Prelithiation of Lithium Peroxide for Silicon Anode: Achieving a High Activation Rate.

The use of lithium peroxide (Li2O2) as a cost-effective low-weight prelithiation cathode additive was successfully demonstrated. Through a series of studies on the chemical stability of Li2O2 and the activation process of Li2O2 on the cathode, we revealed that Li2O2 is more compatible with conventional electrolyte and cathode laminate slurry than lithium oxide. Due to the significantly smaller size of commercial Li2O2, it can be used directly as a cathode additive. Moreover, the activation of Li2O2 on the cathode leads to the impedance growth of the cathode possibly resulting from the release of dioxygen and evacuation of Li2O2 inside the cathode. With the introduction of a new Li2O2 spread-coating technique on the cathode, the capacity loss was suppressed. Si||NMC full cells using Li2O2 spread-coated cathode demonstrated a highly promising activation rate of Li2O2 and significantly enhanced specific capacity and cycling stability compared to the uncoated full cells.

Probing Depth-Dependent Transition-Metal Redox of Lithium Nickel, Manganese, and Cobalt Oxides in Li-Ion Batteries.

Layered lithium nickel, manganese, and cobalt oxides (NMC) are among the most promising commercial positive electrodes in the past decades. Understanding the detailed surface and bulk redox processes of Ni-rich NMC can provide useful insights into material design options to boost reversible capacity and cycle life. Both hard X-ray absorption (XAS) of metal K-edges and soft XAS of metal L-edges collected from charged LiNi0.6Mn0.2Co0.2O2 (NMC622) and LiNi0.8Mn0.1Co0.1O2 (NMC811) showed that the charge capacity up to removing ∼0.7 Li/f.u. was accompanied with Ni oxidation in bulk and near the surface (up to 100 nm). Of significance to note is that nickel oxidation is primarily responsible for the charge capacity of NMC622 and 811 up to similar lithium removal (∼0.7 Li/f.u.) albeit charged to different potentials, beyond which was followed by Ni reduction near the surface (up to 100 nm) due to oxygen release and electrolyte parasitic reactions. This observation points toward several new strategies to enhance reversible redox capacities of Ni-rich and/or Co-free electrodes for high-energy Li-ion batteries.

Enhanced Cycling Performance of Ni-Rich Positive Electrodes (NMC) in Li-Ion Batteries by Reducing Electrolyte Free-Solvent Activity.

The interfacial (electro)chemical reactions between electrode and electrolyte dictate the cycling stability of Li-ion batteries. Previous experimental and computational results have shown that replacing Mn and Co with Ni in layered LiNixMnyCo1-x-yO2 (NMC) positive electrodes promotes the dehydrogenation of carbonate-based electrolytes on the oxide surface, which generates protic species to decompose LiPF6 in the electrolyte. In this study, we utilized this understanding to stabilize LiNi0.8Mn0.1Co0.1O2 (NMC811) by decreasing free-solvent activity in the electrolyte through controlling salt concentration and salt dissociativity. Infrared spectroscopy revealed that highly concentrated electrolytes with low free-solvent activity had no dehydrogenation of ethylene carbonate, which could be attributed to slow kinetics of dissociative adsorption of Li+-coordinated solvents on oxide surfaces. The increased stability of the concentrated electrolyte against solvent dehydrogenation gave rise to high capacity retention of NMC811 with capacities greater than 150 mA h g-1 (77% retention) after 500 cycles without oxide-coating and Ni-concentration gradients or electrolyte additives.

Revealing Electronic Signature of Lattice Oxygen Redox in Lithium Ruthenates and Implications for High-Energy Li-ion Battery Material Designs.

