Prevalence of gestational diabetes mellitus, maternal obesity and associated perinatal outcomes over 10 years in an Australian tertiary maternity provider.

BACKGROUND: The International Association of Diabetes in Pregnancy Study Groups (IADPSG) gestational diabetes mellitus (GDM) criteria have been heavily scrutinised with concerns that the consequent GDM prevalence increase has not been associated with improved perinatal outcomes. AIMS: At a tertiary hospital in Melbourne, Australia we aimed to evaluate prevalence trends for GDM, type 2 diabetes (T2DM), maternal obesity and large-for-gestational age (LGA) and assess changes in perinatal outcomes following IADPSG criteria uptake in 2015. METHODS: A retrospective cohort study of singleton births from 20 weeks' gestation was conducted between 1st January 2011 and 31st December 2020. Maternal characteristics and perinatal outcomes were extracted from medical records. RESULTS: 52,795 pregnancies were included. GDM prevalence increased 2.7 times from 8.9% in 2011 to 23.7% in 2020 and increased annually by 8.59% (95%CI 7.77, 9.42). The rate of T2DM increased annually by 11.69% (95%CI 7.72, 16.67). Obesity prevalence increased annually by 3.18% (95%CI 2.58, 3.78). Induction of labour (IOL) prevalence increased annually by 8.35% (95%CI 5.69, 11.06). LGA prevalence remained unchanged. Increasing maternal obesity was the major contributing factor for LGA prevalence. CONCLUSIONS: From 2011 to 2020 GDM, obesity and T2DM prevalence increased significantly, with associated increased IOL, without change in LGA rates. Prospective studies are required to explore interactions between GDM, obesity, LGA and obstetric interventions.

Loss of bone density and bone strength following premenopausal risk-reducing bilateral salpingo-oophorectomy: a prospective controlled study (WHAM Study).

Prophylactic oophorectomy is recommended for women at high risk for ovarian cancer, but the associated impact on bone health is of clinical concern. This prospective, controlled study demonstrated substantial loss of bone density and bone strength following surgical menopause. Postoperative hormone therapy alleviated, but not fully prevented, spinal bone loss. INTRODUCTION: This prospective study investigated bone health in women following premenopausal oophorectomy. METHODS: Dual-energy x-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and pQCT-based finite element analysis (pQCT-FEA) were used to assess bone health between systemic hormone therapy (HT) users and non-users after premenopausal risk-reducing bilateral salpingo-oophorectomy (RRBSO) compared with premenopausal controls over 24-month follow-up. RESULTS: Mean age was 42.4 ± 2.6 years (n = 30) for the surgery group and 40.2 ± 6.3 years for controls (n = 42), and baseline bone measures were similar between groups. Compromised bone variables were observed at 24 months after RRBSO, among which areal bone mineral density (aBMD) at the lumbar spine, tibial volumetric cortical density (Crt vBMD), and tibial bending stiffness (kbend) had decreased by 4.7%, 1.0%, and 12.1%, respectively (all p < 0.01). In non-HT users, significant losses in lumbar spine (5.8%), total hip (5.2%), femoral neck (6.0%) aBMD, tibial Crt vBMD (2.3%), and kbend (14.8%) were observed at 24 months (all p < 0.01). HT prevented losses in kbend, tibial Crt vBMD, and aBMD, except for modest 2.3% loss at the lumbar spine (p = 0.01). CONCLUSION: This prospective, controlled study of bone health following RRBSO or premenopausal oophorectomy demonstrated substantial loss of bone density and bone strength following RRBSO. HT prevented loss of bone density and bone stiffness, although there was still a modest decrease in lumbar spine aBMD in HT users. These findings may inform decision-making about RRBSO and clinical management following premenopausal oophorectomy.

Peripheral quantitative computed tomography (pQCT)-based finite element analysis provides enhanced diagnostic performance in identifying non-vertebral fracture patients compared with dual-energy X-ray absorptiometry.

