Recognition of Leukaemia Cells as Foreign before and after Autoimmunization

Leukaemia cells in the peripheral blood of nine patients with acute leukaemia were removed and stored. When the patients had been brought into haematological remission these leukaemia cells were cultured with autologous lymphocytes both before and after the patients had been autoimmunized with their own irradiated leukaemia cells. The extent to which the leukaemia cells stimulated the “normal lymphocytes” was increased as the result of autoimmunization.The implications of the use of this test for determining the best regimen for “immunotherapy” in acute leukaemia are discussed.     

In vitro generation of tumour-specific lymphocyte reactivity to colonic carcinoma cells

Summary Purified tumour cells and normal mucosa cells from fresh human colorectal cancer resection specimens, and T-cell-enriched autologous peripheral blood lymphocytes, were mixed in short-term (6 day) mixed lymphocytetumour cell (MLTC) microcultures. Lymphocyte stimulation was measured by ³H-thymidine uptake, and a stimulation index (SI=[lymphocytes vs tumour cells (cpm)–tumour cells (cpm)]/[lymphocytes (cpm)])>3 was regarded as significant. Significant lymphocyte reactivity was found in 10/15 patients with colon carcinoma. However, 1 patient with autologous tumour reactivity, also showed significant stimulation against autologous normal mucosa cells, suggesting tumour-associated reactivity. Maximum stimulation occurred most frequently at a lymphocyte:tumour cell ratio of 2:1 and with nylon wool-passaged lymphocytes.Project was supported by a grant from the Cancer Research CampaignSupported by New South Wales Cancer Council Fellowship     

Early life determinants of physical activity in 11 to 12 year olds: cohort study

Objective To examine factors in early life (up to age 5 years) that are associated with objectively measured physical activity in 11-12 year olds.Design Prospective cohort study.Setting Avon longitudinal study of parents and children, United Kingdom. Participants Children aged 11-12 years from the Avon longitudinal study of parents and children.Main outcome measure Physical activity levels in counts per minute (cpm) and minutes of moderate to vigorous physical activity for seven days measured with a uniaxial actigraph accelerometer.Results Valid actigraph data, defined as at least three days of physical activity for at least 10 hours a day, were collected from 5451 children. Several factors were associated with physical activity at ages 11-12 years. Regression coefficients are compared with the baseline of “none” for categorical variables: maternal brisk walking during pregnancy (regression coefficient 5.0, 95% confidence interval −8.5 to 18.5; cpm for <1 h/wk and ≥2 h/wk of physical activity 17.7, 5.3 to 30.1), maternal swimming during pregnancy (21.5, 10.9 to 32.1 and cpm for <1 h/wk and ≥2 h/wk of physical activity 24.2, 7.8 to 40.7), parents’ physical activity when the child was aged 21 months (28.5, 15.2 to 41.8 and cpm of physical activity for either parent active and both parents active 33.5, 17.8 to 49.3), and parity assessed during pregnancy (2.9, −7.6 to 13.4 and cpm of physical activity for 1 and ≥2 parity 21.2, 7.1 to 35.3).Conclusions Few factors in early life predicted later physical activity in 11-12 year olds. Parents’ physical activity during pregnancy and early in the child’s life showed a modest association with physical activity of the child at age 11-12 years, suggesting that active parents tend to raise active children. Helping parents to increase their physical activity therefore may promote children’s activity.     

Bone-marrow relapse in acute lymphoblastic leukaemia in childhood.

The outcome after bone-marrow relapse was assessed in 53 children with acute lymphoblastic leukaemia (ALL). Twenty-five out of 37 children (67%) whose first remission ended in relapse during treatment (group A) achieved a second remission, as did 15 out of 16 (94%) who relapsed after treatment had been stopped (group B). Nevertheless, the median duration of second remission was only 12 weeks in group A and 35 weeks in group B. The median survival from time of relapse was 32 weeks in group A and 75 weeks in group B. It is concluded that marrow relapse is equally serious whether it occurs during treatment or after treatment has been stopped, and that most children with ALL have a single chance of cure at the time of diagnosis.     

