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Exploring nonequilibrium hot carriers from plasmonic metal nanostructures is a dynamic field in optoelectronics, with applications including photochemical reactions for solar fuel generation. The hot carrier injection mechanism and the reaction rate are highly impacted by the metal/molecule interaction. However, determining the primary type of reaction and thus the injection mechanism of hot carriers has remained elusive. In this work, we reveal an electron injection mechanism deviating from a purely outer-sphere process for the reduction of ferricyanide redox molecule in a gold/p-type gallium nitride (Au/p-GaN) photocathode system. Combining our experimental approach with ab initio simulations, we discovered that an efficient inner-sphere transfer of low-energy electrons leads to an enhancement in the photocathode device performance in the interband regime. These findings provide important mechanistic insights, showing our methodology as a powerful tool for analyzing and engineering hot-carrier-driven processes in plasmonic photocatalytic systems and optoelectronic devices.

Evidence from cross-sectional electron microscopy has previously shown that Se passivates defects in CdSe x Te 1-x solar cells, and that this is the reason for better lifetimes and voltages in these devices. Here, we utilise spatially resolved photoluminescence measurements of CdSe x Te 1-x thin films on glass to directly study the effects of Se on carrier recombination in the material, isolated from the impact of conductive interfaces and without the need to prepare cross-sections through the samples. We find further evidence to support Se passivation of grain boundaries, but also identify an increase in below-bandgap photoluminescence that indicates the presence of Se-enhanced defects in grain interiors. Our results show that whilst Se treatment, in tandem with Cl passivation, does increase radiative efficiencies in CdSe x Te 1-x , it simultaneously increases the defect content within the grain interiors. This suggests that although it is beneficial overall, Se incorporation will still limit the maximum attainable optoelectronic properties of CdSe x Te 1-x thin films., (© 2024. The Author(s).)

Purpose: Overly rigid forms of dietary restraint are associated with poorer weight loss outcomes. Dichotomous ("all or nothing") thinking has been shown to mediate this relationship in non-clinical participants, but this finding has yet to be replicated in clinical samples of individuals who have had weight-loss surgery., Materials and Methods: A cross-sectional design was used, adopting quantitative questionnaires with 129 individuals who had previously underwent bariatric surgery at least 12 months prior to participation. Bootstrapped mediation analysis was used to establish the mediating role of dichotomous thinking., Results: Eating-specific dichotomous thinking was shown to fully mediate the relationship between dietary restraint and post-surgical weight loss. In contrast, no mediation effect was found for generalised dichotomous thinking., Conclusion: Dichotomous thinking specifically about food/eating may play a central role in weight loss maintenance after weight-loss surgery. Pre-surgical assessment of dichotomous thinking, and provision of psychological therapy to think more flexibly about food, is suggested., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Luminescence constitutes a unique source of insight into hot carrier processes in metals, including those in plasmonic nanostructures used for sensing and energy applications. However, being weak in nature, metal luminescence remains poorly understood, its microscopic origin strongly debated, and its potential for unraveling nanoscale carrier dynamics largely unexploited. Here, we reveal quantum-mechanical effects in the luminescence emanating from thin monocrystalline gold flakes. Specifically, we present experimental evidence, supported by first-principles simulations, to demonstrate its photoluminescence origin (i.e., radiative emission from electron/hole recombination) when exciting in the interband regime. Our model allows us to identify changes to the measured gold luminescence due to quantum-mechanical effects as the gold film thickness is reduced. Excitingly, such effects are observable in the luminescence signal from flakes up to 40 nm in thickness, associated with the out-of-plane discreteness of the electronic band structure near the Fermi level. We qualitatively reproduce the observations with first-principles modeling, thus establishing a unified description of luminescence in gold monocrystalline flakes and enabling its widespread application as a probe of carrier dynamics and light-matter interactions in this material. Our study paves the way for future explorations of hot carriers and charge-transfer dynamics in a multitude of material systems., (© 2024. The Author(s).)