Due to limitations of the predominant clinical method for diagnosing osteoporosis, an engineering model based on a dedicated CT scanner for bone density and structure was applied in fracture patients and controls. Improved diagnostic performance was observed, which supports its potential use in future research and clinical practice. INTRODUCTION: Dual-energy X-ray absorptiometry (DXA), the predominant clinical method for diagnosing osteoporosis, has limitations in identifying individuals with increased fracture risk. Peripheral quantitative computed tomography (pQCT) provides additional information and can be used to generate finite element (FE) models from which bone strength properties can be estimated. We investigated the ability of pQCT-FE properties to distinguish peripheral low-trauma fracture patients from healthy controls, by comparison with DXA and standard pQCT. METHODS: One hundred and eight fracture patients (77 females aged 67.7 ± 7.9 years, 31 males aged 69.7 ± 8.9 years) were recruited from a hospital fracture liaison service. One hundred and twenty healthy community controls (85 females aged 69.8 ± 8.5 years, 35 males aged 68.9 ± 7.2 years) were recruited. RESULTS: Significant differences between groups were observed in pQCT-FE properties, especially at the 4% tibia site. Fracture odds increased most per standard deviation decrease in pQCT-FE at this location [shear stiffness estimate, kshear, in females, OR = 10.34, 95% CI (1.91, 43.98); bending stiffness estimate, kbend, in males, OR = 8.32, 95% CI (4.15, 33.84)]. Area under the receiver operating characteristics curve (AUROC) was observed to be highest with pQCT-FE properties at 4% the tibia site. In females, this was 0.83 for the pQCT-FE variable kshear, compared with 0.72 for DXA total hip bone density (TH aBMD) and 0.76 for pQCT tibia trabecular density (Trb vBMD); in males, this was 0.81 for the pQCT-FE variable kbend at the 4% tibia site, compared with 0.62 for TH aBMD and 0.71 for Trb vBMD. There were significant differences in AUROC between DXA and pQCT-FE variables in both females (p = 0.02) and males (p = 0.03), while no difference was observed in AUROC between primary pQCT and pQCT-FE variables. CONCLUSIONS: pQCT-FE modeling can provide enhanced diagnostic performance compared with DXA and, given its moderate cost, may be useful in clinical settings.

A MEN1 pancreatic neuroendocrine tumour mouse model under temporal control.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by occurrence of parathyroid tumours and neuroendocrine tumours (NETs) of the pancreatic islets and anterior pituitary. The MEN1 gene, encoding menin, is a tumour suppressor, but its precise role in initiating in vivo tumourigenesis remains to be elucidated. The availability of a temporally controlled conditional MEN1 mouse model would greatly facilitate the study of such early tumourigenic events, and overcome the limitations of other MEN1 knockout models, in which menin is lost from conception or tumour development occurs asynchronously. To generate a temporally controlled conditional mouse model, we crossbred mice with the MEN1 gene floxed by LoxP sites (Men1L/L ), and mice expressing tamoxifen-inducible Cre recombinase under the control of the rat insulin promoter (RIP2-CreER), to establish a pancreatic ß-cell-specific NET model under temporal control (Men1L/L /RIP2-CreER). Men1L/L /RIP2-CreER mice aged ~3 months were given tamoxifen in the diet for 5 days, and pancreata harvested 2-2.5, 2.9-3.5 and 4.5-5.5 months later. Control mice did not express Cre and did not receive tamoxifen. Immunostaining of pancreata from tamoxifen-treated Men1L/L /RIP2-CreER mice, compared to control mice, showed at all ages: loss of menin in all islets; increased islet area (>4.2-fold); increased proliferation of insulin immunostaining ß-cells (>2.3-fold) and decreased proliferation of glucagon immunostaining α-cells (>1.7-fold). There were no gender and apoptotic or proliferation differences, and extra-pancreatic tumours were not detected. Thus, we have established a mouse model (Men1L/L /RIP2-CreER) to study early events in the development of pancreatic ß-cell NETs.

Impact of insulin initiation on glycaemic variability and glucose profiles in a primary healthcare Type 2 diabetes cohort: analysis of continuous glucose monitoring data from the INITIATION study.

