Right ventricular dysfunction in acute heart failure from emergency department to discharge: Predictors and clinical implications.

BACKGROUND: Among acute heart failure (AHF) inpatients, right ventricular dysfunction (RVD) predicts clinical outcomes independent of left ventricular (LV) dysfunction. Prior studies have not accounted for congestion severity, show conflicting findings on echocardiography (echo) timing, and excluded emergency department (ED) patients. We describe for the first time the epidemiology, predictors, and outcomes of RVD in AHF starting with earliest ED treatment. METHODS: Point-of-care echo and 10-point lung ultrasound (LUS) were obtained in 84 prospectively enrolled AHF patients at two EDs, ≤1 h after first intravenous diuresis, vasodilator, and/or positive pressure ventilation (PPV). Echo and LUS were repeated at 24, 72, and 168 h, unless discharged sooner (n = 197 exams). RVD was defined as <17 mm tricuspid annulus plane systolic excursion (TAPSE), our primary measure. To identify correlates of RVD, a multivariable linear mixed model (LMM) of TAPSE through time was fit. Possible predictors were specified a priori and/or with p ≤ 0.1 difference between patients with/without RVD. Data were standardized and centered to facilitate comparison of relative strength of association between predictors of TAPSE. Survival curves for a 30-day death or AHF readmission primary outcome were assessed for RVD, LUS severity, and LVEF. A multivariable generalized linear mixed model (GLMM) for the outcome was used to adjust RVD for LVEF and LUS. RESULTS: 46% (n = 39) of patients at ED arrival showed RVD by TAPSE (median 18 mm, interquartile range 13-23). 18 variables with p ≤ 0.1 unadjusted difference with/without RVD, and 12 a priori predictors of RVD were included in the multivariable LMM model of TAPSE through time (R2 = 0.76). Missed antihypertensive medication (within 7 days), ED PPV, chronic obstructive pulmonary disease history, LVEF, LUS congestion severity, and right ventricular systolic pressure (RVSP) were the strongest multivariable predictors of RVD, respectively, and the only to reach statistical significance (p < 0.05). 30-day death or AHF readmission was associated with RVD at ED arrival (hazard ratio {HR} 3.31 {95%CI: 1.28-8.53}, p = 0.009), ED to discharge decrease in LUS (HR 0.11 {0.01-0.85}, p < 0.0001 for top quartile Δ), but not LVEF (quartile 2 vs. 1 HR 0.78 {0.22-2.68}, 3 vs. 1 HR 0.55 {0.16-1.92}, 4 vs. 1 HR 0.32 {0.09-1.22}, p = 0.30). The area under the receiver operating curve on GLMM for the primary outcome by TAPSE (p = 0.0012), ΔLUS (p = 0.0005), and LVEF (p = 0.8347) was 0.807. CONCLUSION: In this observational study, RVD was common in AHF, and predicted by congestion on LUS, LVEF, RVSP, and comorbidities from ED arrival through discharge. 30-day death or AHF-rehospitalization was associated with RVD at ED arrival and ΔLUS severity, but not LVEF.

Disrupting gender norms in health systems: making the case for change.

Restrictive gender norms and gender inequalities are replicated and reinforced in health systems, contributing to gender inequalities in health. In this Series paper, we explore how to address all three through recognition and then with disruptive solutions. We used intersectional feminist theory to guide our systematic reviews, qualitative case studies based on lived experiences, and quantitative analyses based on cross-sectional and evaluation research. We found that health systems reinforce patients' traditional gender roles and neglect gender inequalities in health, health system models and clinic-based programmes are rarely gender responsive, and women have less authority as health workers than men and are often devalued and abused. With regard to potential for disruption, we found that gender equality policies are associated with greater representation of female physicians, which in turn is associated with better health outcomes, but that gender parity is insufficient to achieve gender equality. We found that institutional support and respect of nurses improves quality of care, and that women's empowerment collectives can increase health-care access and provider responsiveness. We see promise from social movements in supporting women's reproductive rights and policies. Our findings suggest we must view gender as a fundamental factor that predetermines and shapes health systems and outcomes. Without addressing the role of restrictive gender norms and gender inequalities within and outside health systems, we will not reach our collective ambitions of universal health coverage and the Sustainable Development Goals. We propose action to systematically identify and address restrictive gender norms and gender inequalities in health systems.