Harnessing nonequilibrium hot carriers from plasmonic metal nanostructures constitutes a vibrant research field with the potential to control photochemical reactions, particularly for solar fuel generation. However, a comprehensive understanding of the interplay of plasmonic hot-carrier-driven processes in metal/semiconducting heterostructures has remained elusive. In this work, we reveal the complex interdependence among plasmon excitation, hot-carrier generation, transport, and interfacial collection in plasmonic photocatalytic devices, uniquely determining the charge injection efficiency at the solid/liquid interface. Measuring the internal quantum efficiency of ultrathin (14-33 nm) single-crystalline plasmonic gold (Au) nanoantenna arrays on titanium dioxide substrates, we find that the performance of the device is limited by hot hole collection at the metal/electrolyte interface. Our solid- and liquid-state experimental approach, combined with ab initio simulations, demonstrates more efficient collection of high-energy d-band holes traveling in the [111] orientation, enhancing oxidation reactions on {111} surfaces. These findings establish new guidelines for optimizing plasmonic photocatalytic systems and optoelectronic devices., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The Devonian-Carboniferous transition marks a fundamental shift in the surface environment primarily related to changes in ocean-atmosphere oxidation states 1,2 , resulting from the continued proliferation of vascular land plants that stimulated the hydrological cycle and continental weathering 3,4 , glacioeustasy 5,6 , eutrophication and anoxic expansion in epicontinental seas 3,4 , and mass extinction events 2,7,8 . Here we present a comprehensive spatial and temporal compilation of geochemical data from 90 cores across the entire Bakken Shale (Williston Basin, North America). Our dataset allows for the detailed documentation of stepwise transgressions of toxic euxinic waters into the shallow oceans that drove a series of Late Devonian extinction events. Other Phanerozoic extinctions have also been related to the expansion of shallow-water euxinia, indicating that hydrogen sulfide toxicity was a key driver of Phanerozoic biodiversity., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Mosquitoes can impact military operational readiness by transmission of disease-causing pathogens or through secondary effects, e.g., annoyance and bites. The focus of this research was to determine if an array of novel controlled release passive devices (CRPD) utilizing the spatial repellent, transfluthrin (TF), as the active ingredient could prevent entry of mosquitoes into military tents for up to 4 weeks. The TF-charged CRPDs were spaced along six strands of monofilament and hung across the tent entrance. Efficacy was evaluated with caged Aedes aegypti to indicate knockdown/mortality effects, and four species of free-flying mosquitoes, Ae. aegypti , Aedes taeniorhynchus , Anopheles quadrimaculatus and Culex quinquefasciatus , to indicate repellent effects. Bioassay cages containing Ae. aegypti were hung vertically at 0.5, 1.0 and 1.5 ​m above ground level at designated locations inside of the tents. Knockdown/mortality counts were made every 15 min for the first hour, then at 2, 4 and 24 h post-exposure. Free fliers were recaptured in BG traps operated from 4 to 24 h post-exposure. Knockdown/mortality was gradual until 4 h post-exposure. This increased to near 100% by 24 h in the treated tent but was < 2% in the control tent. There was a significant reduction in the recapture rates of all free-flying species in the treated tent compared with the control tent. Results indicate that TF-charged CRPDs can significantly reduce the numbers of mosquitoes entering military tents and that the four species were affected similarly by the TF. The needs for additional research are discussed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

A method for improving the efficiency of solar cells is combining a low-band-gap semiconductor with a singlet fission material (which converts one high-energy singlet into two low-energy triplets following photoexcitation). Here, we present a study of the interface between singlet fission molecules and low-band-gap halide pervoskites. We briefly present 150 experiments screening for triplet transfer into a halide perovskite. However, in all cases, triplet transfer was not observed. This motivated us to understand the halide perovskite-singlet fission interface better by carrying out first-principles calculations using tetracene and cesium lead iodide. We found that tetracene molecules/thin films preferentially orient themselves parallel to/perpendicular to the halide perovskite's surface. This result is in agreement with simulations of tetracene (and other rodlike molecules) on a wide range of inorganic semiconductors. We present formation energies of all interfaces, which are significantly less favorable than for bulk tetracene, indicative of weak interaction at the interface. It was not possible to calculate excitonic states at the full interface due to computational limitations, so we instead present highly speculative toy interfaces between tetracene and a halide-perovskite-like structure. In these models, we focus on replicating tetracene's electronic states correctly. We find that tetracene's singlet and triplet energies are comparable to that of bulk tetracene, and the triplet is strongly localized on a single tetracene molecule, even at an interface. Our work provides new understanding of the interface between tetracene and halide perovskites, explores the potential for modeling excitons at interfaces, and begins to explain the difficulties in extracting triplets directly into inorganic semiconductors., Competing Interests: The authors declare the following competing financial interest(s): S.D.S. is a Co-Founders of Swift Solar Inc., (© 2022 The Authors. Published by American Chemical Society.)