AIM: To use continuous glucose monitoring to examine the effects of insulin initiation with glargine, with or without glulisine, on glycaemic variability and glycaemia in a cohort of people with Type 2 diabetes receiving maximum oral hypoglycaemic agents in primary healthcare. METHODS: We conducted a post hoc analysis of continuous glucose monitoring data from 89 participants at baseline and at 24 weeks after insulin commencement. Indicators of glycaemic variability (standard deviation, J-index and mean amplitude of glycaemic excursion) and glycaemia (HbA1c , mean glucose, area under the glucose-time curve) were assessed. Multi-level regression analysis was used to identify the predictors of change. RESULTS: Complete glycaemic variability data were available for 78 participants. Of these participants, 41% were women, their mean (sd) age was 59.2 (10.4) years, the median (interquartile range) diabetes duration was 10.4 (6.5, 13.3) years and the median (interquartile range) baseline HbA1c was 82.5 (71.6, 96.7) mmol/mol [9.7 (8.7, 11.0)%]. At baseline, BMI correlated negatively with standard deviation (r = -0.30) and mean amplitude of glycaemic excursion (r = -0.26), but not with J-index; HbA1c correlated with J-index (r = 0.61) but not with mean amplitude of glycaemic excursion and standard deviation. After insulin initiation the mean (sd) glucose level decreased [from 12.0 (3.0) to 8.5 (1.6) mmol/l; P < 0.001], as did the median (interquartile range) J-index [from 66.9 (47.7, 95.1) to 36.9 (27.6, 49.8) mmol/l; P < 0.001]. Baseline HbA1c correlated with a greater J-index reduction (r = -0.45; P < 0.001). The mean amplitude of glycaemic excursion and standard deviation values were unchanged. The baseline temporal profile, showing elevated postprandial morning glucose levels, was unchanged after insulin initiation, despite an overall reduction in glycaemia. CONCLUSION: Insulin initiation reduced hyperglycaemia but did not alter glycaemic variability in adults with Type 2 diabetes receiving maximum oral hypoglycaemic agents. The most significant postprandial excursions were seen in the morning, which identifies prebreakfast as the most effective target for short-acting insulin therapy.

Contemporary pollen-mediated gene immigration reflects the historical isolation of a rare, animal-pollinated shrub in a fragmented landscape.

Fragmentation is generally considered to have negative impacts on widespread outbreeders but impacts on gene flow and diversity in patchy, naturally rare, self-compatible plant species remain unclear. We investigated diversity, gene flow and contemporary pollen-mediated gene immigration in the rare, narrowly distributed endemic shrub Calothamnus quadrifidus ssp. teretifolius. This taxon occurs in an internationally recognized biodiversity hotspot subjected to recent human-induced fragmentation and the condition of the remnants ranges from intact to highly degraded. Using microsatellites, we found that inbreeding, historically low gene flow and significant population differentiation have characterized the genetic system of C. quadrifidus ssp. teretifolius. Inbreeding arises from self-pollination, a small amount of biparental inbreeding and significant correlation of outcross paternity but fecundity was high suggesting populations might have purged their lethals. Paternity analyses show that pollinators can move pollen over degraded and intact habitat but populations in both intact and degraded remnants had few pollen parents per seed parent and low pollen immigration. Genetic diversity did not differ significantly between intact and degraded remnants but there were signs of genetic bottlenecks and reduced diversity in some degraded remnants. Overall, our study suggests human-induced fragmentation has not significantly changed the mating system, or pollen immigration to, remnant populations and therefore genetic connectivity need not be the highest conservation priority. Rather, for rare species adapted to higher levels of inbreeding, conservation efforts may be best directed to managing intact habitats and ecosystem processes.

New-onset diabetes after kidney transplantation-changes and challenges.

