"Before I was like a Tarzan. But now, I take a pause": mixed methods feasibility study of the Naungan Kasih parenting program to prevent violence against children in Malaysia.

BACKGROUND: Despite impressive strides in health, social protection, and education, children continue to experience high rates of child maltreatment in Malaysia. This mixed-methods study assessed the feasibility of a five-session, social learning-based parenting program delivered by government staff in a community setting to reduce violence against children. METHODS: Parents of children from birth to 17 years were recruited from two communities near Kuala Lumpur to participate in the government-run program called the Naungan Kasih Positive Parenting Program ("Protecting through Love" in Bahasa Melayu). Quantitative data from female caregivers (N = 74) and children ages 10-17 (N = 26) were collected along with qualitative interviews and focus groups with parents, children, and facilitators. The primary outcome was child maltreatment with secondary outcomes including neglect, positive parenting, acceptability of corporal punishment, harsh parenting, positive discipline, and child behavior problems. Multilevel Poisson regression and multilevel linear regression were conducted to compare baseline and post-test outcomes. Qualitative interviews and focus groups examined how participants experienced the program utilizing a thematic analysis approach. RESULTS: Quantitative analyses found pre-post reductions in overall child maltreatment, physical abuse, emotional abuse, attitudes supporting corporal punishment, parent sense of inefficacy, and child behavior problems. There were no reported changes on positive and harsh parenting, parental mental health, and marital satisfaction, nor were there any other significant changes reported by children. Qualitative findings suggested that the program had tangible benefits for female caregivers involved in the program, with the benefits extending to their family members. CONCLUSIONS: This feasibility study is one of the few studies in Southeast Asia that examined the feasibility and initial program impact of a parenting program delivered by government staff to families with children across the developmental spectrum from birth to 17 years. Promising results suggest that the program may reduce child maltreatment across a range of child ages. Findings also indicate areas for program improvement prior to further delivery and testing, including additional training and content on sexual and reproductive health, parenting children with disabilities, and online child protection.

The Association Between Facilitator Competent Adherence and Outcomes in Parenting Programs: a Systematic Review and SWiM Analysis.

There is increasing interest about the fidelity with which interventions are implemented because it is theorized that better implementation fidelity by facilitators is associated with better participant outcomes. However, in the parenting program literature, there is mixed evidence on the relationship between implementation fidelity and outcomes. This paper provides a synthesis of the evidence on the relationship between facilitator delivery and outcomes in the parenting program literature. Following PRISMA guidelines, this paper synthesizes the results of a systematic review of studies on parenting programs aiming to reduce violence against children and child behavior problems. Specifically, it examines associations between observational measures of facilitator competent adherence and parent and child outcomes. A meta-analysis was not feasible due to study heterogeneity. As a result, Synthesis Without Meta-Analysis guidelines were followed. Searches in electronic databases, reference searching, forward citation tracking, and expert input identified 9653 articles. After screening using pre-specified criteria, 18 articles were included. The review found that most studies (n = 13) reported a statistically significant positive relationship with at least one parent or child outcome. However, eight studies reported inconsistent findings across outcomes, and four studies found no association with outcomes. The results suggest that better facilitator competent adherence is generally associated with positive parent and child outcomes. However, this finding is weakened by the methodological heterogeneity of included studies and due to the wide variety of ways in which studies conceptualized competent adherence-outcome relationships.

Cyanotic Congenital Heart Disease Modes of Presentation and Prenatal Detection

Prenatal detection of structural congenital heart disease (CHD) optimises cardiovascular stability pre-operatively and post-operative outcomes. We compared prenatal detection rates of critical CHD in units offering universal fetal anomaly scans with those offering imaging to selected women. One hundred and thirteen infants met inclusion criteria. The overall pre-natal detection rate for critical CHD was 57% of liveborn infants. It was 71% (57/80) in hospitals who offered a universal anomaly scan and 29% (9/31) in centres offering a limited service. Postnatal diagnosis was associated with PICU admission (p=0.016) and preoperative mechanical ventilation (p=0.001). One-year mortality was 10 fold higher in the postnatally diagnosed group 15% vs 1.55% (p=0.0066). There is a significant disparity between centres offering universal anomaly versus selective screening. Prenatal detection confers advantage in terms of pre-operative stability and one year survival. Failure to deliver an equitable service exposes infants with CHD to avoidable risk.

Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

Parenting, mental health and economic pathways to prevention of violence against children in South Africa.

BACKGROUND: Parenting programs based on social learning theory have increasing empirical evidence for reducing violence against children. Trials are primarily from high-income countries and with young children. Globally, we know little about how parenting programs work to reduce violence, with no known studies in low or middle-income countries (LMICs). This study examines mechanisms of change of a non-commercialized parenting program, Parenting for Lifelong Health for Teens, designed with the World Health Organization and UNICEF. A cluster randomized trial showed main effects on parenting and other secondary outcomes. We conducted secondary analysis of trial data to investigate five potential mediators of reduced violence against children: improved parenting, adolescent behaviour, caregiver mental health, alcohol/drug avoidance, and family economic strengthening. METHODS: The trial was implemented in rural South Africa with 40 sites, n = 552 family dyads (including adolescents aged 10-18 and primary caregivers). Intervention sites (n = 20) received the 14-session parenting program delivered by local community members, including modules on family budgeting and savings. Control sites (n = 20) received a brief informational workshop. Emotional and physical violence against children/adolescents and each potential mediator were reported by adolescents and caregivers at baseline and 9-13 months post-randomisation. Structural equation modelling was used to test simultaneous hypothesized pathways to violence reduction. RESULTS: Improvements in four pathways mediated reduced violence against children: 1) improved parenting practices, 2) improved caregiver mental health (reduced depression), 3) increased caregiver alcohol/drug avoidance and 4) improved family economic welfare. Improved child behaviour was not a mediator, although it was associated with less violence. CONCLUSIONS: Simultaneously bolstering a set of family processes can reduce violence. Supporting self-care and positive coping for caregivers may be essential in challenging contexts. In countries with minimal or no economic safety nets, linking social learning parenting programs with economic strengthening skills may bring us closer to ending violence against children.

Mapping human autosomes: evidence supporting assignment of rhesus to the short arm of chromosome No. 1.

Rh-negative erythrocytes were found in the blood of an Rh-positive man suffering from myelofibrosis. Nucleated hemopoietic precursors were also circulating in his blood, and these cells had an abnormal chromosome complement from which identifiable chromosome segments had been deleted. Correlation of the serological and cytogenetic findings, combined with previous data, indicates that the Rhesus blood group locus is on the distal portion of the short arm of chromosome No. 1.

Analysis and influence of demographic and risk factors on difficult child behaviors.

This descriptive study examined the distribution of risk factors in a sample that was selected on the basis of existing potential for difficult child behaviors. We inquired into whether exposure to risk factors was distributed equally across different contexts of ethnicity, locality, and child gender. Participants included 731 mother-child dyads recruited from WIC Programs in rural, suburban, and urban localities. Cumulative risk indices were constructed using neighborhood, family, and individual risk factors. The findings generally revealed that African American children and children in urban localities were exposed to higher numbers of risk factors and cumulative risk in relation to other ethnic children and localities. On the other hand, Caucasian children expressed higher levels of vulnerabilities to risk for internalizing behaviors than did other children. The results are discussed in terms of differences in contextual specific rates of risk exposure, vulnerability, and their implications for prevention and intervention research.

Opportunities provision for preventing youth gang involvement for children and young people (7-16).