Objective: Strict competency frameworks exist for training in, and provision of, clinical neuropsychological assessment practice. However, as in all disciplines, daily clinical practice may drift from the gold standard practice without routine monitoring and audit. A simple-to-use, but thorough and evidence-based audit tool has been developed to facilitate the tracking, maintenance, and discussion of best practice over time., Method: A literature search and liaison with experienced neuropsychology colleagues did not unearth any pre-existing audit standards. Therefore, 39 new standards were generated, which were guided by best practice literature and clinical neuropsychology colleague discussions, to form the proposed self-assessment audit tool. Due to the diverse nature of services, both core and supplementary standards are proposed to enable the audit to be tailored to suit individual services' needs., Results: During its development, the tool has so far been trialed in two U.K. National Health Service clinical services in different localities, on three occasions, with a total patient population of N = 78 in order to refine the standards and to generate practice recommendations., Conclusions: This audit tool is presented for services to self-assess their neuropsychological assessment practice. The authors plan to take this work forward with the British Psychological Society's Division of Neuropsychology as a policy document for self-assessment and peer review. Other potential developments include contributing to clinical neuropsychology training tools and refining audit standards for use more widely, such as in pediatric services, or internationally with diverse populations., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Halide perovskite/crystalline silicon (c-Si) tandem solar cells promise power conversion efficiencies beyond the limits of single-junction cells. However, the local light-matter interactions of the perovskite material embedded in this pyramidal multijunction configuration, and the effect on device performance, are not well understood. Here, we characterize the microscale optoelectronic properties of the perovskite semiconductor deposited on different c-Si texturing schemes. We find a strong spatial and spectral dependence of the photoluminescence (PL) on the geometrical surface constructs, which dominates the underlying grain-to-grain PL variation found in halide perovskite films. The PL response is dependent upon the texturing design, with larger pyramids inducing distinct PL spectra for valleys and pyramids, an effect which is mitigated with small pyramids. Further, optimized quasi-Fermi level splittings and PL quantum efficiencies occur when the c-Si large pyramids have had a secondary smoothing etch. Our results suggest that a holistic optimization of the texturing is required to maximize light in- and out-coupling of both absorber layers and there is a fine balance between the optimal geometrical configuration and optoelectronic performance that will guide future device designs., Competing Interests: The authors declare the following competing financial interest(s): The corresponding author is a co-founder of Swift Solar, Inc., (© 2021 The Authors. Published by American Chemical Society.)

Perovskite-based tandem solar cells are of increasing interest as they approach commercialization. Here we use experimental parameters from optical spectroscopy measurements to calculate the limiting efficiency of perovskite-silicon and all-perovskite two-terminal tandems, employing currently available bandgap materials, as 42.0% and 40.8%, respectively. We show luminescence coupling between subcells (the optical transfer of photons from the high-bandgap to low-bandgap subcell) relaxes current matching when the high-bandgap subcell is a luminescent perovskite. We calculate that luminescence coupling becomes important at charge trapping rates (≤10 6 s -1 ) already being achieved in relevant halide perovskites. Luminescence coupling increases flexibility in subcell thicknesses and tolerance to different spectral conditions. For maximal benefit, the high-bandgap subcell should have the higher short-circuit current under average spectral conditions. This can be achieved by reducing the bandgap of the high-bandgap subcell, allowing wider, unstable bandgap compositions to be avoided. Lastly, we visualize luminescence coupling in an all-perovskite tandem through cross-section luminescence imaging., Competing Interests: The authors declare the following competing financial interest(s): S.D.S. and G.E.E. are co-founders of Swift Solar Inc., (© 2021 The Authors. Published by American Chemical Society.)

Photon recycling has received increased attention in recent years following its observation in halide perovskites. It has been shown to lower the effective bimolecular recombination rate and thus increase excitation densities within a material. Here we introduce a general framework to quantify photon recycling which can be applied to any material. We apply our model to idealized solar cells and light-emitting diodes based on halide perovskites. By varying controllable parameters which affect photon recycling, namely, thickness, charge trapping rate, nonideal transmission at interfaces, and absorptance, we quantify the effect of each on photon recycling. In both device types, we demonstrate that maximizing absorption and emission processes remains paramount for optimizing devices, even if this is at the expense of photon recycling. Our results provide new insight into quantifying photon recycling in optoelectronic devices and demonstrate that photon recycling cannot always be seen as a beneficial process.

