Search PubMed⌕ Search

Biomedical subjects

J Bernier

Publications and source records attributed to J Bernier.

At least 55 records · Page 3Linked to original sources

Tumor response, mucosal reactions and late effects after conventional and hyperfractionated radiotherapy.

BACKGROUND: Relationships between normal tissue reactions and tumor response to radiotherapy have generally been investigated in retrospective studies, with the attendant difficulties such as different times of treatment and lack of standard scales for scoring of normal tissue reactions. This study analyses the correlation between normal tissue reactions and tumor response in a randomized trial of hyperfractionation versus conventional radiotherapy. MATERIALS AND METHODS: EORTC trial 22791, which accrued 325 T2-3, N0-1 and M0 oropharynx squamous cell carcinomas, compared conventional radiotherapy (70 Gy in 7 weeks) to a hyperfractionated regime (two daily irradiations of 1.15 Gy up to 80.5 Gy in 7 weeks). Acute and late toxicities were assessed according to the RTOG/EORTC scales. The variables were tumor regression at treatment completion, tumor control for unlimited follow-up, severity of acute mucosal reactions (grade of the peak reaction, time to onset of grade 2 mucositis, or duration of acute reactions of grade 3) and severity of late effects in normal tissues (late ulceration, cervical edema secondary to lymphatic drainage damage, late muscular fibrosis, or late mucosal necrosis as consequential damage). Kendall's rank correlation was used to assess the levels of significance of the correlation. The 95% confidence interval (95% CI) was calculated for each correlation tau-b coefficient. RESULTS: Irradiation doses and overall treatment times were consistent between the treatment arms. The time to onset of patchy mucosal reactions was inversely correlated to tumor regression at treatment completion in the hyperfractionated arm (arm 2) but not in the conventional fractionation arm (arm 1). The other significant correlations were restricted to the following pairs of end-points and patient subgroups: acute mucositis of grade 3 versus tumor regression at the end of treatment in arm 2 for T2 tumors, late ulceration versus tumor control in arm 2 and acute mucosal reactions versus late effects in normal tissues in arm 2 for T3 tumors. By and large, the 95% CIs for Kendall's tau-b included zero and did not include 0.5, an indication that the comparison had sufficient power to detect a difference, if indeed one existed. CONCLUSIONS: These results do not represent clinical evidence strong enough to demonstrate that individual differences in sensitivity influence the response of tumors to radiation.

Carcinoma, Squamous Cell↗

Pharmacokinetics of nicotinamide in cancer patients treated with accelerated radiotherapy: the experience of the Co-operative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer.

BACKGROUND: The EORTC has initiated studies to combine nicotinamide with carbogen in accelerated fractionation schedules (ARCON), since for some tumour types, acute and chronic hypoxia as well as treatment protraction may prejudice the outcome of radiotherapy. The tolerable dose of nicotinamide and the optimal interval for administration need to be ascertained. AIM: Full pharmacokinetic profiles of nicotinamide concentrations in plasma were analyzed repeatedly in 15 patients to determine the inter- and intra-patient variability in peak plasma concentrations and the optimum times for administering nicotinamide as a radiosensitizer. METHODS: Nicotinamide (Nicobion) was administered in tablet form to patients with advanced head and neck and non-small cell lung carcinomas. A standard 6 g dose was given regardless of body weight after an overnight fast and at least 30 min before breakfast. In 15 patients, blood samples were taken prior to and 1, 2, 4, 6, 8, 12 and 24 h after administration of the drug. This full profile was determined on two to four occasions for the head and neck cancer patients and on two occasions for the lung cancer patients. For each profile, the maximum concentration of nicotinamide (Cmax), time to peak plasma concentration (Tmax), elimination half-lives (t1/2) and area under the curve (AUC) were determined. Compliance was recorded and nausea and vomiting were graded on a 0-3 scale. Complete profiles of the five major metabolites were also obtained. RESULTS: In the 48 complete sets of blood samples, peak plasma concentrations ranged from 787 to 2312 nmol/ml with a median value of 1166 nmol/ml. The peak plasma concentration was achieved at 1 h in only 54% of the pharmacokinetic profiles, but at this time 92% of the profiles had already exceeded the target concentration of 700 nmol/ml, the level required in the mouse for tumour radiosensitization. The median t1/2 for all 15 cases was 9.3 h, with minimum and maximum values of 4.2 and 26.8 h. The highest concentrations of nicotinamide metabolites were found to be the N-oxide, 2-pyridone and 1-methylnicotinamide. The toxicity (nausea and vomiting) was scored and found not to be correlated with any of the pharmacokinetic parameters. CONCLUSIONS: The plasma concentrations considered necessary to radiosensitize can easily be exceeded with a dose of 6 g taken as 12 x 500 mg in tablet form; 700 nmol/ml was achieved in all patients and apparently would have been achieved in most even with a considerable reduction in dose. An adequate time between administration and radiotherapy appeared to be 1 h with this drug formulation for 92% of the profiles.