Gender equality and gender norms: framing the opportunities for health.

The Sustainable Development Goals offer the global health community a strategic opportunity to promote human rights, advance gender equality, and achieve health for all. The inability of the health sector to accelerate progress on a range of health outcomes brings into sharp focus the substantial impact of gender inequalities and restrictive gender norms on health risks and behaviours. In this paper, the fifth in a Series on gender equality, norms, and health, we draw on evidence to dispel three myths on gender and health and describe persistent barriers to progress. We propose an agenda for action to reduce gender inequality and shift gender norms for improved health outcomes, calling on leaders in national governments, global health institutions, civil society organisations, academic settings, and the corporate sector to focus on health outcomes and engage actors across sectors to achieve them; reform the workplace and workforce to be more gender-equitable; fill gaps in data and eliminate gender bias in research; fund civil-society actors and social movements; and strengthen accountability mechanisms.

Characterisation of a pucBA deletion mutant from Rhodopseudomonas palustris lacking all but the pucBAd genes.

Rhodopseudomonas palustris is a species of purple photosynthetic bacteria that has a multigene family of puc genes that encode the alpha and beta apoproteins, which form the LH2 complexes. A genetic dissection strategy has been adopted in order to try and understand which spectroscopic form of LH2 these different genes produce. This paper presents a characterisation of one of the deletion mutants generated in this program, the pucBAd only mutant. This mutant produces an unusual spectroscopic form of LH2 that only has a single large NIR absorption band at 800 nm. Spectroscopic and pigment analyses on this complex suggest that it has basically a similar overall structure as that of the wild-type HL LH2 complex. The mutant has the unique phenotype where the mutant LH2 complex is only produced when cells are grown at LL. At HL the mutant only produces the LH1-RC core complex.

Bromodomain-Containing Protein 4: The Epigenetic Origin of Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and suppressed apoptosis. Decreased expression of microRNA-204 has been associated to this phenotype. By a still elusive mechanism, microRNA-204 downregulation promotes the expression of oncogenes, including nuclear factor of activated T cells, B-cell lymphoma 2, and Survivin. In cancer, increased expression of the epigenetic reader bromodomain-containing protein 4 (BRD4) sustains cell survival and proliferation. Interestingly, BRD4 is a predicted target of microRNA-204 and has binding sites on the nuclear factor of activated T cells promoter region. OBJECTIVE: To investigate the role of BRD4 in PAH pathogenesis. METHODS AND RESULTS: BRD4 is upregulated in lungs, distal PAs, and PASMCs of patients with PAH compared with controls. With mechanistic in vitro experiments, we demonstrated that BRD4 expression in PAH is microRNA-204 dependent. We further studied the molecular downstream targets of BRD4 by inhibiting its activity in PAH-PASMCs using a clinically available inhibitor JQ1. JQ1 treatment in PAH-PASMCs increased p21 expression, thus triggering cell cycle arrest. Furthermore, BRD4 inhibition, by JQ1 or siBRD4, decreased the expression of 3 major oncogenes, which are overexpressed in PAH: nuclear factor of activated T cells, B-cell lymphoma 2, and Survivin. Blocking this oncogenic signature led to decreased PAH-PASMC proliferation and increased apoptosis in a BRD4-dependent manner. Indeed, pharmacological JQ1 or molecular (siRNA) inhibition of BRD4 reversed this pathological phenotype in addition to restoring mitochondrial membrane potential and to increasing cells spare respiratory capacity. Moreover, BRD4 inhibition in vivo reversed established PAH in the Sugen/hypoxia rat model. CONCLUSIONS: BRD4 plays a key role in the pathological phenotype in PAH, which could offer new therapeutic perspectives for patients with PAH.

Synthetic toxic Aß1-42 oligomers can assemble in different morphologies.