Despite substantial improvement in short-term results after kidney transplantation, increases in long-term graft survival have been modest. A significant impediment has been the morbidity and mortality attributable to cardiovascular disease (CVD). New-onset diabetes after transplantation (NODAT) is an independent predictor of cardiovascular events. This review examines recent literature surrounding diagnosis, outcomes and management of NODAT. Amongst otherwise heterogeneous studies, a common finding is the relative insensitivity of fasting blood glucose (FBG) as a screening test. Incorporating self-testing of afternoon capillary BG and glycohemoglobin (HbA(1c) ) detects many cases that would otherwise remain undetected without the oral glucose tolerance test (OGTT). Assessing the impact of NODAT on patient and graft survival is complicated by changes to diagnostic criteria, evolution of immunosuppressive regimens and increasing attention to cardiovascular risk management. Although recent studies reinforce a link between NODAT and death with a functioning graft (DWFG), there seems to be little effect on death-censored graft loss. The significance of glycemic control and diabetes resolution for patient outcomes remain notably absent from NODAT literature and treatment is also a neglected area. This review examines new and old therapeutic options, emphasizing the need to assess ß-cell pathology in customizing therapy. Finally, areas warranting further research are considered.

Evaluating the influence of different aspects of habitat fragmentation on mating patterns and pollen dispersal in the bird-pollinated Banksia sphaerocarpa var. caesia.

Habitat fragmentation can significantly affect mating and pollen dispersal patterns in plant populations, although the differential effects of the various aspects of fragmentation are poorly understood. In this study, we used eight microsatellite loci to investigate the effect of fragmentation on the mating system and pollen dispersal within one large and eight small population remnants of Banksia sphaerocarpa var. caesia, a bird-pollinated shrub in the southern agricultural region of Western Australia. The large population had a much larger neighbourhood size and lower selfing rate, maternal pollen pool differentiation and within-plot mean pollen dispersal distance than the small populations. Outcrossing was consistently high and ranged from 85.7% ± 2.6 to 98.5% ± 0.9, and mating patterns suggested nearest-neighbour pollination. Pollen immigration into small populations ranged from 2.8% ± 1.8 to 16.5% ± 3.2. Using the small populations, we tested for correlations between various fragmentation variables and mating system and pollen dispersal parameters. We found significant negative linear relationships between population isolation and outcrossing rate; population shape and neighbourhood size; and conspecific density and mean pollen dispersal distance. There were significant positive linear relationships between population shape and pollen pool differentiation and between population size and number of different fathers per seed crop. Our results suggest that birds may use a series of fragmented populations as a vegetation corridor while foraging across the landscape and that population connectivity is a critical determinant of pollinator visitation. Our results also suggest that the effect of a linear population shape on the mating system and pollen dispersal is routinely underestimated.

Reproductive deficiencies in transgenic mice expressing the rat inhibin alpha-subunit gene.

Inhibin is an important modulator of reproductive function at both the endocrine level, through its regulation of pituitary FSH biosynthesis, and at the paracrine and autocrine levels, as an intragonadal regulatory factor. To investigate the in vivo actions of inhibin in FSH regulation and gonadal function, transgenic mice that overexpress the rat inhibin alpha-subunit gene were generated. A transgene that includes the mouse metallothionein-I gene promoter (MT-alpha) fused to the rat inhibin alpha-subunit precursor coding sequences was used to produce three lines of transgenic mice. Transgene mRNA is expressed in numerous tissues, including the pituitary, liver, testis, ovary, and kidney. Inhibin alpha-subunit protein was also increased in transgenic pituitary and ovary. Serum inhibin alpha-subunit levels are highly increased compared with control mice. Inhibin beta(A)- and beta(B)-subunit protein amounts are lower in transgenic ovaries compared with wild type, although serum levels of activin A are not significantly reduced in transgenic female mice. FSH levels are reduced in both male and female transgenic mice, whereas LH levels are increased in MT-alpha female mice. MT-alpha transgenic females are subfertile and exhibit a 52% reduction in litter size compared with wild-type females. The smaller litter size of MT-alpha female mice was correlated with a reduction in the number of oocytes ovulated during a normal cycle. Treatment of the transgenic females with exogenous gonadotropins resulted in an ovulation rate similar to that of stimulated wild-type animals, suggesting that altered gonadotropin levels may be responsible for the decreased ovulation rates. MT-alpha transgenic male mice are fertile and sire litters of equivalent size to those sired by wild-type males, despite an approximately 50% reduction in sperm numbers. These results indicate that overexpression of the rat inhibin alpha-subunit gene in mice leads to a disruption of the normal inhibin-to-activin ratio and to reproductive deficiencies, and they support the hypothesis that inhibin and activin act to regulate FSH secretion in vivo and are essential for normal gonadal function.