BACKGROUND: Youth gangs have long been studied in the United States and interest elsewhere is increasing. Many studies document a robust and consistent relationship between gang membership and elevated delinquency. One theory of gang involvement, drawing on anomie and strain theories, proposes that the gang provides a means of fulfilling the economic needs of youth excluded from legitimate labour markets. Opportunities provision is a gang prevention strategy based on this theory and the principle that providing youth with educational and employment opportunities may reduce gang involvement. Common techniques within opportunities provision include tutoring, remedial education, job training, and job placement. OBJECTIVES: To determine the effectiveness of opportunities provision for preventing youth gang involvement for children and young people aged 7 to 16. SEARCH STRATEGY: Electronic searches were conducted of ASSIA, CINAHL, CJA, Cochrane Library, Dissertations Abstracts, EMBASE, ERIC, IBSS, LILACs, LexisNexis Butterworths, MEDLINE, NCJR Service Abstracts Database, PsycINFO, and Sociological Abstracts, to April 2007. Reviewers contacted relevant organisations, individuals and list-servs and searched pertinent websites and reference lists. SELECTION CRITERIA: All randomised controlled trials or quasi-randomised controlled trials of interventions that have opportunities provision as the majority component, delivered to children and youths aged 7 to 16 not involved in a gang, compared to any other or no intervention. DATA COLLECTION AND ANALYSIS: Searches yielded 2,696 unduplicated citations. 2,676 were excluded based on title and abstract. Two were excluded based on personal communication with study authors. Full-text reports for 18 citations were retrieved. 16 were excluded because they were not evaluations, did not address a gang prevention programme, did not include gang-related outcomes, did not include opportunities provision intervention components, or presented preliminary findings for outcomes reported in another citation. The remaining two reports were at least partially relevant to opportunities provision for gang prevention, but methodological flaws excluded both from analysis. MAIN RESULTS: No randomised controlled trials or quasi-randomised controlled trials were identified. AUTHORS' CONCLUSIONS: No evidence from randomised controlled trials or quasi-randomised controlled trials currently exists regarding the effectiveness of opportunities provision for gang prevention. Only two studies addressed opportunities provision as a gang prevention strategy, a case study and a qualitative study, both of which had such substantial methodological limitations that even speculative conclusions as to the impact of opportunities provision were impossible. Rigorous primary evaluations of gang prevention strategies are crucial to develop this research field, justify funding of existing interventions, and guide future gang prevention programmes and policies.

Cognitive-behavioural interventions for preventing youth gang involvement for children and young people (7-16).

BACKGROUND: Many studies document a robust and consistent relationship between gang membership and elevated delinquency, with gang members disproportionately involved in crime compared to non-gang peers. Research also indicates that both delinquent youth and youth who join gangs often show a wide range of deficient or distorted social-cognitive processes compared to non-delinquent peers. Cognitive-behavioural interventions are designed to address cognitive deficits in order to reduce maladaptive or dysfunctional behaviour, and studies have documented their positive impact on a number of behavioural and psychological disorders among children and youth. OBJECTIVES: To determine the effectiveness of cognitive-behavioural interventions for preventing youth gang involvement for children and young people (ages 7-16). SEARCH STRATEGY: Electronic searches of ASSIA, CINAHL, CJA, Cochrane Library, Dissertations Abstracts A, EMBASE, ERIC, IBSS, LILACs, LexisNexis Butterworths, MEDLINE, NCJR Service Abstracts Database, PsycINFO, and Sociological Abstracts, to April 2007. Reviewers contacted relevant organisations, individuals, and list-servs and searched pertinent websites and reference lists. SELECTION CRITERIA: All randomised controlled trials or quasi-randomised controlled trials of interventions with a cognitive-behavioural intervention as the majority component, delivered to youth and children aged 7-16 not involved in a gang. DATA COLLECTION AND ANALYSIS: Searching yielded 2,284 unduplicated citations, 2,271 of which were excluded as irrelevant based on title and abstract. One was excluded following personal communication with investigators. One citation, of a large randomised prevention trial, awaits assessment; personal communication with study authors yielded unpublished reports addressing gang outcomes, but insufficient detail precluded determining inclusion status. Seven remaining reports were excluded as irrelevant because they were narrative reviews or descriptions of programs without evaluations, did not address a gang prevention programme, or did not address a gang prevention program that included a cognitive-behavioural intervention. The remaining four full-text reports excluded because of study design, leading to 0 included studies. MAIN RESULTS: No randomised controlled trials or quasi-randomised controlled trials were identified. AUTHORS' CONCLUSIONS: No evidence from randomised controlled trials or quasi-randomised controlled trials exists regarding the effectiveness of cognitive-behavioural interventions for gang prevention. Four evaluations of Gang Resistance Education and Training (GREAT) have been conducted, two of which were part of a US national evaluation, but all were excluded based on study design. Reviewers conclude there is an urgent need for rigorous primary evaluations of cognitive-behavioural interventions for gang prevention to develop this research field and guide future gang prevention programmes and policies.

Platelet storage at 22 degrees C; metabolic, morphologic, and functional studies.