Anion redox in lithium transition metal oxides such as Li2RuO3 and Li2MnO3, has catalyzed intensive research efforts to find transition metal oxides with anion redox that may boost the energy density of lithium-ion batteries. The physical origin of observed anion redox remains debated, and more direct experimental evidence is needed. In this work, we have shown electronic signatures of oxygen-oxygen coupling, direct evidence central to lattice oxygen redox (O2-/(O2)n-), in charged Li2-xRuO3 after Ru oxidation (Ru4+/Ru5+) upon first-electron removal with lithium de-intercalation. Experimental Ru L3-edge high-energy-resolution fluorescence detected X-ray absorption spectra (HERFD-XAS), supported by ab-initio simulations, revealed that the increased intensity in the high-energy shoulder upon lithium de-intercalation resulted from increased O-O coupling, inducing (O-O) σ*-like states with π overlap with Ru d-manifolds, in agreement with O K-edge XAS spectra. Experimental and simulated O K-edge X-ray emission spectra (XES) further supported this observation with the broadening of the oxygen non-bonding feature upon charging, also originated from (O-O) σ* states. This lattice oxygen redox of Li2-xRuO3 was accompanied by a small amount of O2 evolution in the first charge from differential electrochemistry mass spectrometry (DEMS) but diminished in the subsequent cycles, in agreement with the more reduced states of Ru in later cycles from Ru L3-edge HERFD-XAS. These observations indicated that Ru redox contributed more to discharge capacities after the first cycle. This study has pinpointed the key spectral fingerprints related to lattice oxygen redox from a molecular level and constructed a transferrable framework to rationally interpret the spectroscopic features by combining advanced experiments and theoretical calculations to design materials for Li-ion batteries and electrocatalysis applications.

Chemical versus Electrochemical Electrolyte Oxidation on NMC111, NMC622, NMC811, LNMO, and Conductive Carbon.

We compare the stability of alkyl carbonate electrolyte on NMC111, -622, and -811, LNMO, and conductive carbon electrodes. We prove that CO2 and CO evolution onset potentials depend on the electrode material and increase in the order NMC811 < NMC111 ≈ NMC622 < conductive carbon ≈ LNMO, which we rationalize by two fundamentally different oxidation mechanisms, the chemical and the electrochemical electrolyte oxidation. Additionally, in contrast to the widespread understanding that transition metals in cathode active materials catalyze the electrolyte oxidation, we will prove that such a catalytic effect on the electrochemical electrolyte oxidation does not exist.

Site-Specific Variations in Bone Mineral Density under Systemic Conditions Inducing Osteoporosis in Minipigs.

Osteoporosis is a systemic bone disease with an increasing prevalence in the elderly population. There is conflicting opinion about whether osteoporosis affects the alveolar bone of the jaws and whether it poses a risk to the osseointegration of dental implants. The aim of the present study was to evaluate the effects of systemic glucocorticoid administration on the jaw bone density of minipigs. Thirty-seven adult female minipigs were randomly divided into two groups. Quantitative computed tomography (QCT) was used to assess bone mineral density BMD of the lumbar spine as well as the mandible and maxilla, and blood was drawn. One group of minipigs initially received 1.0 mg prednisolone per kg body weight daily for 2 months. The dose was tapered to 0.5 mg per kg body weight per day thereafter. The animals in the other group served as controls and received placebo. QCT and blood analysis were repeated after 6 and 9 months. BMD was compared between the two groups by measuring Hounsfield units, and serum levels of several bone metabolic markers were also assessed. A decrease in BMD was observed in the jaws from baseline to 9 months. This was more pronounced in the prednisolone group. Statistically significant differences were reached for the mandible (p < 0.001) and the maxilla (p < 0.001). The administration of glucocorticoids reduced the BMD in the jaws of minipigs. The described model shows promise in the evaluation of osseointegration of dental implants in bone that is compromised by osteoporosis.

Impact of long-term exposure to the tyrosine kinase inhibitor imatinib on the skeleton of growing rats.

The tyrosine kinase (TK) inhibitor imatinib provides a highly effective therapy for chronic myeloid leukemia (CML) via inhibition of the oncogenic TK BCR-ABL1. However, off-target TKs like platelet-derived growth factor receptors (PDGF-R) and colony-stimulating factor-1 receptor (c-fms), involved in bone remodeling, are also inhibited. Thus, pediatric patients with CML on imatinib exhibit altered bone metabolism, leading to linear growth failure. As TKI treatment might be necessary for a lifetime, long-term effects exerted on bone in children are of major concern. Therefore, we studied the skeletal long-term effects of continuous and intermittent imatinib exposure in a juvenile rat model. Four-weeks-old male Wistar rats were chronically exposed to imatinib via drinking water over a period of 10 weeks. Animals were exposed to a standard and high imatinib dosage continuously and to the high imatinib dose intermittently. Bone mass and strength were assessed using pQCT, micro-computed tomography (µCT), and biomechanical testing at the prepubertal, pubertal, and postpubertal age. Bone length and vertebral height as well as biochemical markers of bone turnover were analyzed. Femoral and tibial bone length were dose-dependently reduced by up to 24% (p<0.0001), femoral and tibial trabecular bone mass density (BMD) were reduced by up to 25% (p<0.01), and femoral breaking strength was lowered by up to 20% (p<0.05). Intermittent exposure mitigated these skeletal effects. Long-term exposure resulted in reduced vertebral height by 15% and lower trabecular BMD by 5%. Skeletal changes were associated with suppressed serum osteocalcin (p<0.01) and non-significantly elevated serum CTX-I and PINP levels. In conclusion, imatinib mainly impaired longitudinal growth of long bones rather than the vertebrae of growing rats. Interestingly, intermittent imatinib exposure has less skeletal side effects, which may be beneficial in pediatric patients taking imatinib.

