Editorial: ‘The giant’s shoulders’: understanding Michael Rutter’s impact on science and society

The recent death of our colleague and friend Professor Sir Michael Rutter has quite rightly been greeted by an outpouring of gratitude and respect from distinguished commentators across the globe working in diverse fields of the basic, social and clinical sciences as well as from clinicians and policy makers. These have without exception highlighted his seminal role as a pioneer, perhaps The Pioneer, of the application of the scientific method to the study of child and adolescent mental health and disorder – the father of evidence-based Child Psychiatry and the most influential voice in the new field of Developmental Psychopathology (Stevenson, 2022). In this editorial, we will attempt to build on these commentaries. We will parse Mike’s scientific contributions to our field, in order to identify the personal characteristics and intellectual modus operandi that made him such a uniquely important figure, whose influence will resonate through the many fields he influenced for decades to come. We will also attempt something of a reframing of that contribution. Our thesis being that, although he never agitated for it politically or even stated it as a goal explicitly, Mike’s work was motivated by a desire for social reform and created the scientific catalyst for such reform to occur.     

Alleles of RUNX2/CBFA1 gene are associated with differences in bone mineral density and risk of fracture.

The aim of this study was to determine if DNA polymorphism within runt-related gene 2 (RUNX2)/core binding factor A1 (CBFA1) is related to bone mineral density (BMD). RUNX2 contains a glutamine-alanine repeat where mutations causing cleidocranial dysplasia (CCD) have been observed. Two common variants were detected within the alanine repeat: an 18-bp deletion and a synonymous alanine codon polymorphism with alleles GCA and GCG (noted as A and G alleles, respectively). In addition, rare mutations that may be related to low BMD were observed within the glutamine repeat. In 495 randomly selected women of the Geelong Osteoporosis Study (GOS), the A allele was associated with higher BMD at all sites tested. The effect was maximal at the ultradistal (UD) radius (p = 0.001). In a separate fracture study, the A allele was significantly protective against Colles' fracture in elderly women but not spine and hip fracture. The A allele was associated with increased BMD and was protective against a common form of osteoporotic fracture, suggesting that RUNX2 variants may be related to genetic effects on BMD and osteoporosis.     

Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Geelong Osteoporosis Study.

This population-based study documented beta-blocker use in 59/569 cases with incident fracture and 112/775 controls. OR for fracture associated with beta-blocker use was 0.68 (95%CI, 0.49-0.96). Beta-blockers were associated with higher BMD at the total hip (2.5%) and UD forearm (3.6%) after adjusting for age, anthropometry, and thiazide use. Beta-blocker use is associated with reduced fracture risk and higher BMD. INTRODUCTION: Animal data suggests that bone formation is under beta-adrenergic control and that beta-blockers stimulate bone formation and/or inhibit bone resorption. MATERIALS AND METHODS: We evaluated the association between beta-blocker use, bone mineral density (BMD), and fracture risk in a population-based study in Geelong, a southeastern Australian city with a single teaching hospital and two radiological centers providing complete fracture ascertainment for the region. Beta-blocker use was documented for 569 women with radiologically confirmed incident fractures and 775 controls without incident fracture. Medication use and lifestyle factors were documented by questionnaire. RESULTS: Odds ratio for fracture associated with beta-blocker use was 0.68 (95% CI, 0.49-0.96) for any fracture. Adjusting for age, weight, medications, and lifestyle factors had little effect on the odds ratio. Beta-blocker use was associated with a higher BMD at the total hip (2.5%, p = 0.03) and ultradistal forearm (3.6%, p = 0.04) after adjustment for age, anthropometry, and thiazide use. CONCLUSION: Beta-blockers are associated with a reduction in fracture risk and higher BMD.     

Sex differences in estradiol-induced progestin receptor immunoreactivity in the guinea pig preoptic area and hypothalamus

Progesterone exerts on the central nervous system a number of effects, some of which are estrogen dependent mostly in the preoptic area and the mediobasal hypothalamus. In these regions, an immunocytochemical study was used to evaluate differences in progesterone receptor (PR) immunoreactivity between the male and the female guinea pig in response to 10 μg/day estradiol benzoate (EB) for 5 consecutive days. Compared to EB-treated females, EB-treated males showed a slightly lower number of PR-immunoreactive cells in the preoptic area whereas PR-immunoreactivity appeared in more cells in the anterior part of the ventrolateral nucleus. The numbers of PR-immunoreactive cells in the arcuate nucleus did not differ significantly between males and females. These results show that regionally localized sex differences exist in the induced PR system after 5 days exposure to EB.     