Monolithic [Cs 0.05 (MA 0. 17 FA 0. 83 ) 0.95 ]Pb(I 0.83 Br 0.17 ) 3 /Cu(In,Ga)Se 2 (perovskite/CIGS) tandem solar cells promise high performance and can be processed on flexible substrates, enabling cost-efficient and ultra-lightweight space photovoltaics with power-to-weight and power-to-cost ratios surpassing those of state-of-the-art III-V semiconductor-based multijunctions. However, to become a viable space technology, the full tandem stack must withstand the harsh radiation environments in space. Here, we design tailored operando and ex situ measurements to show that perovskite/CIGS cells retain over 85% of their initial efficiency even after 68 MeV proton irradiation at a dose of 2 × 10 12 p + /cm 2 . We use photoluminescence microscopy to show that the local quasi-Fermi-level splitting of the perovskite top cell is unaffected. We identify that the efficiency losses arise primarily from increased recombination in the CIGS bottom cell and the nickel-oxide-based recombination contact. These results are corroborated by measurements of monolithic perovskite/silicon-heterojunction cells, which severely degrade to 1% of their initial efficiency due to radiation-induced recombination centers in silicon., Competing Interests: S.D.S. is a co-founder of Swift Solar, Inc., a company commercializing high-power, lightweight perovskite solar panels., (© 2020 The Authors.)

Mixed lead-tin halide perovskites have sufficiently low bandgaps (∼1.2 eV) to be promising absorbers for perovskite-perovskite tandem solar cells. Previous reports on lead-tin perovskites have typically shown poor optoelectronic properties compared to neat lead counterparts: short photoluminescence lifetimes (<100 ns) and low photoluminescence quantum efficiencies (<1%). Here, we obtain films with carrier lifetimes exceeding 1 μs and, through addition of small quantities of zinc iodide to the precursor solutions, photoluminescence quantum efficiencies under solar illumination intensities of 2.5%. The zinc additives also substantially enhance the film stability in air, and we use cross-sectional chemical mapping to show that this enhanced stability is because of a reduction in tin-rich clusters. By fabricating field-effect transistors, we observe that the introduction of zinc results in controlled p-doping. Finally, we show that zinc additives also enhance power conversion efficiencies and the stability of solar cells. Our results demonstrate substantially improved low-bandgap perovskites for solar cells and versatile electronic applications., Competing Interests: The authors declare the following competing financial interest(s): Dr. Samuel D. Stranks is a co-founder of Swift Solar Inc. Prof. Henry J. Snaith FRS is a co-founder of Oxford PV.

Visual hallucinations are a common, distressing, and disabling symptom of Lewy body and other diseases. Current models suggest that interactions in internal cognitive processes generate hallucinations. However, these neglect external factors. Pareidolic illusions are an experimental analogue of hallucinations. They are easily induced in Lewy body disease, have similar content to spontaneous hallucinations, and respond to cholinesterase inhibitors in the same way. We used a primed pareidolia task with hallucinating participants with Lewy body disorders (n = 16), non-hallucinating participants with Lewy body disorders (n = 19), and healthy controls (n = 20). Participants were presented with visual "noise" that sometimes contained degraded visual objects and were required to indicate what they saw. Some perceptions were cued in advance by a visual prime. Results showed that hallucinating participants were impaired in discerning visual signals from noise, with a relaxed criterion threshold for perception compared to both other groups. After the presentation of a visual prime, the criterion was comparable to the other groups. The results suggest that participants with hallucinations compensate for perceptual deficits by relaxing perceptual criteria, at a cost of seeing things that are not there, and that visual cues regularize perception. This latter finding may provide a mechanism for understanding the interaction between environments and hallucinations.