Dose-dependent histological alterations in the rat lung following intravenous application of Re-188-labeled microspheres.

PURPOSE: The objective of this study was to determine the dose-effect correlation of pneumopathy after application of Rhenium-188 microspheres (Re-188 MS) in an animal model using histological changes as an end-point. METHODS AND MATERIALS: Wistar rats received an intravenous injection of Re-188 MS yielding doses that ranged from ˜ 2 to ˜ 55 Gy. Lungs were removed after ˜ 25 weeks and prepared for histology. Sections were evaluated using a semi-quantitative 5-tiered score. Dose groups of 10 Gy intervals were statistically analyzed using the Chi-square test with respect to grade and extent of connective tissue accumulation, thickness of vessel walls and accumulation of alveolar macrophages (AM). RESULTS: There was a statistically significant increase in connective tissue content and extent in all dose groups compared to control lungs and at least between each other dose group. The steepest increase in connective tissue was at doses higher than 40 Gy. Starting from that dose, a statistically significant increase of AM accumulation and vessel wall thickness occurred. CONCLUSIONS: There was a clear dose-effect correlation between radiation dose and histological changes. These findings allow an estimation of potential normal tissue damage especially during tumor treatments of liver lesions with radioactive particles in patients with significant liver-to-lung shunts.

Treatment of fractures of the condylar head with resorbable pins or titanium screws: an experimental study.

We aimed to compare in vivo the stability of fixation of condylar fractures in sheep using sonic bone welding and standard titanium screws. We assessed stability of the osteosynthesis and maintenance of the height of the mandibular ramus. Height decreased slightly in both groups compared with the opposite side. The volume of the condyle increased considerably in both groups mainly because callus had formed. The results showed no significant disadvantages for pin fixation compared with osteosynthesis using titanium screws.

Radiation pneumopathy in the rat after intravenous application of (188)Re-labeled microspheres.

PURPOSE: To determine the dose dependence and kinetics of pneumopathy after systemic administration of rhenium-188 ((188)Re)-labeled microspheres in a rat model. METHODS AND MATERIALS: (188)Re-microspheres were injected intravenously into adult Wistar rats (n = 54, age, 8 ± 2 months). The rats were divided into 6 groups according to the intended absorbed dose in the lung (maximum 60 Gy). Gamma camera scans were used to estimate the individual whole lung doses. One control group (n = 5) received nonlabeled microspheres. The breathing rate was measured before and weekly after the treatment using whole body plethysmography until 24 weeks. An increase in the breathing rate by 20% compared with the individual pretreatment control value was defined as the quantal endpoint for dose-effect analyses. RESULTS: A biphasic increase in the breathing rate was observed. The first impairment of lung function occurred in Weeks 3-6. For late changes, the interval to onset was clearly dose dependent and was 17 weeks (10-30 Gy) and 10 weeks (50-60 Gy), respectively. The incidence of the response was highly dependent on the estimated lung dose. The median effective dose for an early and late response was virtually identical (19.9 ± 0.6 Gy and 20.4 ± 3.1 Gy, respectively). A significant correlation was found between the occurrence of an early and a late effect in the same rat, suggesting a strong consequential component. CONCLUSIONS: The effects of radiolabeled microspheres can be studied longitudinally in a rat model, using changes in the breathing rate as the functional, clinically relevant response. The isoeffective doses from the present study using radionuclide administration and those from published investigations of homogeneous external beam radiotherapy are almost similar.