Gonadal pathologies in transgenic mice expressing the rat inhibin alpha-subunit.

Inhibin and activin are structurally related dimeric peptide hormones and are members of the TGF-beta superfamily of proteins. In the accompanying paper, we describe transgenic mice that overexpress the inhibin alpha-subunit gene from a metallothionein-I promoter (MT-alpha) and examine the effects of the MT-alpha transgene on gonadotropin levels and fertility. To characterize the effects of increased inhibin alpha-subunit on gonadal morphology and function, in this report we investigate gonadal histology, steroid hormone levels, and the basis of ovarian cyst formation in MT-alpha transgenic mice. MT-alpha transgenic female mice develop large fluid-filled ovarian cysts of follicular origin as early as 3 months of age. By 12 months of age, more than 92% of female MT-alpha transgenic mice develop ovarian cysts compared with less than 25% of wild-type littermates. Ovarian cysts form unilaterally or bilaterally, and cystic ovaries often have a greatly expanded bursal sac. Additionally, the ovaries of MT-alpha transgenic mice contain polyovular follicles and have fewer mature antral follicles and corpora lutea. MT-alpha female mice exhibit abnormal steroid hormone production, with increased serum T levels and reductions in serum E with corresponding reductions in uterine mass. In the MT-alpha transgenic males, testis size was decreased by 20-40% compared with control males, and there is a corresponding reduction in seminiferous tubule volume. After a chronic treatment with a GnRH antagonist, MT-alpha female mice continued to develop ovarian cysts and bursal sac expansions, although the cysts were markedly reduced in size. These results indicate that the expression of the rat inhibin alpha-subunit in mice results in significant ovarian pathology, reduced testicular size, and altered ovarian steroidogenesis. The antagonist studies are consistent with a direct ovarian effect of the alpha-subunit transgene product mediated by changes in the inhibin-to-activin ratio in these mice.

Asthmatic bronchial hyperresponsiveness varies with ambient levels of summertime air pollution.

It is widely believed that the mechanisms of action of outdoor air pollutants are the same as those found in the laboratory, although few studies have attempted to clarify this issue. This study investigates the relationship of asthmatic bronchial hyperresponsiveness (BHR), a marker of airway inflammation, and pulmonary function to ambient levels of summertime air pollution. Thirty eight nonsmoking adult asthmatic subjects underwent repeated measurement of methacholine BHR, using Yan's method, at differing levels of air pollution (O3, SO2, NO2, smoke) during summer 1993. A total of 109 evaluable tests were performed: 31 subjects completed three or more challenge tests, and seven managed two. Levels of all pollutants remained within current World Health Organization (WHO) Guidelines for Health. Changes in BHR were found to correlate significantly with changes in the levels of 24 h mean SO2, NO2 and smoke; 48 h mean NO2 and smoke; 24 h lag NO2; although the effect was only small, accounting for approximately 10% of the variability in within-subject BHR between visits. Twenty four hour lag NO2 was also associated with forced vital capacity (FVC). In conclusion, in subjects with asthma, methacholine bronchial hyperresponsiveness varies with ambient levels of summertime air pollution. This suggests that changes in airway inflammation underlie the increased respiratory morbidity known to accompany pollution episodes.

Effects of air pollution on symptoms and peak expiratory flow measurements in subjects with obstructive airways disease.