Background: Carotid endarterectomy (CEA) is one of the most frequently performed surgical procedures in the United States. Traditionally, this procedure has been performed by surgeons in at least four specialties. The purpose of this study was to examine the effect of surgeon specialty on the long-term outcomes of CEA among patients receiving the procedure in Pennsylvania., Materials and Methods: Data included 17,635 patient admissions for CEA performed between 1995 and 1997, and patient readmission data for the 5-y follow-up period ending in 2002. Five-y outcomes for these patients were compared between vascular, cardiothoracic, general, and neurosurgeons. The primary outcome measures were mortality, stroke, combined stroke and mortality, transient ischemic attack (TIA), and re-occlusion of the ipsilateral artery. Secondary outcomes measured were length of stay and total charges., Results: Using general surgeon as the reference group, and controlling for age, race, severity, and admission type, we found no significant difference across surgical specialties in overall mortality at 5 y post-CEA. Patients treated by vascular surgeons were found to have significantly fewer (P=0.012) strokes and significantly lower re-occlusion rate (P=0.021) at 5 y compared with patients of general surgeons. Patients treated by vascular surgeons also had significantly shorter hospital stay (P<0.0001) but significantly higher charges (P<0.0001) relative to general surgeons., Conclusions: These results suggest that there are significant differences in outcomes following carotid endarterectomy according to surgeon training. Additional research is needed to explore differences across specialties that may be driving outcomes and to explore the role of surgeon volume at the profession level and cross-volume effects on CEA outcomes., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Cyclosporine A (CsA), a potent immunosuppressant used in transplantation, induces increased formation with excess resorption in the rat with resultant osteopenia. These findings are confirmed in the human model. Transforming growth factor-beta (TGF-beta) is reported to be involved in the coupling of bone formation with resorption and in vivo and in vitro stimulates osteoblasts, and in vitro inhibits osteoclasts. CsA stimulates secretion of TGF-beta1 in humans, which, while improving immunosuppression, may also contribute to renal toxicity. This study was performed determine whether exogenously administered TGF-beta would modify the bone effects of CsA. Male Sprague-Dawley rats, 6 months of age, were randomized to receive: TGF-beta and CsA vehicle (group A); TGF-beta 5 microg/kg three times per week and CsA vehicle (group B); TGF-beta vehicle and CsA 10 mg/kg (group C); or TGF-beta 5 microg/kg three times per week and CsA 10 mg/kg (group D). These were compared with control over 28 days. CsA, but not TGF-beta, increased serum 1,25(OH)(2)D levels throughout the study. CsA increased osteocalcin (BGP), but TGF-beta negated this effect. Histomorphometry confirmed the known effects of CsA, whereas TGF-beta alone had no effect. However, in combination, TGF-beta blocked CsA's effect and increased osteoblast recruitment and activity, as reflected by increased percent mineralizing surface, percent osteoid perimeter, bone formation rate (bone volume referent), and activation frequency. Thus, it appears as if TGF-beta administration may have potential in modulating the deleterious bone effects of CsA.

Cyclosporine A (CsA) induces high turnover osteopenia in the rat and there is evidence for this in humans. Recent studies suggest that increases in parathyroid hormone (PTH) may be involved in posttransplantation bone loss. However, human studies are difficult to interpret since transplant patients usually receive a cocktail of immunosuppressants and have underlying disease. Our aim was to try to resolve the influence of the absence or presence of PTH on CsA-induced bone disease. Male Sprague Dawley rats aged 7-9 months, either sham operated or parathyroidectomized (PTX), were randomly divided into vehicle and CsA groups. All PTX rats were given oral calcium supplementation ad libitum. The rats were divided into groups: basal, sham/vehicle, sham/CsA, PTX/vehicle, and PTX/CsA. Serial biochemistry was performed 0, 14, and 28 days after the start of the experimental period; bone histomorphometry was performed 28 days after the start of the experimental period. Statistical analysis consisted of group comparisons and factorial analyses. The results showed that CsA alone produced a high turnover osteopenia consistent with previous studies. In the PTX animals there was an increase in bone mass. PTX also decreased osteoblast activity and recruitment, and serum 1,25OH2D levels. Serum levels of osteocalcin (BGP) were unaffected by PTX. The combination group (PTX/CsA) did not differ statistically from the controls in most of the histomorphometric parameters measured, with the exception of reduced mineral apposition and bone formation rates, reflecting the effects of PTX. Serum BGP and 1,25OH2D levels did not differ, but PTH was reduced from the control. Explanations for these results are (1) CsA and PTX exert their effects via separate mechanisms, negating each other; (2) in the absence of PTH, CsA managed to cause bone loss, and thus PTH may not be essential for CsA-induced bone loss; or (3) the profound accelerated bone loss produced by CsA in normal rats requires PTH. These findings may help explain the discrepancies found in clinical studies where bone loss occurs with either elevated or normal PTH levels.

Pancreatic tumors frequently metastasize widely, though it is rare to diagnose pancreatic cardiac metastases in the antemortem state. We report an unusual case of metastatic pancreatic adenocarcinoma to the right atrium. Transesophageal echocardiography showed that the tumor was attached to the superior aspect of the right atrium, prolapsing through and obstructing the tricuspid valve in diastole and retracting back into the right atrium during systole. The tumor was excised, and histologic examination confirmed the presence of moderately differentiated adenocarcinoma with a papillary architectural pattern and with desmoplastic stroma, features comparable to the original primary pancreatic neoplasm.