BACKGROUND: Alzheimer's disease is the most common neurodegenerative disease associated with aggregation of Aß peptides. Aß toxicity is mostly related to the capacity of intermediate oligomers to disrupt membrane integrity. We previously expressed Aß1-42 in a eukaryotic cellular system and selected synthetic variants on their sole toxicity. The most toxic mutant G37C forms stable oligomers. METHODS: Different biophysical methods (Fluorescence spectroscopy, cross-linking, mass spectrometry (MS), Small Angle X-ray Scattering (SAXS), Atomic Force Microscopy (AFM), Transmission Electron Microscopy (TEM), calcein leakage) were used. RESULTS: The oligomers are mostly populated by a 14mers resulting from the packing of homodimers. These homodimers come from the formation of a disulfide bridge between two monomers. This link stabilizes the multimers and prevents the assembly into amyloid fibrils. These oligomers affect the membrane integrity. The reduction of disulfide bonds leads to a rearrangement and redirects assembly of Aß amyloid fibrils. CONCLUSION: The toxic synthetic AßG37C mutant can assemble into an amyloid of unusual morphology through the formation of anti-parallel ß-sheets. This pathway involves the formation of oligomers resulting from the arrangement of Aß dimers linked by covalent di-sulfide link, being these oligomers harmful for the membranes. GENERAL SIGNIFICANCE: The capacity to produce large amount of stable oligomers without additional detergents or extrinsic cross-linkers allow further structural and biophysical studies to understand their capacity to assemble and disrupt the membranes, a key event in Alzheimer's disease.

The role of tryptophans on the cellular uptake and membrane interaction of arginine-rich cell penetrating peptides.

Cell-penetrating peptides (CPP) are able to efficiently transport cargos across cell membranes without being cytotoxic to cells, thus present a great potential in drug delivery and diagnosis. While the role of cationic residues in CPPs has been well studied, that of Trp is still not clear. Herein 7 peptide analogs of RW9 (RRWWRRWRR, an efficient CPP) were synthesized in which Trp were systematically replaced by Phe residues. Quantification of cellular uptake reveals that substitution of Trp by Phe strongly reduces the internalization of all peptides despite the fact that they strongly accumulate in the cell membrane. Cellular internalization and biophysical studies show that not only the number of Trp residues but also their positioning in the helix and the size of the hydrophobic face they form are important for their internalization efficacy, the highest uptake occurring for the analog with 3 Trp residues. Using CD and ATR-FTIR spectroscopy we observe that all peptides became structured in contact with lipids, mainly in α-helix. Intrinsic tryptophan fluorescence studies indicate that all peptides partition in the membrane in about the same manner (Kp~10(5)) and that they are located just below the lipid headgroups (~10 Å) with slightly different insertion depths for the different analogs. Plasmon Waveguide Resonance studies reveal a direct correlation between the number of Trp residues and the reversibility of the interaction following membrane washing. Thus a more interfacial location of the CPP renders the interaction with the membrane more adjustable and transitory enhancing its internalization ability.

DNA-directed spatial assembly of photosynthetic light-harvesting proteins.

This manuscript describes the surface immobilization of a light-harvesting complex to prescribed locations directed by the sequence-selective recognition of duplex DNA. An engineered light-harvesting complex (RC-LH1) derived from Rhodopseudomonas (Rps.) palustris containing the zinc finger (ZF) domain zif268 was prepared. The zif268 domain directed the binding of zfRC-LH1 to target double-stranded DNA sequences both in solution and when immobilized on lithographically defined micro-patterns. Excitation energy transfer from the carotenoids to the bacteriochlorophyll pigments within zfRC-LH1 confirmed that the functional and structural integrity of the complex is retained after surface immobilization.

An Examination of Juveniles' Miranda Abilities: Investigating Differences in Miranda Recall and Reasoning.