BACKGROUND: Evidence from laboratory studies suggests that air pollution can produce bronchoconstriction and respiratory symptoms in selected subjects, but the relevance of these findings to exposure to natural pollution is unclear. This study was performed to determine whether air pollution at typical levels found in the UK has demonstrable effects on respiratory function and symptoms in subjects with airways disease. METHODS: Seventy five adult patients with diagnoses of asthma or chronic obstructive pulmonary disease (COPD) were studied for a period of four weeks during which they kept records of their peak expiratory flow (PEF) rates, symptoms (wheeze, dyspnoea, cough, throat and eye irritation), and bronchodilator use. Thirty six patients in whom the provocative dose of methacholine causing a 20% fall in FEV1 was below 12.25 mumol were classified as reactors. Ambient air pollution was measured with absorption spectroscopy. RESULTS: There were modest but significant increases in PEF variability, bronchodilator use, and wheeze with increasing sulphur dioxide levels; bronchodilator use, dyspnoea, eye irritation, and minimum PEF readings were related to ozone levels. In the subgroup of reactors falls in mean and minimum peak flow and increases in wheeze, dyspnoea, and bronchodilator use were associated with increases in levels of both sulphur dioxide and ozone. Some associations were seen with pollution levels on the same day, but for others the pollution effects appeared to be delayed by 24 or 48 hours. Pollution levels did not breach the WHO guide levels during the course of the study. CONCLUSIONS: Increases in environmental levels of ozone and sulphur dioxide are associated with adverse changes in peak flow measurements and both ocular and respiratory symptoms in subjects with obstructive airways disease. Although the peak flow and symptom changes were modest, they occurred at pollution levels below current WHO guide levels.

Clinical relevance of blood viscosity and red cell deformability including newer therapeutic aspects.

Peripheral ischemia is mostly due to narrowing of the vessels, although blood supply is also influenced by the hemorheologic properties of the blood. Recent research has revealed that abnormally high blood viscosity can be a contributing cause in ischemia. Therapeutically decreasing the blood viscosity improves the ischemia by increasing flow through the narrowed vessels and may as such offer a valuable alternative to surgery. Different possible therapeutic approaches for decreasing blood viscosity and the related clinical evidence are discussed.

Is haemodilution a good thing?

Some of the evidence linking a high normal haematocrit with increased risk of cardiovascular disease has been reviewed and studies have been described which show that lowering the haematocrit, even if it is in the normal range initially, may be of clinical benefit. Haemodilution in no way treats the primary cause of ischemia, but it may compensate in some measure for narrowing of the vessels.

Haemorrheological response to plasma exchange in Raynaud's syndrome.

Eight patients with Raynaud's syndrome were treated by weekly plasma exchange for four weeks using a Haemonetics Model 30 Blood Processor. The mean whole-blood viscosity at a shear rate of 0.77/s was significantly lower after treatment, and the mean index of red-cell deformability was significantly improved. In four patients studied serially the mean percentage fall in whole-blood viscosity after a single plasma exchange was 49% at 0.77/s but only 14% at 91/s. All patients noticed symptomatic improvement including healing of ischaemic digital ulcers. In six patients the number of digital arterial segments containing detectable blood flow was measured by directional Doppler; in all six the number increased. It is concluded that plasma exchange is an effective means of haemorrheological treatment and may be beneficial in patients with digital ischaemia.

Increase in leg blood-flow by normovolaemic haemodilution in intermittent claudication.

Normovolaemic haemodilution down to a packed-cell volume of 35% was done in 10 patients with stable intermittent claudication. For a mean reducation in the packed-cell volume of 21.5% there was a 170% increase in peak calf blood-flow and a 111% increase in haemoglobin delivery. 7 of the 10 patients reported an increased walking distance. Normovolaemic haemodilution may be of use in the management of some patients with peripheral vascular disease.

Preoperative haemoglobin as predictor of outcome of diabetic amputations.

Simple factors which may serve as predictors of the success or failure of amputations in the feet were examined in 59 consecutive diabetics. Age, sex, method of diabetic control, smoling, presence of neuropathy or peripheral pulses, preoperative blood-urea, and temperature did not correlate with success of amuptations. The average preoperative white-cell count and blood-sugar were higher in the failure group (p less than 0.01 and p less than 0.05 respectively), but there was considerable overlap between the groups. By contrast, the preoperative haemoglobin level was significantly lower (p less than 0.001) in patients whose amputations healed than in those with failure of healing, both at the digital and metatarsal or transmetatarsal levels; also, there was very little overlap in haemoglobin levels between the success and failure groups. All 18 amputations done in patients with a preoperative haemoglobin less than 12.0 g/dl were successful, whilst all 30 amputations in those with a preoperative level greater than 13.0 g/dl failed.