in a pig model.MethodsIn 12 pigs (general anaesthesia/intubation) ventricular fibrillation was induced and continuous chest compressions were started after 3min. Pigs were mechanically ventilated in a cross-over setting with 5 ventilation periods of 4min each: Ventilation modes were during the first and last period IPPV (100% O₂, tidalvolumes = 7ml/kgKG, respiratoryrate = 10/min), during the 2nd, 3rd and 4th period CCSV (100% O₂), a pressure-controlled and with each chest compression synchronized breathing pattern with three different presets in randomized order. Presets: CCSV_A: P_insp = 60mbar, inspiratorytime = 205ms; CCSV_B: P_insp = 60mbar, inspiratorytime = 265ms; CCSV_C: P_insp = 45mbar, inspiratorytime = 265ms. Blood gas samples were drawn for each period, mean arterial (MAP) and centralvenous (CVP) blood pressures were continuously recorded. Results as median (25%/75%percentiles).ResultsVentilation with each CCSV mode resulted in higher PaO₂ than IPPV: PaO₂: IPPV_first: 19.6(13.9/36.2)kPa, IPPV_last: 22.7(5.4/36.9)kPa (p = 0.77 vs IPPV_first), CCSV_A: 48.9(29.0/58.2)kPa (p = 0.028 vs IPPV_first, p = 0.0001 vs IPPV_last), CCSV_B: 54.0 (43.8/64.1) (p = 0.001 vs IPPV_first, p = 0.0001 vs IPPV_last), CCSV_C: 46.0 (20.2/58.4) (p = 0.006 vs IPPV_first, p = 0.0001 vs IPPV_last). Both the MAP and the difference MAP-CVP did not decrease during twelve minutes CPR with all three presets of CCSV and were higher than the pressures of the last IPPV period.ConclusionsAll patterns of CCSV lead to a higher PaO₂ and avoid an arterial blood pressure drop during resuscitation compared to IPPV in this pig model of cardiac arrest.     

3D Fluid-Structure Interaction Canine Heart Model with Patch to Quantify Mechanical Conditions for Optimal Myocardium Stem Cell Growth and Tissue Regeneration

Right ventricular (RV) dysfunction is a common cause of heart failure in patients with congenital heart defects and often leads to impaired functional capacity and premature death. Myocardial tissue regeneration techniques are being developed for the potential that viable myocardium may be regenerated to replace scar tissues in the heart or used as patch material in heart surgery. 3D computational RV/LV/Patch models with fluid-structure interactions (FSI) were constructed based on data from a healthy dog heart to obtain local fluid dynamics and structural stress/strain information and identify optimal conditions under which tissue regeneration techniques could achieve best outcome. RV/LV/Patch geometry and blood pressure data were obtained from a dog following established procedures. Four FSI models were used to quantify the influence of different patch materials (Dacron scaffold, treated pericardium) on local environment around the patch area, especially focusing on the thickness and stiffness of the patch. Our results indicated that changes in patch stiffness had little impact on the ejection fraction of the right ventricle because the total patch area was small. However, patch stiffness had huge impact on local RV maximum principal stress (Stress-P1) and strain (Strain-P1) around the patch area. Compared to the no-patch model, patch models had increased Stress-P1 and decreased Strain-P1 values in the patch area. Softer patches were associated with greater stress/strain variations. Thinner patch led to complex local flow environment which may have impact on myocytes seeding and RV remodeling. Our multi-physics RV/LV/Patch FSI model can serve as a useful tool to investigate cellular biology and tissue regeneration under localized flow and structural stress environment.     

Changes in 24-h substrate oxidation in older and younger men in response to exercise.