Movement Discordance between Healthy and Non-Healthy US Adults

Introduction

Physical activity is known to significantly impact cardiometabolic health. Accelerometer data, as a measure of physical activity, can be used to objectively identify a disparity in movement (movement discordance) between healthy and unhealthy adults. The purpose of this study was to examine the Movement Discordance between healthy and unhealthy adults in a large US population sample.

Methods

Demographic, health and accelerometer data from the National Health and Nutrition Examination Study (NHANES) 2003–2004 and 2005–2006 cohorts were used for this study. Participants were classified as either having a “normal” or “abnormal” value for each cardiometabolic health parameter examined, based on published criteria. Linear regression analyses were performed to determine significance of each abnormal health parameter (risk factor) in its unique effect on the accelerometer counts, controlling for age and gender. Average accelerometer counts per minute (cpm) by gender and age categories were estimated separately for the groups of normal and abnormal cardiometabolic risk.

Results

Average cpm for those with healthy levels of each individual cardiometabolic health parameter range from 296 cpm (for C reactive protein) to 337 cpm (for waist circumference), while average cpm for those with abnormal levels of each individual cardiometabolic health parameter range from 216 cpm (for insulin) to 291 cpm (for LDL-cholesterol). After controlling for age and gender, waist circumference, HbA1c, Insulin, Homocysteine, and HDL-Cholesterol were the cardiometabolic health parameters that showed significant, unique and independent effects on cpm. Overall, individuals who have abnormal values for all significant cardiometabolic health parameters (“unhealthy”) averaged 267 cpm (SE = 15 cpm), while the healthy sample of this study averaged 428 cpm (SE = 10 cpm). The difference in cpm between the unhealthy and healthy groups is similar between males and females. Further, for both males and females, the cpm gap between unhealthy and healthy is largest in the 30s (males: 183 cpm; females 144 cpm) and lessens as age increases, with the lowest gap seen in those 80+ years (males, 81 cpm; females, 85 cpm).

Conclusion

This Movement Discordance between healthy and unhealthy adults represents a gap in movement that needs to be closed to improve the health of individuals with, or at risk for cardiometabolic disease.     

Spontaneous and busulphan-induced sister-chromatid exchange (SCE) frequencies in haematologically normal human bone marrow and lymphocytes

In a study of 14 patients who were not treated with either chemotherapy or irradiation, 13 patients had lower siste-chromatid exchange (SCE) frequencies in their bone-marrow cells than in their lymphocytes. For both bone marrow and lymphocytes, there was significant inter-patient variability in SCE frequencies, but there was no correlation between the bone-marrow and lymphocyte values.

The effect of exposing bone-marrow cells to busulphan (BUS) in vitro was investigated using doses up to 5.0 μg/ml. The dose-response relationships between BUS and SCEs in vitro were found to be similar for bone marrow and lymphocytes.     

Treatment of Acute Lymphoblastic Leukaemia: PRELIMINARY REPORT BY THE LEUKAEMIA COMMITTEE AND THE WORKING PARTY ON LEUKAEMIA IN CHILDHOOD

One hundred and ninety-one cases of acute lymphoblastic leukaemia were entered in a trial in which, for five months, all received cytotoxic therapy with prednisolone, vincristine, mercaptopurine, L-asparaginase, and methotrexate (the latter in high dosage followed by folinic acid). Patients were then randomized to receive immunotherapy (B.C.G.), twice-weekly methotrexate, or no further treatment.One hundred and seventy-seven patients (93%) achieved full remission and at the time of analysis, 26 months from the beginning of the trial, 143 were still alive, including 70 in their first remission. Median “post-intensive” remission lengths were 17 weeks (no treatment), 27 weeks (B.C.G.), and 52 weeks (methotrexate). The prolongation of remission by methotrexate was most evident in those patients with low initial white cell counts. B.C.G. seemed to cause lymphocytosis but was without other conspicuous effect. The incidence of toxic reactions is reported, including an unusually low rate of anaphylaxis with L-asparaginase.These preliminary results are discussed and compared with those of similar trials.     