Administration, Oral↗

Decreased corticosteroid-binding globulin in burn patients: relationship with interleukin-6 and fat in nutritional support.

OBJECTIVES: To analyze the effect of low-fat nutritional solutions, with or without fish oil, on serum interleukin (IL)-6, and to explore the relationships between IL-6, corticosteroid-binding globulin (CBG; the main cortisol carrier in plasma), and protein metabolism in severely burned adult patients. DESIGN: Randomized, double-blind study with control and low fat-fed groups. SETTING: Burn center of Hôtel-Dieu Hospital of Montréal. PATIENTS: Thirty-seven men and women with thermal burn injury over >20% of body surface area and no other known medical condition. INTERVENTIONS: Within 24 hrs after admission, nutritional support was started through a gastroenteral tube inserted under endoscopic guidance. The goal for energy intake was calculated using the Curreri formula, and was adjusted with biweekly measurements of resting energy expenditure. Patients were randomly assigned to one of the following groups: control (35% of energy as fat); low fat 1 (15% of energy as fat); and low fat 2 (50% of fat in the form of fish oil). MEASUREMENTS AND MAIN RESULTS: Tumor necrosis factor (TNF)-alpha and TNF-beta, IL-6, CBG, and cortisol free fraction were measured every 3 days for 28 days. Nitrogen balance and urinary 3-methylhistidine excretion were measured daily. IL-6 concentrations were high in all patients, with the highest value (460 +/- 111 units/mL) observed on day 4. Concentrations of IL-6 were higher in control patients than in low fat-fed patients between days 13 and 28, but not between days 1 and 13. Multivariate analysis showed that IL-6, total body surface area burned, and sepsis scores were independent predictors of CBG between days 1 and 13 (n = 170; p<.00001). High IL-6 concentrations were predictors of low CBG concentrations and high cortisol free fractions. There was no relationship between IL-6, nitrogen balance, and 3-methylhistidine excretion. TNF-alpha and TNF-beta activity measurements by biological assay showed no correlation with other factors measured. CONCLUSIONS: a) Low-fat feeding, with or without fish oil, does not change the early production of IL-6 after burn injury; b) serum IL-6 is negatively correlated with CBG, which supports the hypothesis that this cytokine inhibits hepatic CBG production; and c) IL-6 does not appear to directly influence protein metabolism in burn patients.

Adult↗

Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin.

BACKGROUND: We conducted a randomized, prospective trial comparing external irradiation with external irradiation plus goserelin (an agonist analogue of gonadotropin-releasing hormone that reduces testosterone secretion) in patients with locally advanced prostate cancer. METHODS: From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. The patients had a median age of 71 years (range, 51 to 80). Patients in both groups received 50 Gy of radiation to the pelvis over a period of five weeks and an additional 20 Gy over an additional two weeks as a prostatic boost. Patients in the combined-treatment group received 3.6 mg of goserelin (Zoladex) subcutaneously every four weeks starting on the first day of irradiation and continuing for three years; those patients also received cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone associated with the administration of goserelin. RESULTS: Data were available for analysis on 401 patients. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at five years were 79 percent (95 percent confidence interval, 72 to 86 percent) in the combined-treatment group and 62 percent (95 percent confidence interval, 52 to 72 percent) in the radiotherapy group (P=0.001). The proportion of surviving patients who were free of disease at five years was 85 percent (95 percent confidence interval, 78 to 92 percent) in the combined-treatment group and 48 percent (95 percent confidence interval, 38 to 58 percent) in the radiotherapy group (P<0.001). CONCLUSIONS: Adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer.