Platelets stored at 22 degrees C for transfusion purpose have been examined with metabolic, morphologic, and functional studies. Evaluations were made of platelet-rich plasma (PRP) stored for 3-4 days and platelet concentrates (PC) stored for 24 hr. During these periods, lactate accumulated continuously without significant change in platelet count, pH, or plasma glucose. Platelet glycogen fell dramatically both chemically and by electron microscopy, but adenosine triphosphate (ATP), adenosine diphosphate (ADP), and intracellular potassium did not change. After storage, the cell's capacity for glucose utilization through glycolysis, the hexose monophosphate shunt, and the tricarboxylic acid cycle appeared to be intact. Although platelet volume during storage did not change, disc to sphere transformation was observed by phase microscopy. Platelet aggregration with ADP was reduced even after 1 day of storage. After transfusion of stored platelets to thrombocytopenic recipients, recovery of platelet glycogen and capacity for aggregation occurred within 24 hr. In summary, the platelet remains surprisingly intact during the intervals studied; those defects which do develop are reversible in the circulation of a thrombocytopenic recipient if viability has been maintained. A "storage lesion" responsible for loss of viability has not been defined.

Effective erythropoiesis induced by 5beta-pregnane-3beta-hydroxy-20-one in squirrel monkeys.

The erythropoietic effect of 5beta-pregnane-3beta-hydroxy-20-one, a naturally occurring steroid metabolite of progesterone, was evaluated in the squirrel monkey by ferrokinetic studies. red cell survival, and blood volume measurements. The intramuscular administration of this steroid in pharmacologic doses shortened the (59)Fe plasma clearance and increased the plasma iron turnover, thereby indicating an increase in erythropoiesis. A normal (59)Fe red cell uptake was observed, and the bone marrow maturation time was not altered. Red cell survival was the same in the treated and control groups. After five weekly injections of the steroid, the monkeys increased their red cell mass by 57%. A significant increase in white blood cells and a slight elevation of platelet counts in the treated monkeys also suggest a possible direct stimulation of hemopoietic stem cells by the steroid metabolite. These observations indicate that some steroid metabolites can stimulate an early increase in iron turnover (within 48 h) that is not secondary to hemolysis. The increased red cell mass indicates effective erythropoiesis in primates.

Biogenesis of erythrocyte membrane proteins. In vivo studies in anemic rabbits.

To study the process of red cell membrane protein synthesis we have followed the time course of [3-H]leucine appearance in total protein and individual peptides of the erythrocyte membrane following injection of the amino acid into phenylhydrazine-anemic rabbits. Multiple peripheral blood samples were taken from single animals over a 5-week period. Erythrocyte membrane proteins were separated by polyacrylamide gel electrophoresis in sodium dodecylsulfate and dithiothreitol; incorporation of radioactivity was determined by gel slicing and liquid scintillation spectrometry. Appearance of [3-H]leucine in circulating erythrocytes reached a peak at 1-3 days, with a steady decline thereafter. The radioactive amino acid appeared first in the lowest molecular weight peptides and last in the largest peptides; at the earliest time point (8 h), little radioactivity was observed in any of the four largest peptides present in the membranes (bands A, 1, 2 and 3). Certain smaller peptides (bands 4, 5 and 9) were the predominant species labeled at this time. By 24 h all peptides showed significant incorporation. With maturation of the red cells, label largely disappeared from bands A, 9 and several smaller peptides; this was confirmed by finding that the peptides are virtually absent from mature circulating erythrocytes. These data are interpreted as showing that red cell membrane proteins are synthesized asynchronously during the life cycle of the erythrocyte; the largest peptides are made predominantly in the earlier marrow stages of development, while certain of the smaller peptides are still being synthesized in the reticulocyte stage. Several membrane proteins appear to be specific to the reticulocyte and are lost during the process of cell maturation in the circulation.

Biogenesis of erythrocyte membrane proteins. In vitro studies with rabbit reticulocytes.

The capability of rabbit reticulocytes to synthesize red cell membrane proteins has been tested in vitro. Reticulocyte-rich blood from phenylhydrazine-treated rabbits was incubated in vitro in a complete amino acid medium containing ferrous salts, glucose, rabbit plasma and [3-H]leucine. Red cell ghost membranes were prepared by hypotonic lysis and leucine incorporation into hemoglobin and total membrane proteins determined. The pattern of incorporation into individual peptides was determined by polyacrylamide gel electrophoresis of labeled membranes on large (19 mm) gels which were then sliced into 1 mm sections; radioactivity was compared with densitometric tracings of Coomassie blue stained analytical (6 mm) gels. Incorporation of [3-H]leucine into both hemoglobin and membrane protein was linear over 1 h. Gel analysis of labeled membranes revealed that the amino acid was primarily incorporated into peptides with molecular weights of 90 000 or less; three peptides of molecular weights 90 000, 60 000 and 33 000 showed the highest specific activity. Synthesis of the four largest peptide species was negligible. Removable of ferrous salts inhibited synthesis of both globin and membrane protein equally (approx. 50%). However, puromycin and cycloheximide preferentially inhibited the synthesis of globin as compared to membrane proteins. Reticulocytes remain capable of synthesizing a number of membrane proteins; these results are consistent with studies of red cell membrane synthesis in anemic rabbits in vivo.