Juvenile suspects are routinely expected to possess an accurate recall of written or oral Miranda warnings. This study addresses the Miranda-related comprehension recall and reasoning of legally involved juveniles. It is the first juvenile research to compare systematically two levels of complexity for Miranda warnings with the three modalities (oral, written, or combined) of administration. Unexpectedly, easily read written warnings marginally outperformed the combined modality. In order to examine Miranda reasoning, three juvenile groups were operationalized: impaired, questionable, and likely adequate. Predictably, the impaired and questionable groups possessed significantly lower verbal abilities than the likely-adequate reasoning group. In addition, the likely-adequate group exhibited the strongest appreciation of the adversarial context in which Miranda waiver decisions are rendered. The discussion addresses the marked disparities in Miranda recall from a total recall versus component-by-component understanding of Miranda rights. It also considers more generally how crucially important Miranda misconceptions might be remedied. Copyright © 2016 John Wiley & Sons, Ltd.

Elementary Energy Transfer Pathways in Allochromatium vinosum Photosynthetic Membranes.

Allochromatium vinosum (formerly Chromatium vinosum) purple bacteria are known to adapt their light-harvesting strategy during growth according to environmental factors such as temperature and average light intensity. Under low light illumination or low ambient temperature conditions, most of the LH2 complexes in the photosynthetic membranes form a B820 exciton with reduced spectral overlap with LH1. To elucidate the reason for this light and temperature adaptation of the LH2 electronic structure, we performed broadband femtosecond transient absorption spectroscopy as a function of excitation wavelength in A. vinosum membranes. A target analysis of the acquired data yielded individual rate constants for all relevant elementary energy transfer (ET) processes. We found that the ET dynamics in high-light-grown membranes was well described by a homogeneous model, with forward and backward rate constants independent of the pump wavelength. Thus, the overall B800→B850→B890→ Reaction Center ET cascade is well described by simple triexponential kinetics. In the low-light-grown membranes, we found that the elementary backward transfer rate constant from B890 to B820 was strongly reduced compared with the corresponding constant from B890 to B850 in high-light-grown samples. The ET dynamics of low-light-grown membranes was strongly dependent on the pump wavelength, clearly showing that the excitation memory is not lost throughout the exciton lifetime. The observed pump energy dependence of the forward and backward ET rate constants suggests exciton diffusion via B850→ B850 transfer steps, making the overall ET dynamics nonexponential. Our results show that disorder plays a crucial role in our understanding of low-light adaptation in A. vinosum.

Rubber particle proteins, HbREF and HbSRPP, show different interactions with model membranes.

The biomembrane surrounding rubber particles from the hevea latex is well known for its content of numerous allergen proteins. HbREF (Hevb1) and HbSRPP (Hevb3) are major components, linked on rubber particles, and they have been shown to be involved in rubber synthesis or quality (mass regulation), but their exact function is still to be determined. In this study we highlighted the different modes of interactions of both recombinant proteins with various membrane models (lipid monolayers, liposomes or supported bilayers, and multilamellar vesicles) to mimic the latex particle membrane. We combined various biophysical methods (polarization-modulation-infrared reflection-adsorption spectroscopy (PM-IRRAS)/ellipsometry, attenuated-total reflectance Fourier-transform infrared (ATR-FTIR), solid-state nuclear magnetic resonance (NMR), plasmon waveguide resonance (PWR), fluorescence spectroscopy) to elucidate their interactions. Small rubber particle protein (SRPP) shows less affinity than rubber elongation factor (REF) for the membranes but displays a kind of "covering" effect on the lipid headgroups without disturbing the membrane integrity. Its structure is conserved in the presence of lipids. Contrarily, REF demonstrates higher membrane affinity with changes in its aggregation properties, the amyloid nature of REF, which we previously reported, is not favored in the presence of lipids. REF binds and inserts into membranes. The membrane integrity is highly perturbed, and we suspect that REF is even able to remove lipids from the membrane leading to the formation of mixed micelles. These two homologous proteins show affinity to all membrane models tested but neatly differ in their interacting features. This could imply differential roles on the surface of rubber particles.

Interaction of Aß(1-42) amyloids with lipids promotes "off-pathway" oligomerization and membrane damage.