Adenocarcinoma↗

Immunomodulatory and protective effects of N-acetylcysteine in mitogen-activated murine splenocytes in vitro.

N-Acetylcysteine (NAC) is a pro-glutathione drug used to treat chronic lung disorders and because of its anti-AIDS virus activity in vitro, has been proposed for AIDS therapy. The effect of NAC on mitogen-activated-lymphocyte blastogenesis in C57B1/6 mouse splenocytes and ability of NAC to protect lymphocytes against mitogen-induced cytotoxicity was examined in vitro. NAC increased splenocyte proliferation in the presence of optimal and suboptimal concentrations of concanavalin A (Con A) and lipopolysaccharide (LPS). Stimulatory and costimulatory effects of NAC on mitogen-induced responses were also evident. The dose-response relationship describing the effects of NAC on lymphocyte proliferation with Con A-induced responses were enhanced in a dose-dependent manner, whereas the corresponding LPS-induced responses increased to a maximum level followed by decline in responses at higher concentrations of NAC. When splenocytes were incubated with inhibitory supraoptimal concentrations of Con A (10 microg/ml) or LPS (150 microg/ml), NAC partially enhanced the Con A-induced response but completely prevented the inhibitory effect of supraoptimal concentrations of LPS on splenocyte blastogenesis. Optimal and supraoptimal concentrations of Con A caused activation-induced cell death in the splenocytes whereas comparable concentrations of LPS did not produce a similar effect. Splenocyte cell death produced by the optimal mitogenic concentrations of Con A was completely blocked by the addition of NAC to cultures. Immunomodulation and protective effects of NAC were observed in mitogen-activated lymphocytes in vitro.

Acetylcysteine↗

Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy.

PURPOSE: The effect of hyaluronic acid (Ialugen cream) on acute skin reactions after radiotherapy, was assessed in a randomized, double-blind, placebo-controlled study. MATERIAL AND METHODS: Out of the 152 patients presenting with head and neck, breast or pelvic carcinomas and registered in the study, 134 cases-70 in the Ialugen group (IA) and 64 in the placebo group (PBO)-completed their IA or PBO treatment. At the time of randomisation, these two groups were balanced for sex, age, weight and height. The mean total dose of radiation given during the study was 60.6 +/- 10.9 Gy in the IA group and 64.3 +/- 10.8 Gy in the PBO group (P = 0.47). RESULTS: Acute radio-epithelitis scores were significantly higher in the PBO group than in the IA group, starting from the control at week 3 and throughout the 6 weeks of treatment (P < 0.01 from week 3 to week 7; P < 0.05 at weeks 8 and 10). Likewise, the global efficacy judgement expressed, at the end of treatment, by both the physician and the patient showed a significant difference in favour of Ialugen (P < 0.01 and P < 0.05, respectively). There was no significant difference of tolerance between the IA and PBO treatments (P = 0.18 according to the physician and P = 0.42 from the patient's viewpoint). CONCLUSION: The prophylactic use of a cream with hyaluronic acid is shown to reduce the incidence of high grade radio-epithelitis, suggesting an interesting role of the hyaluronic acid cream as supportive treatment to improve compliance and quality of life in patients undergoing radiation therapy.

Adult↗

Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial.