The hip trial: psychosocial consequences for mothers of using ultrasound to manage infants with developmental hip dysplasia.

BACKGROUND: The hip trial aimed to assess clinical effectiveness, economic and psychosocial costs, and benefits of ultrasound imaging (US) compared with conventional clinical assessment alone to guide the management of infants with neonatal hip instability. OBJECTIVE: To report on psychosocial consequences for mothers and the developing mother-child relationship of US, and associations between abduction splinting and maternal psychosocial distress. DESIGN: Multicentre randomised controlled trial. SETTING: Thirty three hospitals in the United Kingdom and Ireland. PARTICIPANTS, INTERVENTIONS: A total of 629 infants with neonatal hip instability randomised to US examination or clinical assessment alone before treatment decision. Questionnaires were completed by 561 (89%) mothers at 8 weeks and 494 (79%) at 1 year. MAIN OUTCOME MEASURES: Anxiety, postnatal depression, parenting stress assessed by standardised questionnaires. Maternal concerns about hip problems were assessed using the Infant hip worries inventory. RESULTS: At 8 weeks, there were no differences between US and non-US groups of the trial in maternal anxiety (mean difference (MD) -1.2, 95% confidence interval (CI) -3.2 to 0.8), depression (MD 0.0, 95% CI -0.7 to 0.8), parenting stress (MD -1.2, 95% CI -2.8 to 0.4), or other measures. The same pattern was evident at 1 year. In an explanatory analysis, early splinting was associated with increased anxiety at 8 weeks (MD 3.8, 95% CI 1.7 to 5.9) and increased level of hip worries at 8 weeks (MD 6.8, 95% CI 5.6 to 7.9) and 1 year (MD 1.3, 95% CI 0.3 to 2.4). CONCLUSIONS: Although early splinting is associated with maternal anxieties, US is not associated with any increase or reduction in psychosocial effects on mothers. Together with the clinical findings, this suggests that the use of US allows reduction in splinting rates without increased risk of adverse clinical or psychosocial outcomes.

Persistence of abnormal RBC and platelet phenotype during recovery from aplastic anemia.

Sixteen adults with chronic acquired aplastic anemia had abnormally large RBCs and abnormally small platelets before chemotherapy. During their therapy, transfusion initially obscured these macrocytic RBCs. In the eight who had erythropoietic recovery, endogenous RBCs again were macrocytic, and platelets remained small whether or not the platelet count increased. The percentage of cells containing hemoglobin F changed in only one of the eight subjects. In contrast, the eight who did not have erythropoietic recovery had no reappearance of macrocytes. Of 19 other previously treated patients whose hemoglobin level had recovered to normal for seven to 196 months, 16 had increased mean corpuscular volume (101 to 133 femtoliters) and abnormally small platelets. We conclude that in aplastic anemia the appearance of macrocytes reliably and easily predicts RBC recovery. Furthermore, even in treated, apparently recovered subjects, an abnormality of blood cell size remains.

Template bleeding time and clinical hemorrhage in myeloproliferative disease.

In 32 patients with myeloproliferative disorders (MPD), correlations were made among clinical observations of hemorrhagic tendency, template Ivy bleeding time, and platelet aggregation studies. Bleeding time was commonly prolonged, particularly in myelofibrosis. In two cases, this prolongation appeared to reflect a defect in platelet function, which resulted in clinical bleeding. Prolongation of bleeding time did not correlate with degree of thrombocytosis. Two patients with thrombocytosis had serious clinical bleeding at a time when bleeding time was normal. Of the patients, 35% had abnormal findings from aggregation studies, but there was no correlation between aggregation studies and prolongation of bleeding time or clinical hemorrhage. We conclude that bleeding in MPD arises either from a defect in platelet function, which is reflected in a prolonged bleeding time, or from thrombocytosis.

