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.     

Inhibition of tumor cell proliferation by type IV collagen requires increased levels of cAMP

Previous studies from our laboratories demonstrated that a peptide from the noncollagenous domain of the alpha3 chain of basement membrane collagen (COL IV), comprising residues 185-203, inhibits polymorphonuclear leukocyte activation and melanoma cell proliferation; this property requires the presence of the triplet -SNS- in residues 189-191 (Monboisse et al., J. Biol. Chem., 269, 25475, 1994; Han et al., J. Biol. Chem., 272, 20395, 1997). In the present study, we demonstrate that whole native COL IV and -SNS- containing synthetic peptides (10 microg/ml) added to culture medium inhibit the proliferation of not only melanoma cells, but also breast-, pancreas- and stomach-tumor cells up to 67%, and prostate tumor cells by 15%. ALC-COL IV at 5 microg/ml was shown to inhibit melanoma cell proliferation maximally at 69% and the alpha3(IV)185-203 peptide inhibited proliferation (62%) maximally at 10 microg/ml. Treatment of the alpha3(IV)185-203 peptide with either a specific mAb or a polyclonal antibody, prepared against the sequence alpha3(IV)179-208, decreased the ability of the peptide to inhibit cell proliferation by 97%, while treatment of ALC-COL IV with the same antibodies inhibited proliferation by 44%. Exposure of the above tumor cells to COL IV or the peptides resulted in an increase of intracellular cAMP that was inhibited by prior treatment of the protein with the above antibodies. To investigate the role of cAMP in the inhibition of cell proliferation, cAMP analogs and inhibitors were used. cAMP analogs mimicked the inhibitory effect of the peptide. Rp-cAMPS, a cAMP competitive inhibitor, suppressed the inhibitory effect of ALC-COL IV and of the cAMP analogs. The protein kinase-A inhibitor H-89 blocked the ability of ALC-COL IV and of the alpha3(IV)185-203 peptide to inhibit tumor cell proliferation. These data suggest that ALC-COL IV, through its alpha3(IV) chain, inhibits tumor cell proliferation utilizing a signal transduction pathway which includes cAMP and cAMP-dependent protein kinase(s).     

Correction to: Prenatal attachment: Using measurement invariance to test the validity of comparisons across eight culturally diverse countries

Archives of Women's Mental Health - A Correction to this paper has been published: https://doi.org/10.1007/s00737-021-01122-7     

Social disadvantage, bone mineral density and vertebral wedge deformities in the Tasmanian Older Adult Cohort

Summary

The relationship between social disadvantage and bone mineral density (BMD) is complex and remains unclear; furthermore, little is known of the relationship with vertebral deformities. We observed social disadvantage to be associated with BMD for females, independent of body mass index (BMI). A lower prevalence of vertebral deformities was observed for disadvantaged males.

Introduction

The relationship between social disadvantage and BMD appears complex and remains unclear, and little is known about the association between social disadvantage and vertebral wedge deformities. We examined the relationship between social disadvantage, BMD and wedge deformities in older adults from the Tasmanian Older Adult Cohort.

Methods

BMD and wedge deformities were measured by dual-energy X-ray absorptiometry and associations with extreme social disadvantage was examined in 1,074 randomly recruited population-based adults (51 % female). Socioeconomic status was assessed by Socio-economic Indexes for Areas values derived from residential addresses using Australian Bureau of Statistics 2001 census data. Lifestyle variables were collected by self-report. Regression models were adjusted for age, BMI, dietary calcium, serum vitamin D (25(OH)D), smoking, alcohol, physical inactivity, calcium/vitamin D supplements, glucocorticoids and hormone therapy (females only).

Results

Compared with other males, socially disadvantaged males were older (65.9 years versus 61.9 years, p?=?0.008) and consumed lower dietary calcium and alcohol (both p?≤?0.03). Socially disadvantaged females had greater BMI (29.9?±?5.9 versus 27.6?±?5.3, p?=?0.002) and consumed less alcohol (p?=?0.003) compared with other females. Socially disadvantaged males had fewer wedge deformities compared with other males (33.3 % versus 45.4 %, p?=?0.05). After adjustment, social disadvantage was negatively associated with hip BMD for females (p?=?0.02), but not for males (p?=?0.70), and showed a trend for fewer wedge deformities for males (p?=?0.06) but no association for females (p?=?0.85).

Conclusions

Social disadvantage appears to be associated with BMD for females, independent of BMI and other osteoporosis risk factors. A lower prevalence of vertebral deformities was observed for males of extreme social disadvantage. Further research is required to elucidate potential mechanisms for these associations.