BACKGROUND AND PURPOSE: A 5 week-hyperfractionated and accelerated radiotherapy regimen without reduction of the total dose was developed to fight tumour repopulation during treatment and tumour hypoxia. The purpose of the study was to try to improve loco-regional control in high risk head and neck carcinoma treated with curative radiotherapy. METHODS AND MATERIALS: From 1985 to 1995, a randomised controlled trial of the EORTC Cooperative Group of Radiotherapy (EORTC 22851) compared the experimental regimen (72 Gy/45 fractions/5 weeks) to standard fractionation and overall treatment time (70 Gy/35 fractions/7 weeks) in T2, T3 and T4 head and neck cancers (hypopharynx excluded). The end-point criteria were local and loco-regional control, overall and disease-free survival, and acute and late toxicities. Five hundred twelve patients were accrued. RESULTS: Patients in the AF (accelerated fractionation) arm did significantly better with regard to loco-regional control (P = 0.02) resulting at 5 years in a 13% gain (95% CI 3-23% gain) in loco-regional control over the CF (conventional fractionation) arm. This improvement is of larger magnitude in patients with poorer prognosis (N2-3 any T, T4 any N) than in patients with more favourable stage. Multivariate analysis confirmed AF as an independent prognostic factor of good prognosis for loco-regional control (P = 0.03). Specific survival shows a trend (P = 0.06) in favour of the AF arm. ACUTE AND LATE TOXICITIES: Acute and late toxicity were increased in the AF arm. Late severe functional irradiation damage occurred in 14% of patients of the AF arm versus 4% in the CF arm. Two cases of radiation-induced myelitis occurred after doses of 42 and 48 Gy to the spinal cord. CONCLUSIONS: This trial shows that accelerated radiotherapy improves loco-regional control in head and neck squamous cell carcinomas. A less toxic scheme should, however, be investigated and documented before using accelerated radiotherapy as a standard regimen of curative radiotherapy for head and neck cancers.

Adult↗

[Late effects of radiotherapy on the neuroendocrine system].

When the hypothalamic-pituitary axis (HPA) is included in the treatment field in children and adults, a variety of neuroendocrine disturbances are more common than has been appreciated in the past. Clinical damage to the pituitary and thyroid glands usually occurs months to years after treatment, and is preceded by a long subclinical phase. Primary brain tumors represent the largest group of malignant solid tumors in children. The survival rates of 50% reported in the literature are achieved at the expense of late occurring effects. Radiation-induced abnormalities are generally dose-dependent. Growth hormone deficiency and premature sexual development can occur at doses as low as 18 Gy in conventional fractionation, and is the most common neuroendocrine problem in children. In patients treated with > 40 Gy on the HPA, deficiency of gonadotropins, thyroid stimulating hormone, and adrenocorticotropin can be found. Following high-dose radiotherapy (> 50 Gy), hyperprolactinemia can be seen, especially among young women. Most neuroendocrine disturbances that develop as a result of HPA can be treated efficiently, provided that an early detection of these endocrine dysfunctions abnormalities is done.

Adult↗

Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group.

PURPOSE: A controversy exists regarding whether it is safe to delay radiation therapy until the completion of chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. Within the context of two concurrent randomized clinical trials we had the opportunity to evaluate outcomes for patients who received breast irradiation after completing different durations of chemotherapy. METHODS AND MATERIALS: From July 1986 to April 1993 the International Breast Cancer Study Group (IBCSG) Trial VI randomly assigned 1554 pre/perimenopausal node-positive breast cancer patients to receive cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for either three consecutive courses on months 1-3, or six consecutive courses on months 1-6, both with or without reintroduction CMF. IBCSG Trial VII randomly assigned 1266 postmenopausal node-positive breast cancer patients to receive tamoxifen for 5 years, or tamoxifen for 5 years with three early cycles of CMF, both with or without three courses of delayed CMF. Both trials allowed a choice of mastectomy, or breast-conserving surgery plus radiation therapy, and both were stratified by type of surgery. Radiotherapy was delayed until the initial block of CMF was completed; 4 or 7 months after surgery for pre/perimenopausal patients, and 2 or 4 months after surgery for postmenopausal patients. Over both trials, 718 eligible patients elected to receive breast-conserving surgery plus radiation therapy: 433 on Trial VI, and 285 on Trial VII. Four-year actuarial total failure rates (failure at any site), risks of developing distant metastases (DM at any time during observation), and overall survival (OS) were estimated using the Kaplan-Meier method. To avoid potential bias due to competing causes of failure, only patients who could be followed for at least 4 years (enrolled prior to July 1, 1990) were used to evaluate the patterns of first relapse site. Crude percents of local failure with or without other sites (LF), distant metastases including regional nodal failure (DM/RNF), or other first events (second primaries/death without recurrence) were estimated for each treatment group. For this report, an intent to treat analysis was performed at a median follow-up of 48 months. RESULTS: No differences were found in the 4-year actuarial total failure rates, risk of developing distant metastases, and overall survival among the two radiotherapy groups of each study. The cumulative incidence of types of first failure and the 4-year crude rates showed no treatment differences in the patterns of site of first event. Estimates for the 4-year crude percent of local failures were 8 and 9% for pre/perimenopausal patients who had radiation therapy at 4 or 7 months after surgery, and 3 and 6% for postmenopausal patients who had radiation therapy at 2 months or 4 months after surgery. CONCLUSIONS: For node positive patients receiving breast-conserving surgery followed by radiation therapy, the incidence of breast recurrence in the conserved ipsilateral breast within 4 years was between 8 and 9% for pre/perimenopausal patients and between 3 and 6% for postmenopausal patients. After 48 months of median follow-up, administering radiation therapy after three or six cycles of CMF for pre/perimenopausal women, or after no cycles or three cycles of CMF for postmenopausal women does not influence overall efficacy or local control in this series.