Functionally abnormal marrow stromal cells in aplastic anemia.

We studied the myeloid colony-stimulating activity (CSA) of marrow stromal cells (MSC) derived from normal subjects and patients with aplastic anemia, acute leukemia, and other myeloproliferative disorders. CSA of the MSC was determined in a bilayer system. Feeder layers with varying numbers of MSC (10(4) to 2 X 10(5)) were used. Of 40 MSC tested, 39 stimulated myeloid colony formation by the normal target marrow mononuclear cells. The optimal concentration of MSC exhibiting the maximal stimulation of myeloid progenitors (CFU-GM) varied with different MSC. MSC from normal subjects and from patients with acute leukemia and myeloproliferative disorders were potent stimulators of CFU-GM differentiation. In contrast, MSC from patients with aplastic anemia had poor CSA, suggesting that the marrow microenvironment is functionally abnormal in aplastic anemia.

Isolation of human bone marrow myeloid cells by ion exchange filtration.

A method is described for the separation of early and intermediate myeloid cells from human bone marrow aspirates. This easily performed procedure is based on preferential binding of lymphoid and late myeloid cells to DEAE-Cellulose-Sephadex G-25 columns.

The abrogation of in vivo resistance to parental bone marrow transplantation and of in vitro natural cell-mediated cytotoxicity to the YAC lymphoma by in vivo growth of a transformed thymus-derived cell culture.

A thymus-derived monolayer culture, referred to as E1, from (C57Bl/6 X A)F1 hybrid mice was continuously passaged in vitro for over three years and formed rapidly growing, non-metastasizing tumors when injected s.c. into syngeneic mice. The spleens of tumor-bearing mice were greatly enlarged, but no tumor cells were detected in these spleens. The natural cell-mediated cytotoxic activity of spleen cells of tumor-bearing mice decreased with increasing tumor size. In addition, the expression of genetic resistance to transplantation of C57Bl/6 parental bone marrow cells was decreased in the spleens of irradiated tumor-bearing mice. This correlation between the expressions of natural cell-mediated cytotoxicity and of genetic resistance to bone marrow transplantation is consistent with the hypothesis that both of these responses are mediated by the same population of effector cells.

Abnormal marrow fibroblasts in aplastic anemia.

Human bone marrow fibroblasts (BMF) were grown in vitro from normal (N) subjects and patients with aplastic anemia (AA). Growth studies in vitro revealed that both the N-BMF and AA-BMF had a logarithmic growth phase of eight days. Population doubling time for six of the 12 N-BMF and seven of the 12 AA-BMF was greater than 50 h. Five of the 12 AA-BMF studied in contrast to only two of the 12 N-BMF had a population doubling time of less than 50 h. The remaining four N-BMF had a population doubling time of greater than 100 h. During a similar duration in the logarithmic phase of growth, the AA-BMF underwent an average of 2.499 population doublings in comparison to 1.586 doublings by N-BMF (P = less than 0.01). The AA-BMF grew in multiple layers compared with the N-BMF, which usually grew as a monolayer. At the end of the logarithmic phase of growth, the AA-BMF also had a significantly higher number of cells per dish than the N-BMF (P = 0.02 on analysis of variance and covariance). These data suggest that a subgroup of AA-BMF grows faster than N-BMF and that the AA-BMF lack cell-to-cell inhibition. Testosterone, 3 alpha-etiocholanolone, and dexamethasone at 1 X 10(-8)M concentration, a physiological concentration, stimulated the growth of N-BMF as evidenced by increase in cell numbers and radioactive thymidine (3H-TdR) uptake. While dexamethasone had a stimulating effect on growth of N-BMF, it suppressed the growth of AA-BMF. Specific binding of radioactive dexamethasone (3H-dexa) was determined both for the N-BMF and AA-BMF. Specific binding sites for dexamethasone (Bmax) present on the N-BMF ranged from 460 to 770 fmol/mg protein). Bmax for AA-BMF was low (27-215 fmol/mg protein). In addition, the dissociation constant (Kd) was ten times lower for AA-BMF (1.0 X 10(-7) M) than for N-BMF (1.1 X 10(-8) M). The observations on the growth studies, the paradoxical response to dexamethasone, and the difference in the number of binding sites for dexamethasone indicate that the marrow fibroblasts from patients with aplastic anemia are abnormal.