Leukemia in Animals and Man

General comparative aspects of leukemia were reviewed. Leukemia in adult cattle occurs frequently within certain multiple case herds. Cattle in these herds often have persistent lymphocytosis and increased numbers of atypical lymphocytes in blood. Attempts are being made to demonstrate the frequency in which this is a “pre-leukemic” or “perileukemic” condition.With the recognition of viral causative agent(s) in chickens, laboratory rodents and cats, there is increased interest in the leukemia of dogs, cattle and other animals, for the disease in these animals may serve as valuable models in the study and isolation of human leukemogenic agents.Epidemiologic and clinicopathologic aspects of animal leukemias share comparative similarities with themselves and with lymphoreticular neoplasms of man. Causative factor(s) probably act on the host, regardless of species, in a similar fashion. It is not likely, but neither improbable, that leukemia in domesticated animals and leukemia in man share common causal relationships.     

Obesity and Respiratory Infection in Infants and Young Children

A controlled trial has been carried out to test the widely held “clinical impression” that overweight infants have a greater liability to respiratory infections than those of normal weight. Two matched groups of children aged between 3 months and 2 years were studied, containing children whose weight was above the 90th percentile, or was between the 25th and 75th percentiles, at the start of the trial.Data from 120 children of the overweight group were available for analysis, of whom 47 experienced at least one respiratory infection during the trial and 73 did not. Of children remaining over the 90th percentile at the end of the trial 19 had suffered respiratory infections and 28 had not. One baby in the overweight group suffered a “cot death” from acute bronchiolitis. In the control group, 103 cases were analysed—23 had suffered a respiratory infection and 80 had remained free of respiratory infection throughout the trial. These figures are statistically significant and suggest that obesity in infants and young children is associated with an increased incidence of acute respiratory infections.     

Cell-mediated immunity in human acute myeloblastic leukemia

Summary Lymphocyte stimulation tests with autologous myeloblasts were performed in 31 patients with nonlymphatic acute leukemia. Twenty-five patients were receiving chemotherapy combined with immunotherapy; six received chemotherapy only. Thirteen nonleukemic patients with various disorders and six healthy control patients were also studied.It was found that 4/15 patients in 9/38 tests had autologous lymphocytes stimulated by autologous circulating myeloblasts. Bone marrow cells also effected stimulation, significantly more often if the marrow was taken in relapse than when it was taken in remission.However, so-called immunotherapy with allogeneic leukemic myeloblasts and BCG could not be shown to increase these frequencies. Nor did it significantly increase the degree of stimulation measured as DNA synthesis in lymphocytes.Moreover, nonleukemic bone marrow cells from patients with other disorders also stimulated autologous lymphocytes in 1/13 patients. No recognition of autologous myeloblasts was observed when the responding lymphocytes were taken in incomplete remission or during the month preceding relapse.with the technical assistance of T. Lehtinen and A. M. SjögrenSupported by the Swedish Cancer Research Foundation Grant no. 699-B76-04XA     

Pathophysiological characterization of asthma transitions across adolescence

Background

Adolescence is a period of change, which coincides with disease remission in a significant proportion of subjects with childhood asthma. There is incomplete understanding of the changing characteristics underlying different adolescent asthma transitions. We undertook pathophysiological characterization of transitional adolescent asthma phenotypes in a longitudinal birth cohort.

Methods

The Isle of Wight Birth Cohort (N = 1456) was reviewed at 1, 2, 4, 10 and 18-years. Characterization included questionnaires, skin tests, spirometry, exhaled nitric oxide, bronchial challenge and (in a subset of 100 at 18-years) induced sputum. Asthma groups were “never asthma” (no asthma since birth), “persistent asthma” (asthma at age 10 and 18), “remission asthma” (asthma at age 10 but not at 18) and “adolescent-onset asthma” (asthma at age 18 but not at age 10).