Adult↗

Profile of radiotherapy departments contributing to the Cooperative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer.

PURPOSE: Since 1982, the Radiotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC) is carrying out a Quality Assurance program that includes the evaluation of the structure and human resources of 50 centers actively participating in protocols of clinical research in radiotherapy. METHODS AND MATERIALS: One or two site visits were made by a team of radiation physicists and physicians. A detailed questionnaire was circulated to these radiotherapy centers to collect and update standardized figures on the status and activities of each center, to clarify some obscurities encountered during on-site visits, and to extend investigations to issues that were not addressed during local audits. RESULTS: This article reports on departmental infrastructure, staff and equipment workload, and quality control procedures carried out by single institutions. Large variations in equipment and staff are observed among participating centers. Comparisons between data collected in the early 1980s and during a recent update show no difference in workload per megavoltage equipment and per simulator. The number of cancer patients treated per year per radiotherapist seems to slightly diminish, especially in centers that experienced a considerable staff shortage a few years ago. The most significant improvement is observed for the number of cases treated per year per member of the radiation physics team. The radiographer's workload shows an opposite trend. CONCLUSIONS: Our database provides participating centers with strong comparative arguments to correct staff and equipment unbalances and to convince administrative authorities of priorities in decision making. The current analysis shows that the situation for equipment is unchanged in comparison with that observed 6 years ago. Efforts have to be put forth in some institutions to reduce the workload at simulators. A tentative profile and guidelines for minimum recommendations for European radiotherapy departments involved in clinical research are presented.

Cancer Care Facilities↗

Immune functions in beluga whales (Delphinapterus leucas): evaluation of mitogen-induced blastic transformation of lymphocytes from peripheral blood, spleen and thymus.

A quantitative assay was developed to evaluate mitogen-induced lymphoblastic transformation in beluga whales (Delphinapterus leucas) using peripheral blood mononuclear cells, splenocytes and thymocytes. Optimal concentrations of four different mitogens (Con-A, PHA, LPS and PWM) were determined with the use of standard curves. Addition of human recombinant IL-2 (rhIL-2) after 48 h in culture with the different mitogens suggests that Con-A, PHA and PWM, but not LPS, stimulate T cells in belugas, as they do in other animal species. The addition of 2-mercaptoethanol did not enhance significantly the proliferation of cells stimulated by Con-A, PHA and LPS, while it did with the cells stimulated by PWM and those cultured without mitogen. The proliferative response of cells was suppressed when the culture medium was supplemented by beluga serum instead of fetal calf serum. This assay will be useful to assess the status of the immune functions in different populations of beluga whales as well for further in vitro immunotoxicological experiments.

Animals↗

Quality assessment: is the focus on providers or on patients?