Long-bone critical-size defects treated with tissue-engineered polycaprolactone-co-lactide scaffolds: a pilot study on rats.

The aim of this study was to evaluate the osteogenic potential of embroidered, tissue-engineered polycaprolactone-co-lactide (trade name: PCL) scaffolds for the reconstruction of large bone defects. Ten piled-up PCL scaffolds were implanted in femura with a critical size defect of immunodeficient nude rats for 12 weeks [n = 4, group 1: noncoated, group 2: collagen I (coll I), group 3: collagen I/chondroitin sulfate (coll I/CS), and group 4: collagen I/chondroitin sulfate/human mesenchymal stem cells (coll I/CS/hMSC)]. X-ray examination, computer tomography, and histological analyses of the explanted scaffold pads were performed. The quantification of the bone volume ratio showed a significantly higher rate of new bone formation at coll I/CS-coated scaffolds compared with the other groups. Histological investigations revealed that the defect reconstruction started from the peripheral bone ends and incorporated into the scaffold material. Additionally seeded hMSC on coll I/CS-coated scaffolds showed a higher matrix deposition inside the implant but no higher bone formation was observed. These data imply that the coll I/CS-coated PCL scaffolds have the highest potential for treating critical size defects. The scaffolds, being variable in size and structure, can be adapted to any bone defect.

Pharmacological modification of the epithelial permeability by benzalkonium chloride in UVA/Riboflavin corneal collagen cross-linking.

PURPOSE: To examine the biomechanical effect and the UVA-absorption of a riboflavin/UVA cross-linking method, which suggests leaving the epithelium intact and applying benzalkonium chloride (BAC) on rabbits' corneas. METHODS: In total, 32 eyes from 16 rabbits were divided into 4 groups. Group 1 was treated with intact epithelium and without BAC. In groups 2 and 3, the epithelium was left intact and a hypoosmolar solution of riboflavin that contained BAC 0.02% or 0.04% was used. Group 4 was treated according to the standard protocol with mechanical debridement of the epithelium. After the treatment of both eyes, the rabbits were euthanized to prepare the corneas in order for the determination of the riboflavin absorption coefficient and biomechanical properties. RESULTS: The absorption coefficients of groups 2, 3, and 4 were significantly increased compared to group 1. There were no significant differences between groups 2, 3, and 4. Stress-strain values and Young's modulus for groups 2, 3, and 4 were significantly increased compared to group 1. The stiffening effects did not differ within groups 2, 3, and 4. The resistance to enzymatic digestion was significantly increased in groups 2, 3, and 4 as compared to group 1. CONCLUSIONS: Treatment with BAC 0.02% induces sufficient epithelial permeability for the passage of riboflavin, which enables its stromal diffusion and results in increased corneal stiffening after cross-linking as compared to the standard protocol. Further safety studies will be required before clinical use.

Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice.

In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system.

Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy.

CONTEXT: For patients on T(4) replacement, the dose is guided by serum TSH concentrations, but some patients request higher doses due to adverse symptoms. OBJECTIVE: The aim of the study was to determine the safety of patients having a low but not suppressed serum TSH when receiving long-term T(4) replacement. DESIGN: We conducted an observational cohort study, using data linkage from regional datasets between 1993 and 2001. SETTING: A population-based study of all patients in Tayside, Scotland, was performed. PATIENTS: All patients taking T(4) replacement therapy (n = 17,684) were included. MAIN OUTCOME MEASURES: Fatal and nonfatal endpoints were considered for cardiovascular disease, dysrhythmias, and fractures. Patients were categorized as having a suppressed TSH (4.0 mU/liter). RESULTS: Cardiovascular disease, dysrhythmias, and fractures were increased in patients with a high TSH: adjusted hazards ratio, 1.95 (1.73-2.21), 1.80 (1.33-2.44), and 1.83 (1.41-2.37), respectively; and patients with a suppressed TSH: 1.37 (1.17-1.60), 1.6 (1.10-2.33), and 2.02 (1.55-2.62), respectively, when compared to patients with a TSH in the laboratory reference range. Patients with a low TSH did not have an increased risk of any of these outcomes [hazards ratio: 1.1 (0.99-1.123), 1.13 (0.88-1.47), and 1.13 (0.92-1.39), respectively]. CONCLUSIONS: Patients with a high or suppressed TSH had an increased risk of cardiovascular disease, dysrhythmias, and fractures, but patients with a low but unsuppressed TSH did not. It may be safe for patients treated with T(4) to have a low but not suppressed serum TSH concentration.