Results

Participants whose asthma remitted during adolescence had lower bronchial reactivity (odds ratio (OR) 0.30; CI 0.10 -0.90; p = 0.03) at age 10 plus greater improvement in lung function (forced expiratory flow 25-75% gain: 1.7 L; 1.0-2.9; p = 0.04) compared to persistent asthma by age 18. Male sex (0.3; 0.1-0.7; p < 0.01) and lower acetaminophen use (0.4; 0.2-0.8; p < 0.01) independently favoured asthma remission, when compared to persistent asthma. Asthma remission had a lower total sputum cell count compared to never asthma (31.5 [25–75 centiles] 12.9-40.4) vs. 47.0 (19.5-181.3); p = 0.03). Sputum examination in adolescent-onset asthma showed eosinophilic airway inflammation (3.0%, 0.7-6.6), not seen in persistent asthma (1.0%, 0–3.9), while remission group had the lowest sputum eosinophil count (0.3%, 0–1.4) and lowest eosinophils/neutrophils ratio of 0.0 (Interquartile range: 0.1).

Conclusion

Asthma remission during adolescence is associated with lower initial BHR and greater gain in small airways function, while adolescent-onset asthma is primarily eosinophilic.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0153-7) contains supplementary material, which is available to authorized users.     

Validity of Antibodies in Lymphocyte Supernatant in Diagnosing Tuberculosis in Severely Malnourished Children Presenting with Pneumonia

BackgroundThe diagnosis of tuberculosis (TB) in young children can be challenging, especially in severely malnourished children. There is a critical need for improved diagnostics for children. Thus, we sought to evaluate the performance of a technique that measures antibodies in lymphocyte supernatant (ALS) for the diagnosis of TB in severely malnourished children presenting with suspected pneumonia.MethodsChildren less than 5 years with severe acute malnutrition and radiological features of pneumonia admitted to the Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh, were enrolled consecutively following informed written consent. In addition to clinical and radiological assessment, samples taken for TB diagnosis included gastric lavage fluid and induced sputum for microbiological confirmation. ALS was measured from venous blood, and results were evaluated in children classified as “confirmed”, “non-confirmed TB” or “not TB”.ResultsAmong 224 children who had ALS analysis, 12 (5.4%) children had microbiologically “confirmed TB”, a further 41 (18%) had clinically diagnosed “non-confirmed TB” and the remaining 168 (75%) were considered not to have TB. ALS was positive in 89 (40%) and negative in 85 (39%) of children, with a large number (47 or 21%) reported as “borderline”. These proportions were similar between the three diagnostic groups. The sensitivity and specificity of ALS when comparing “Confirmed TB” to “Not TB” was only 67% (95% CI: 31–91%) and 51% (95% CI: 42–60%), respectively.

Conclusions and Significance

Our data suggest that ALS is not sufficiently accurate to improve the diagnosis of TB in children with severe malnutrition.     

Clinical Forms of Canine Visceral Leishmaniasis in Naturally Leishmania infantum–Infected Dogs and Related Myelogram and Hemogram Changes

Hematological analysis has limited applications for disease diagnosis in Leishmania infantum–infected dogs, but it can be very important in evaluating the clinical forms of the disease and in understanding the evolution of canine visceral leishmaniasis (CVL) pathogenesis. Recently, we demonstrated that alterations in leucopoiesis and erythropoiesis are related to clinical status and bone marrow parasite density in dogs naturally infected by L. infantum. To further characterize these alterations, we evaluated the association between the hematological parameters in bone marrow and peripheral blood alterations in groups of L. infantum–infected dogs: asymptomatic I (AD-I: serum negative/PCR+), asymptomatic II (AD-II: serum positive), oligosymptomatic (OD), and symptomatic (SD). Results were compared with those from noninfected dogs (NID). The SD group was found to present a decrease in erythropoietic lineage with concomitant reductions in erythrocytes, hemoglobin, and hematocrit parameters, resulting in anemia. The SD group also had increased neutrophils and precursors and decreased band eosinophils and eosinophils, leading to peripheral blood leucopenia. In the AD-II group, lymphocytosis occurred in both the peripheral blood and the bone marrow compartments. The SD group exhibited lymphocytosis in the bone marrow, with lymphopenia in the peripheral blood. In contrast, the AD-I group, showed no significant changes suggestive of CVL, presenting normal counts in bone marrow and peripheral blood. Our results showed for the first time that important changes in hematopoiesis and hematological parameters occur during ongoing CVL in naturally infected dogs, mainly in symptomatic disease. Taken together, our results based on myelogram and hemogram parameters enable better understanding of the pathogenesis of the anemia, lymphocytosis, and lymphopenia, as well as the leucopenia (eosinopenia and monocytopenia), that contribute to CVL prognosis.     