Most studies of ambulatory care quality are based on chart reviews of episodes of care in single settings, rather than on care received by a patient over time and across settings. The purpose of this study was to compare ambulatory care quality scores based on information from the usual source of care to scores based on information from all providers seen during a year. The quality of well child care for 55 two-year-olds and asthma care for 70 children and adults continuously enrolled in the Maryland Medicaid program throughout 1988 was assessed. Combining data from multiple providers changed quality scores in both directions. For well child care, quality scores generally improved because of an increased opportunity to perform desirable actions, such as lead screening. However, quality scores for asthma care generally decreased because undesirable clinician actions, such as the failure to document follow-up plans, increased as more problems were uncovered. Thus, the findings of quality assessments differ according to whether the focus is on care delivered by individual providers or on care received by patients. The direction of the difference will depend upon whether the indicators of quality represent omission of recommended care or commission of improper care.

Adult↗

Immunotoxicity of aminocarb. III. Exposure route-dependent immunomodulation by aminocarb in mice.

Aminocarb, a phenylsubstituted methylcarbamate pesticide (4-dimethylamino-3-methyl-N-carbamate; matacil), previously suspected of a relatively low immunotoxic potential, was administered by four different exposure routes to C57BL/6 mice. A single sublethal exposure by oral and dermal routes stimulated humoral immune response at a relatively low dose; 1/256 LD50 of aminocarb. Intraperitoneal (i.p.) injection decreased the humoral PFC response, whereas inhalation of aminocarb had no marked effect on peripheral immune status in exposed animals. Thus, i.p. exposure resulted in higher immunotoxicity over oral administration of aminocarb. Similarly, marked route-related exposure differences in immunomodulatory effects of aminocarb were noted for mitogenic stimulation of spleen lymphocytes and mixed lymphocyte response. Other indices, such as delayed type hypersensitivity (DTH) and production of interleukin-2 (IL-2) were unchanged. Interestingly, expression of major histocompatibility complex (MHC) class II by purified, lipopolysaccharide (LPS)-stimulated B cells increased equally after i.p. and oral exposures to aminocarb. Overall, a weak immunosuppressive potential of aminocarb was concluded, which was possibly due to indirect interaction of the pesticide with the immune system. However, aminocarb may represent an autoimmunity-inducing toxic.

Administration, Cutaneous↗

Decreased interleukin-2 receptor and cell cycle changes in murine lymphocytes exposed in vitro to low doses of cadmium chloride.

Relationships between in vitro cadmium-related cell cytotoxicity, ultrastructural changes and altered cell cycle were determined at 21-72 h after mitogenic stimulation of C57BL/6 mouse spleen lymphocytes with concanavalin A (Con A). Relatively low doses, 0.6-10 microM cadmium (Cd), added at 4 h after the mitogen activation, induced a significant cell cytotoxicity and reduced the lymphoblastic activity of the cells. Cytometric analysis of the lymphoid cell cycle at 72 h revealed that at concentrations > or = 0.6 microM Cd, the number of cells arrested in G0 + G1 phase increased, whereas the proportions of cells of the S and G2 + M phases were substantially reduced. Staining of cells with fluorescent anti-CD25 monoclonal antibody showed a cadmium-related decreased number and relative mean fluorescence of CD25+ cells, demonstrating a decreased level of interleukin-2 receptor (IL-2R). Furthermore, immunogold ultramicroscopic assay was developed for determination of intracellular interleukin-2 (IL-2) in cadmium-treated lymphocytes. The level of cytoplasmic and nuclear IL-2, localized in situ by colloidal gold ultraimmunocytochemical technique, has been estimated as markedly decreased in cells treated with > or = 1.2 microM Cd, as compared with the untreated controls. Disorganization/fragmentation of mitochondrion cristae and dilatation of cisternae of the Golgi apparatus appeared as the major ultrastructural change in 1.2 microM Cd-treated lymphocytes. Interestingly, addition of cadmium in the incubation medium, up to 4 h after mitogen activation, also interacted with lymphoproliferative mechanisms of cells in G0 + G1, S and G2 + M phase. Overall, multiple ultrastructural changes of Cd-treated lymphoid cells were clearly related with the reduced cell viability and reduced number of activated lymphoblasts.

Animals↗