The toxicity of amyloids, as Aß(1-42) involved in Alzheimer disease, is a subject under intense scrutiny. Many studies link their toxicity to the existence of various intermediate structures prior to fiber formation and/or their specific interaction with membranes. In this study we focused on the interaction between membrane models and Aß(1-42) peptides and variants (L34T, mG37C) produced in E. coli and purified in monomeric form. We evaluated the interaction of a toxic stable oligomeric form (oG37C) with membranes as comparison. Using various biophysical techniques as fluorescence and plasmon waveguide resonance, we clearly established that the oG37C interacts strongly with membranes leading to its disruption. All the studied peptides destabilized liposomes and accumulated slowly on the membrane (rate constant 0.02 min(-1)). Only the oG37C exhibited a particular pattern of interaction, comprising two steps: the initial binding followed by membrane reorganization. Cryo-TEM was used to visualize the peptide effect on liposome morphologies. Both oG37C and mG37C lead to PG membrane fragmentation. The PG membrane promotes peptide oligomerization, implicated in membrane disruption. WT (Aß(1-42)) also perturbs liposome organization with membrane deformation rather than disruption. For all the peptides studied, their interaction with the membranes changes their fibrillization process, with less fibers and more small aggregates being formed. These studies allowed to establish, a correlation between toxicity, fiber formation, and membrane disruption.

Tracking energy transfer between light harvesting complex 2 and 1 in photosynthetic membranes grown under high and low illumination.

Energy transfer (ET) between B850 and B875 molecules in light harvesting complexes LH2 and LH1/RC (reaction center) complexes has been investigated in membranes of Rhodopseudomonas palustris grown under high- and low-light conditions. In these bacteria, illumination intensity during growth strongly affects the type of LH2 complexes synthesized, their optical spectra, and their amount of energetic disorder. We used a specially built femtosecond spectrometer, combining tunable narrowband pump with broadband white-light probe pulses, together with an analytical method based on derivative spectroscopy for disentangling the congested transient absorption spectra of LH1 and LH2 complexes. This procedure allows real-time tracking of the forward (LH2 â†’ LH1) and backward (LH2←LH1) ET processes and unambiguous determination of the corresponding rate constants. In low-light grown samples, we measured lower ET rates in both directions with respect to high-light ones, which is explained by reduced spectral overlap between B850 and B875 due to partial redistribution of oscillator strength into a higher energetic exciton transition. We find that the low-light adaptation in R. palustris leads to a reduced elementary backward ET rate, in accordance with the low probability of two simultaneous excitations reaching the same LH1/RC complex under weak illumination. Our study suggests that backward ET is not just an inevitable consequence of vectorial ET with small energetic offsets, but is in fact actively managed by photosynthetic bacteria.

Statistical considerations on the formation of circular photosynthetic light-harvesting complexes from Rhodopseudomonas palustris.

Depending on growth conditions, some species of purple photosynthetic bacteria contain peripheral light-harvesting (LH2) complexes that are heterogeneous owing to the presence of different protomers (containing different αß-apoproteins). Recent spectroscopic studies of Rhodopseudomonas palustris grown under low-light conditions suggest the presence of a C 3-symmetric LH2 nonamer comprised of two distinct protomers. The software program Cyclaplex, which enables generation and data-mining of virtual libraries of molecular rings formed upon combinatorial reactions, has been used to delineate the possible number and type of distinct nonamers as a function of numbers of distinct protomers. The yield of the C 3-symmetric nonamer from two protomers (A and B in varying ratios) has been studied under the following conditions: (1) statistical, (2) enriched (preclusion of the B-B sequence), and (3) seeded (pre-formation of an A-B-A block). The yield of C 3-symmetric nonamer is at most 0.98 % under statistical conditions versus 5.6 % under enriched conditions, and can be dominant under conditions of pre-seeding with an A-B-A block. In summary, the formation of any one specific nonamer even from only two protomers is unlikely on statistical grounds but must stem from enhanced free energy of formation or a directed assembly process by as-yet unknown factors.

Maternal overnutrition programs changes in the expression of skeletal muscle genes that are associated with insulin resistance and defects of oxidative phosphorylation in adult male rat offspring.