Cryopreservation of bone marrow for the autologous transplantation in children

In preparing the autologous transplantation of children a method for cryoconservation of bone-marrow was developed by means of investigating the donor's bone-marrow. This method is adapted to our conditions, can easily be practised and is cell-preserving. Quantity and quality of the stored bone-marrow cells were evaluated concerning their proliferation capability by means of CFU-c assays. The highest recovery in CFU-c (78%) and cells (98%) was observed if isolated mononuclear cells with cryoprotective addition of 5% DMSO, 20% of human albumin, and 20% of serum were slowly frozen at a controllable rate, stored in liquid oxygen and thawed very quickly. According to the elaborated method the remission marrow was taken from 15 children affected with malignant diseases for autologous reinfusion. The data gained here confirm the experimental experiences.     

Event-Related Brain Potentials during a Semantic Priming Task in Children with Learning Disabilities Not Otherwise Specified

Learning disabilities (LDs) are the most common psychiatric disorders in children. LDs are classified either as “Specific” or “Learning Disorder Not Otherwise Specified”. An important hypothesis suggests a failure in general domain process (i.e., attention) that explains global academic deficiencies. The aim of this study was to evaluate event-related potential (ERP) patterns of LD Not Otherwise Specified children with respect to a control group. Forty-one children (8−10.6 years old) participated and performed a semantic judgment priming task while ERPs were recorded. Twenty-one LD children had significantly lower scores in all academic skills (reading, writing and arithmetic) than twenty controls. Different ERP patterns were observed for each group. Control group showed smaller amplitudes of an anterior P200 for unrelated than related word pairs. This P200 effect was followed by a significant early N400a effect (greater amplitudes for unrelated than related word pairs; 350–550 ms) with a right topographical distribution. By contrast, LD Not Otherwise Specified group did not show a P200 effect or a significant N400a effect. This evidence suggests that LD Not Otherwise Specified children might be deficient in reading, writing and arithmetic domains because of their sluggish shifting of attention to process the incoming information.     

Sudden and Unexpected Deaths in Infants: Histology and Virology

The histological appearance of lungs of children whose death had been sudden and unexpected has been studied in relation with the viruses found at necropsy. Fifty-one children were investigated and in 33 the lungs had the histological appearance widely accepted as characteristic of the condition previously termed “cot death.” Sixteen had the histological appearance of lymphocytic bronchiolitis, and it was from this group only that viruses were isolated. The viruses isolated were those associated with respiratory infections. Two patients showed the histological appearance of bacterial bronchopneumonia. Viruses are probably responsible for a substantial proportion of unexpected sudden deaths in infancy.     

THE RELEVANT USE OF THE TRADITIONAL TUNISIAN GAME ‘‘RAQASSA’’ FOR CARDIOVASCULAR STIMULATION IN SCHOOLCHILDREN

The aim of this study was to investigate the heart rate (HR) responses, the rate of perceived exertion (RPE), and the feeling during physical education schooling while performing traditional games activities compared to intermittent exercise. Nineteen pre-pubertal children randomly performed on different days two types of lessons (intermittent running mode vs. traditional Tunisian “Raqassa” game) lasting 12-min each. HR was continuously recorded during both lessons, while ratings of perceived exertion and Feeling values were recorded after the sessions. The mean HR value during the traditional game was significantly higher than during intermittent exercise (p<0.05). Conversely, the perceived exertion score was significantly higher after intermittent exercise than the traditional exercise game (p<0.05), showing that the higher cardiovascular strain of the game was perceived as “lighter” than the run. Simultaneously, the children''s Feeling was significantly higher after the traditional game than intermittent exercise (p<0.001), showing a higher satisfaction from playing with respect to running. Exercise based on the “Raqassa” traditional game could be used in pre-pubertal children as an alternative or as an additional method for suitable cardiovascular stimulation during physical education lessons with lower perceived exertion and better feeling compared to intermittent running.     