The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.

OBJECTIVE: To determine whether aspirin and antioxidant therapy, combined or alone, are more effective than placebo in reducing the development of cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease. DESIGN: Multicentre, randomised, double blind, 2x2 factorial, placebo controlled trial. SETTING: 16 hospital centres in Scotland, supported by 188 primary care groups. PARTICIPANTS: 1276 adults aged 40 or more with type 1 or type 2 diabetes and an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease. INTERVENTIONS: Daily, 100 mg aspirin tablet plus antioxidant capsule (n=320), aspirin tablet plus placebo capsule (n=318), placebo tablet plus antioxidant capsule (n=320), or placebo tablet plus placebo capsule (n=318). MAIN OUTCOME MEASURES: Two hierarchical composite primary end points of death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or amputation above the ankle for critical limb ischaemia; and death from coronary heart disease or stroke. RESULTS: No evidence was found of any interaction between aspirin and antioxidant. Overall, 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups (18.2% v 18.3%): hazard ratio 0.98 (95% confidence interval 0.76 to 1.26). Forty three deaths from coronary heart disease or stroke occurred in the aspirin groups compared with 35 in the no aspirin groups (6.7% v 5.5%): 1.23 (0.79 to 1.93). Among the antioxidant groups 117 of 640 (18.3%) primary events occurred compared with 116 of 636 (18.2%) in the no antioxidant groups (1.03, 0.79 to 1.33). Forty two (6.6%) deaths from coronary heart disease or stroke occurred in the antioxidant groups compared with 36 (5.7%) in the no antioxidant groups (1.21, 0.78 to 1.89). CONCLUSION: This trial does not provide evidence to support the use of aspirin or antioxidants in primary prevention of cardiovascular events and mortality in the population with diabetes studied. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53295293.

O-phospho-L-serine: a modulator of bone healing in calcium-phosphate cements.

Bone substitution materials are seen as an alternative to autogenous bone transplants in the reconstruction of human bone structures. The aim of the present animal study was to evaluate the clinical handling and the conditions of bone healing after the application of a phosphoserine and collagen-I-modified calcium-phosphate cement (Biozement D). The application of phosphoserine is supposed to influence the texture of the extracellular matrix. Standardised bone defects were created in the lower jaw of 10 adult minipigs. These defects were reconstructed with a pasty calcium-phosphate cement mixture. After a healing time of 4 months, the animals were sacrificed. The mandibles of all animals were resected and non-decalcified histological sections of the areas of interest were prepared. The experiment was evaluated by means of qualitative histology and histomorphometry. The hydroxyapatite cement entirely hardened intraoperatively. Modelling and handling of the cement was facile and the margin fit to the host bone was excellent. Histology showed that resorption started in the periphery and proceeded exceptionally fast. The bony substitution, especially in phosphoserine-endowed cements, was very promising. After a healing period of 4 months, phosphoserine cements showed a bone regeneration of nearly two-thirds of the defect sizes. In the applied animal experiment, the newly developed hydroxyapatite collagen-I cement is well suited for bone substitution due to its easy handling, its excellent integration and good resorption characteristics. The addition of phosphoserine is very promising in terms of influencing resorption features and bone regeneration.

Histologic study of incorporation and resorption of a bone cement-collagen composite: an in vivo study in the minipig.

OBJECTIVE: Calcium phosphates are clinically established as bone defect fillers. They have the capability of osseoconduction and are characterized by a slow resorption process. The present study evaluated the suitability of a newly developed calcium phosphate cement modified with collagen type I. STUDY DESIGN: The modified cement paste was inserted in differently designed defects of 10 minipigs. Further, an alveolar ridge augmentation was performed, applying the cement paste. The cement hardened in situ during the operation, forming a hydroxyapatite collagen composite. Animals were sacrificed after 1, 3, 6, 12, and 18 months. The tissue integration and resorption process was then evaluated using nondecalcified microsections. All animals were evaluated for histology. RESULTS: The implanted material showed osseoconductive characteristics. Resorption started from the edge of the defect zone, and bone substitution followed rapidly. Twelve months after placement of the cement, complete remodeling was observed. CONCLUSION: It can be concluded that the applied hydroxyapatite-collagen cement composite shows good resorption and bone integration.