Children of obese mothers have increased risk of metabolic syndrome as adults. Here we report the effects of a high-fat diet in the absence of maternal obesity at conception on skeletal muscle metabolic and transcriptional profiles of adult male offspring. Female Sprague Dawley rats were fed a diet rich in saturated fat and sucrose [high-fat diet (HFD): 23.5% total fat, 9.83% saturated fat, 20% sucrose wt:wt] or a normal control diet [(CD) 7% total fat, 0.5% saturated fat, 10% sucrose wt:wt] for the 3 wk prior to mating and throughout pregnancy and lactation. Maternal weights were not different at conception; however, HFD-fed dams were 22% heavier than controls during pregnancy. On a normal diet, the male offspring of HFD-fed dams were not heavier than controls but demonstrated features of insulin resistance, including elevated plasma insulin concentration [40.1 ± 2.5 (CD) vs 56.2 ± 6.1 (HFD) mU/L; P = 0.023]. Next-generation mRNA sequencing was used to identify differentially expressed genes in the offspring soleus muscle, and gene set enrichment analysis (GSEA) was used to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 upregulated pathways, including cytokine signaling (P < 0.005), starch and sucrose metabolism (P < 0.017), inflammatory response (P < 0.024), and cytokine-cytokine receptor interaction (P < 0.037). A further 8 pathways were downregulated, including oxidative phosphorylation (P < 0.004), mitochondrial matrix (P < 0.006), and electron transport/uncoupling (P < 0.022). Phosphorylation of the insulin signaling protein kinase B was reduced [2.86 ± 0.63 (CD) vs 1.02 ± 0.27 (HFD); P = 0.027] and mitochondrial complexes I, II, and V protein were downregulated by 50-68% (P < 0.005). On a normal diet, the male offspring of HFD-fed dams did not become obese adults but developed insulin resistance, with transcriptional evidence of muscle cytokine activation, inflammation, and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of prepregnancy obesity, can promote metabolic dysregulation and predispose offspring to type 2 diabetes.

Maternal dietary intake during pregnancy has longstanding consequences for the health of her offspring.

Over the past 100 years, advances in pharmaceutical and medical technology have reduced the burden of communicable disease, and our appreciation of the mechanisms underlying the development of noncommunicable disease has broadened. During this time, a number of studies, both in humans and animal models, have highlighted the importance of maintaining an optimal diet during pregnancy. In particular, a number of studies support the hypothesis that suboptimal maternal protein and fat intake during pregnancy can have long-term effects on the growing fetus, and increase the likelihood of these offspring developing cardiovascular, renal, or metabolic diseases in adulthood. More recently, it has been shown that dietary intake of a number of micronutrients may offset or reverse the deleterious effects of macronutrient imbalance. Furthermore, maternal fat intake has also been identified as a major contributor to a healthy fetal environment, with a beneficial role for unsaturated fats during development as well as a beneficial impact on cell membrane physiology. Together these studies indicate that attempts to optimise maternal nutrition may prove to be an efficient and cost-effective strategy for preventing the development of cardiovascular, renal, or metabolic diseases.

Duration of diabetes and pancreatic cancer in a case-control study in the Midwest and the Iowa Women's Health Study (IWHS) cohort.