The purpose of this study was to compare 24-h substrate oxidation in older (OM; 60-75 yr, n = 7) and younger (YM; 20-30 yr, n = 7) men studied on sedentary day (Con) and on a day with exercise (Ex; net energy expenditure = 300 kcal). Plasma glucose and free fatty acids were also measured at several time points during the 24-h measurement. Weight was not different in OM and YM (means +/- SD; 84.8 +/- 16.9 vs. 81.4 +/- 10.4 kg, respectively), although percent body fat was slightly higher in OM (25.9 +/- 3.5 vs. 21.9 +/- 9.7%; P = 0.17).Values of 24-h energy expenditure did not differ in OM and YM on the Con (means +/- SE; 2,449 +/- 162 vs. 2,484 +/- 104 kcal/day, respectively) or Ex (2,902 +/- 154 vs. 2,978 +/- 122 kcal/day) days. Under both conditions, 24-h respiratory quotient was significantly lower and fat oxidation significantly higher in OM. Glucose concentrations were not different at any time point, but plasma free fatty acid concentrations were higher in OM, particularly following meals. Thus, under these controlled conditions, 24-h fat oxidation was not reduced and was in fact greater in OM. We speculate that differences in the availability of circulating free fatty acids in the postprandial state contributed to the observed differences in 24-h fat oxidation in OM and YM.     

Body composition and performance: influence of sport and gender among adolescents

Body composition is well known to be associated with endurance performance among adult skiers; however, the association among adolescent crosscountry and alpine skiers is inadequately explored. The study sample comprised 145 male and female adolescent subjects (aged 15-17 years), including 48 crosscountry skiers, 33 alpine skiers, and 68 control subjects. Body composition (%body fat [BF], %lean mass [LM], bone mineral density [grams per centimeter squared]) was measured with a dual-emission x-ray absorptiometer, and pulse and oxygen uptake was measured at 3 break points during incremental performance tests to determine physical fitness levels. Female crosscountry and alpine skiers were found to have significantly higher %LM (mean difference = 7.7%, p < 0.001) and lower %BF (mean difference = 8.1%, p < 0.001) than did female control subjects. Male crosscountry skiers were found to have lower %BF (mean difference = 3.2%, p < 0.05) and higher %LM (mean difference = 3.3%, p < 0.01) than did male alpine skiers and higher %LM (mean difference = 3.7%, p < 0.05) and %BF (mean difference = 3.2%, p < 0.05) than did controls. This study found strong associations between %LM and the onset of blood lactate accumulation and VO2max weight adjusted thresholds among both genders of the crosscountry skiing cohort (r = 0.47-0.67, p < 0.05) and the female alpine-skiing cohort (r = 0.77-0.79, p < 0.001 for all). This study suggests that body composition is associated with physical performance amongst adolescents.     

Hypersensitivity of ataxia telangiectasia skin fibroblasts to DNA alkylating agents

3 ataxia telangiectasia (AT) fibroblast cell strains, AT4BI, AT5BI and AT2BE (CRL1343) were studied for their colony-forming ability after treatment with various concentrations of 4 different DNA alkylating agents. The results were compared to the response of fibroblast strains from 3 normal individuals. None of the AT strains were abnormally sensitive to N-methyl-N'-nitro-N-nitrosoguanidine. 1 strain (AT5BI) was significantly more sensitive to treatment with methyl methanesulfonate (MMS) based on a survival curve D0 value of 0.29 mM vs. the normal average D0 of 0.38 mM (P less than 0.02) and a D10 value of 0.85 mM vs. the normal average D10 of 1.2 mM (P less than 0.025). Strain AT4BI was also significantly more sensitive to MMS treatment when D10 values were compared (0.73 mM, P less than 0.01). All 3 AT cell strains were significantly more sensitive to treatment with ethyl methanesulfonate when D10 values were the criterion of sensitivity, AT4BI 16 mM, AT5BI 13 mM and AT2BE 15 mM vs. the normal human fibroblast average D10 value of 28 mM (P less than 0.01 for all 3 AT strains). 2 of the 3 AT cell strains (AT4BI and AT2BE) were abnormally sensitive to treatment with 4-nitroquinoline-1-oxide; the D0 values were 0.045 microM and 0.05 microM, respectively, vs. the normal average D0 value of 0.11 microM (P less than 0.01 for both AT strains). The corresponding D10 values were 0.08 microM and 0.11 microM, respectively, vs. the normal average D10 value of 0.27 microM (P less than 0.01 for AT4BI and P less than 0.025 for AT2BE). These results indicate that there is a heterogeneity in the response of AT fibroblast cell strains to treatment with DNA alkylating agents, except possibly in the case of ethylating compounds.