Bone welding--a histological evaluation in the jaw.

The expansion of biodegradable osteosynthesis systems in clinical application correlates well to the progress in development of new materials as to the improvement of application methods. One of those new application methods is the ultrasound-aided insertion of Resorb-X pins. The aim of this study was the histological evaluation of possible thermal damage to bone due to the ultrasound insertion. For this purpose, condylar neck fractures in 12 sheep were produced, repositioned and fixed by Resorb-X plates and pins. The animals were sacrificed in two groups, one after 2 weeks and one after 9 weeks. The bone-pin interlinkage and the structure of the bone were histologically evaluated. After 2 weeks a tight bone-polymer interlinkage was seen. Neither a pronounced foreign body reaction nor an interposition of fibrous tissue at the interface or a thermally induced necrosis was observed. The late phase of wound healing after 9 weeks showed pathomorphological characteristics within the normal range of bone healing. The bone seemed to be free of any alteration caused by process engineering. We conclude that thermal stress caused by ultrasound-aided pin insertion does not lead to cellular reaction in the bone. The fast and easy application of this improved biodegradable osteosynthesis system will bring a clear advantage in clinical use.

Effects of weight loss in overweight/obese individuals and long-term hypertension outcomes: a systematic review.

Many studies have assessed short-term effects of weight loss on blood pressure, whereas little attention has been paid to long-term effects. We conducted a systematic review to evaluate the long-term effects of weight loss on hypertension outcome measures in adults using literature published from 1966 to 2001. All prospective studies and trials, performed on participants with body mass index of > or =28 kg/m2 with a follow-up of >2 years and weight changes recorded, were included. The data from these studies were used to model the long-term effects on blood pressure. Previous reviews on shorter-term studies indicate a 1:1 drop in blood pressure (mm Hg) with weight loss (kilograms). Our findings, based on studies with follow-up of > or =2 years, demonstrate blood pressure decreases less than this after weight loss. The surgical intervention studies exhibited huge weight losses with undramatic blood pressures changes. When surgical interventions are excluded, the models suggest that for 10 kg weight loss, decreases of 4.6 mm Hg and 6.0 mm Hg in diastolic and systolic blood pressure, respectively, may be expected, about half of that predicted from the short-term trials. Initial blood pressure, the length of follow-up, medication changes, and physiological restrictions may contribute to this reduced effect in the long-term studies. Extrapolation of short-term blood pressure changes with weight loss to the longer term is potentially misleading. The weight/hypertension relationship is complex and needs well-conducted studies with long-term follow-up to examine the effects of weight loss on hypertension outcomes.

Variation at the aldosterone synthase (CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio.

The aldosterone-to-renin ratio (ARR) is a marker of aldosterone activity in hypertension. We examined the relationship of the ARR to the distribution of two biallelic polymorphisms at the CYP11B2 gene locus. One polymorphism affects a putative steroidogenic factor-1 binding site (-344 T/C) in the 5'-regulatory region, whereas the other marker reflects replacement of the intron-2 from CYP11B2 with that from the neighboring gene encoding 11beta-hydroxylase (CYP11B1; wild-type/conversion). We studied consecutive referrals to the Tayside hypertension clinic in 1998. Because the specificity of ARR (pmol/liter/ng/ml/h) for hyperaldosteronism increases with its threshold, ARRs of at least 750 and 1000 were used. A total of 375 patients were assessed; 86.9% had complete data. There were significant excesses of steroidogenic factor-1 (T) (ARR >/= 750, 0.62 vs. 0.51, P = 0.014; ARR >/= 1000, 0.63 vs. 0.51, P = 0.039) and intron-2 (conversion) (ARR >/= 750, 0.49 vs. 0.41, P = 0.205; ARR >/= 1000, 0.54 vs. 0.41, P = 0.029) alleles in patients with a raised ARR. The odds ratio for a raised ARR was 2.27 [95% confidence interval, 1.01, 5.09; P < 0.05] comparing patients with a homozygous haplotype for these alleles with those without any such alleles, and this risk increased with age. This study supports the notion that there is a genetic component that regulates aldosterone production and that hyperaldosteronism might develop over time in susceptible individuals.