CONTEXT: Studies have shown a relationship between history of diabetes and the risk of pancreatic cancer; however, the temporal relation between diabetes and pancreatic cancer is not clearly established. OBJECTIVES: Diabetes and diabetes duration were examined in relation to pancreatic cancer in a population-based case-control study and prospective cohort. METHODS: Case-control study: pancreatic cancer cases (n=200) from the Midwest were frequency matched by age and sex to population controls (n=673). Logistic regression yielded odds ratios (ORs) and 95% confidence intervals (95% CI). Iowa Women's Health Study (IWHS) cohort: 292 incident pancreatic cancer cases occurred between 1986-2008 among 36,084 post-menopausal, initially cancer-free women. Diabetes status and diagnosis age were ascertained at baseline and follow-ups. Proportional hazards regression yielded hazard ratios (HR, 95% CI) for pancreatic cancer in relation to baseline diabetes. Time-dependent analyses accounted for diabetes diagnosed after baseline. A nested-case control analysis assessed diabetes duration as a risk factor. RESULTS: In the case-control study, compared to participants without diabetes, the multivariate ORs (95% CI) for pancreatic cancer were 2.35 (1.24-4.47) for those with diabetes and 4.00 (0.94-16.9), 2.79 (0.97-8.04), and 2.40 (0.97-5.98) for diabetes durations of 2-5 years, 5.1-10 years, and more than 10 years, respectively. In IWHS, compared to no diabetes, multivariate-adjusted HRs for pancreatic cancer were 1.86 (1.23-2.83) for baseline diabetes and 1.94 (1.40-2.69) adding diabetes during follow-up. In an IWHS nested case-control analysis, ORs were 1.70 (0.78-3.67), 2.62 (1.48-4.65), and 2.10 (1.36-3.24) for diabetes durations of 2-5 years, 5.1-10 years and more than 10 years, respectively, versus no diabetes. CONCLUSIONS: Diabetes is associated with pancreatic cancer risk and this is similar across different duration categories.

Cardiovascular and renal profiles in rat offspring that do not undergo catch-up growth after exposure to maternal protein restriction.

Maternal protein restriction is often associated with structural and functional sequelae in offspring, particularly affecting growth and renal-cardiovascular function. However, there is little understanding as to whether hypertension and kidney disease occur because of a primary nephron deficit or whether controlling postnatal growth can result in normal renal-cardiovascular phenotypes. To investigate this, female Sprague-Dawley rats were fed either a low-protein (LP, 8.4% protein) or normal-protein (NP, 19.4% protein) diet prior to mating and until offspring were weaned at postnatal day (PN) 21. Offspring were then fed a non 'growth' (4.6% fat) which ensured that catch-up growth did not occur. Offspring growth was determined by weight and dual energy X-ray absorptiometry. Nephron number was determined at PN21 using the disector-fractionator method. Kidney function was measured at PN180 and PN360 using clearance methods. Blood pressure was measured at PN360 using radio-telemetry. Body weight was similar at PN1, but by PN21 LP offspring were 39% smaller than controls (Pdiet < 0.001). This difference was due to proportional changes in lean muscle, fat, and bone content. LP offspring remained smaller than NP offspring until PN360. In LP offspring, nephron number was 26% less in males and 17% less in females, than NP controls (Pdiet < 0.0004). Kidney function was similar across dietary groups and sexes at PN180 and PN360. Blood pressure was similar in LP and NP offspring at PN360. These findings suggest that remaining on a slow growth trajectory after exposure to a suboptimal intrauterine environment does not lead to the development of kidney dysfunction and hypertension.

Developmental origins of obesity-related hypertension.

1. In the past 30 years the prevalence of obesity and overweight have doubled. It is now estimated that globally over 500 million adults are obese and a further billion adults are overweight. Obesity is a cardiovascular risk factor and some studies suggest that up to 70% of cases of essential hypertension may be attributable, in part, to obesity. Increasingly, evidence supports a view that obesity-related hypertension may be driven by altered hypothalamic signalling, which results in inappropriately high appetite and sympathetic nerve activity to the kidney. 2. In addition to the adult risk factors for obesity and hypertension, the environment encountered in early life may 'programme' the development of obesity, hypertension and cardiovascular disease. In particular, maternal obesity or high dietary fat intake in pregnancy may induce changes in fetal growth trajectories and predispose individuals to develop obesity and related sequelae. 3. The mechanisms underlying the programming of obesity-related hypertension are becoming better understood. However, several issues require clarification, particularly with regard to the role of the placenta in transferring fatty acid to the fetal compartment, the impact of placental inflammation and cytokine production in obesity. 4. By understanding which factors are most associated with the development of obesity and hypertension in the offspring, we can focus therapeutic and behavioural interventions to most efficiently reduce the intergenerational propagation of the obesity cycle.