Effect of Regular Circus Physical Exercises on Lymphocytes in Overweight Children

Obesity associated with a sedentary lifestyle can lead to changes in the immune system balance resulting in the development of inflammatory diseases. The aim of this study was to compare lymphocyte activation mechanisms between overweight children practicing regular circus physical exercises with non-exercised children. The study comprised 60 pubescent children randomly divided into 4 groups: Overweight Children (OWC) (10.67 ± 0.22 years old), Overweight Exercised Children (OWE) (10.00 ± 0.41 years old), Eutrophic Children (EC) (11.00 ± 0.29 years old) and Eutrophic Exercised Children (EE) (10.60 ± 0.29 years old). OWE and EE groups practiced circus activities twice a week, for 4.3 ± 0.5 and 4.4 ± 0.5 months, respectively. Percentage of T regulatory cells (Treg) and the expression of CD95 and CD25 in CD4⁺ lymphocytes were evaluated by flow cytometry. Lymphocyte proliferation capacity was measured by [¹⁴C]-thymidine incorporation and mRNA expression of IL-35, TGF-beta, IL-2 and IL-10 by real-time PCR. Lymphocyte proliferation was higher in OWC and OWE groups compared with the EC (3509 ± 887; 2694 ± 560, and 1768 ± 208 cpm, respectively) and EE (2313 ± 111 cpm) groups. CD95 expression on lymphocytes was augmented in the EC (953.9 ± 101.2) and EE groups (736.7 ± 194.6) compared with the OWC (522.1 ± 125.2) and OWE groups (551.6 ± 144.5). CTLA-4 expression was also lower in the OWC and OWE groups compared with the EC and EE groups. Percentage of Treg, IL-35, and IL-10 mRNA expression were lower in the OWC and OWE groups compared with the EC and EE groups. In conclusion, overweight children present altered immune system balance characterized by elevated lymphocyte proliferation due to a decrease in T regulatory cell percentage. These effects were partially reverted by moderate physical exercise, as demonstrated by decreased lymphocyte proliferation.     

Social Effects of Genetic Counselling

In a follow-up study of 104 subjects referred for genetic counselling between 1965 and 1969 all were at risk of having children with a variety of serious genetic disorders. Most subjects were in social classes III and IV, were married, in their late 20s, and already had an affected child. Sixty-three per cent. were referred by hospital consultants, 27% by their general practitioners, and 10% were self-referrals. All of those counselled appeared to have appreciated the genetic implications, although four overestimated the risks and 11 underestimated the risks.Of those at high risk (greater than 1 in 10) of having an affected child 10 out of 55 couples “planned” further pregnancies despite the risks. In two this was because they had been unable to adopt a child, in four because they had no living children and the disorders in question usually resulted in stillbirth or death in infancy so that the “burden” of an affected child would be of relatively short duration, and one mother had had antenatal diagnosis and selective abortion. Most of the couples in the low-risk group (less than 1 in 20) were reassured and planned further pregnancies.     

Young Toddlers’ Word Comprehension Is Flexible and Efficient

Much of what is known about word recognition in toddlers comes from eyetracking studies. Here we show that the speed and facility with which children recognize words, as revealed in such studies, cannot be attributed to a task-specific, closed-set strategy; rather, children’s gaze to referents of spoken nouns reflects successful search of the lexicon. Toddlers’ spoken word comprehension was examined in the context of pictures that had two possible names (such as a cup of juice which could be called “cup” or “juice”) and pictures that had only one likely name for toddlers (such as “apple”), using a visual world eye-tracking task and a picture-labeling task (n = 77, mean age, 21 months). Toddlers were just as fast and accurate in fixating named pictures with two likely names as pictures with one. If toddlers do name pictures to themselves, the name provides no apparent benefit in word recognition, because there is no cost to understanding an alternative lexical construal of the picture. In toddlers, as in adults, spoken words rapidly evoke their referents.