Properties of simian virus 40 mutants lacking the Asp4-Glu-Asp stretch at the carboxyl-terminus of large T antigen

The biological activity carried by the carboxy-terminal domain of SV40 large T antigen has been investigated by isolating mutants deleted for a stretch of six acidic residues which by analogy with polyoma middle T antigen might be essential for the activity of the protein. We have constructed an "in-phase" deletion of 37 residues that includes the complete acid residues cluster. In order to parallel the polyoma hr-t mutants genotype, the deletion was introduced in virus strains either competent or defective for the small t antigen. We conclude from these experiments that the deletion of this unusual sequence does not affect per se any of the known biological properties of the virus.     

Escherichia coli strains from pregnant women and neonates: intraspecies genetic distribution and prevalence of virulence factors

To determine the extent to which the vagina, endocervix, and amniotic fluid screen the Escherichia coli strains responsible for neonatal infections, we studied the genetic relationships among 105 E. coli strains isolated from all of the ecosystems involved in this infectious process. Twenty-four strains were isolated from the intestinal flora, and 25 strains were isolated from the vaginas of pregnant women. Twenty-seven strains were isolated from the amniotic fluid, blood, and cerebrospinal fluid (CSF) of infected neonates. The intraspecies genetic characteristics of all of the isolates were determined by random amplified polymorphic DNA (RAPD) analysis, PCR ECOR (E. coli reference) grouping, and PCR virulence genotyping. A correlation was found between the intraspecies distributions of the strains in the A, B1, B2, and D ECOR groups and in the two major RAPD groups (I and II). Nevertheless, the distribution of the E. coli strains in the RAPD groups according to their anatomical origins was more significant than their distribution in the ECOR groups. This may be explained by the existence of an E. coli subpopulation, defined by the RAPD I group, within the ECOR B2 group. This RAPD I group presents a major risk for neonates: 75% of the strains isolated from patients with meningitis and 100% of the strains isolated from patients with bacteremia were in this group. The vagina and the amniotic fluid are two barriers that favor colonization by highly infectious strains. Indeed, only 17% of fecal strains belonged to the RAPD I group, whereas 52% of vaginal strains and 67% of amniotic fluid strains belonged to this subpopulation. The ibeA and iucC genes were significantly associated with CSF strains, whereas the hly and sfa/foc genes were more frequent in blood strains. These findings could serve as a basis for developing tools to recognize vaginal strains, which present a high risk for neonates, for use in prophylaxis programs.     

Identical abnormality of the short arm of chromosome 18 in two Philadelphia-positive chronic myelocytic leukemia patients with erythroblastic transformation,resulting in duplication of BCR-ABL1 fusion

Two patients with Ph-positive chronic myelocytic leukemia in erythroblastic transformation and rearrangement of the short arm of chromosome 18 are reported. Fluorescence in situ hybridization studies showed that the 18p rearrangement resulted from translocation of the main part of chromosome 22 long arm to 18p, including BCR-ABL1 fusion. The 18p abnormality resulted, thus, in loss of 18p and duplication of BCR-ABL1 in both patients. The possible relation to the erythroblastic type of blastic phase is briefly discussed. In addition an apparently intact germline ABL1 gene was duplicated and inserted into chromosome 6 at band p21 in one of these patients.     

Synthèse par voie radicalaire de polymères à extrémités hydroxylées, 8. Synthèse de polybutadiènes: Etude de différents paramètres influençant la polymolécularité

It was shown that radical polymerization of butadiene in 1-butanol and 2-butanol, initiated by hydrogen peroxide cleaved into two hydroxyl radicals by heat, leads to three types of polymers according to their respective polydispersity. It was found that the formation of these products — oligomers, polymers, and high polymers — can be influenced by modifying the experimental conditions. Thus, it is possible to obtain selectively oligomers free of polymers and polymers free of low molecular weight oligomers.     

Double trisomy 8 and 21 in acute myelocytic leukemias,one with rearrangement of the RUNX1 gene

Fluorescence in situ hybridization analysis was carried out in five patients with acute myeloblastic leukemia of various French-American-British subtypes and with double trisomy of chromosomes 8 and 21. PML-RARA fusion was detected with appropriate molecular probes in one patient with acute promyelocytic leukemia without t(15;17). Two PAC probes covering the 5' and 3' part of the RUNX1 gene were used in the four other patients. While three copies were present in three patients, as expected from conventional karyotype analysis, only two hybridization signals were present in the fifth patient. This was due to the apparent loss of the 3' part of RUNX1. Since chromosome number abnormalities may be associated with submicroscopic gene rearrangements, it should be important to search for them for a better understanding of mechanisms of leukemogenesis, and to understand the prognostic heterogeneity in leukemic patients with aneusomies without apparent chromosome structure rearrangements.