Estrogen deficiency following ovariectomy or menopause results in bone loss. Although evidence strongly suggests that the immune system is involved in the pathogenesis of estrogen-deficient osteoporosis, it is not clear what role, if any, the T-lymphocyte plays in this process. Therefore, we examined the distribution of T-cell subsets in lymphoid organs and tissues, under varying estrogenic states in the rat. Six-month-old female Sprague-Dawley rats, ovariectomized (Ovx) and sham-operated, were randomized 5 d post-surgery into six groups to receive the following treatments: (A) sham/placebo; (B) sham/low-dose E2; (C) sham/high-dose E2; (D) Ovx/placebo; (E) Ovx/low-dose E2; (F) Ovx/high-dose E2. Half of the treated rats (groups A-F) were sacrificed on d 14; the remainder on d 28. Following euthanasia, mononuclear cells were isolated from the thymus, peripheral blood, spleen, lymph node and bone marrow, and were labeled for flow cytometric analysis using mouse anti-rat monoclonal antibodies directed against CD5, CD4, and CD8 antigenic markers. In the thymus, ovariectomy caused a dramatic increase and E2 treatment caused a dose-dependent decrease in weight that was proportional to the number of thymocytes. In the bone marrow, ovariectomy caused a significant reduction in the percentage of all T-cell subsets examined and this effect persisted throughout the duration of the study. Estrogen replacement therapy at the low-dose reversed the effects of ovariectomy and high-dose E2 treatment caused an increase in T-cell subsets in both the sham and Ovx groups, an effect that was more pronounced at d 14 compared with d 28. Although the percentages of some T-cell subsets in the other lymphoid organs/tissues were altered by ovariectomy or E2 treatment at d 0 and 14, all these changes had normalized by d 28 except for CD5 and CD4 cells in peripheral blood. In summary, with the exception of T-lymphocytes in the bone marrow, the effects of varying estrogenic states on T-cells were variable and transient. The influence of estrogen status on bone marrow T-lymphocytes suggests that these cells may play a role in mediating the effects of estrogen on bone turnover and warrant additional studies focusing on the functional role of T-cells in the bone marrow compartment.

Background: Posttransplantation bone disease is a well-described phenomenon; among its etiology is immunosuppressant-induced bone disease. Mycophenolate mofetil (MMF) has emerged as a promising new immunosuppressant. Our study was designed to investigate the effect of MMF on in vivo bone mineral metabolism., Methods: Twenty-four 6-month-old male Sprague-Dawley rats were randomized into two groups to receive either MMF vehicle daily for 28 days or 30 mg/kg MMF daily for 28 days. The serum was assayed for osteocalcin and 1,25-dihydroxy vitamin D3. Subsequent to double-labeling, the right tibiae were removed on day 28 for histomorphometry., Results: MMF suppressed bone gla protein (osteocalcin) levels on days 14 and 28 (P < 0.05). Except for percentage osteoid perimeter, there was no difference in bone histomorphometry between the two groups., Conclusion: In this relatively short-term study, MMF did not cause osteopenia in the rat model, but the suppressed bone gla protein merits further study.

Post-transplantation bone disease is an increasingly recognized clinical entity whose etiology is multifactorial. The immunosuppressant agent cyclosporine-A (CsA) has repeatedly been shown experimentally to induce a high-turnover osteopenic state. Alendronate (Alen.) is a new generation bisphosphonate having far greater antiresorptive potency than previous bisphosphonates. It inhibits osteoclast resorption in vitro and in vivo without adversely affecting bone mineralization. This study was designed to investigate whether alendronate could prevent CsA-induced osteopenia in the rat. Forty-eight 8-month-old male Sprague Dawley rats were randomized into four groups to receive the following for 28 days: (1) CsA vehicle (veh.) p.o. daily and alendronate vehicle subcutaneously (s.c.) twice/week, (2) CsA 15 mg/kg p.o. daily and Alen. veh. s.c. twice/week, (3) Alen. 70 micrograms/kg s.c. twice/ week and CsA veh. p.o. daily, and (4) CsA 15 mg/kg p.o. daily and Alen. 70 micrograms/kg s.c. twice/week. Rats were weighed and bled and serum was assayed serially for calcium, PTH, 1,25(OH)2vit.D, and osteocalcin. Tibiae were removed following sacrifice on day 28, after double demeclocycline and calcein labeling, for histomorphometric analysis. Treated groups were compared to the vehicle-treated control. We confirmed previous findings that CsA produces elevated 1,25(OH)2 vitamin D and serum osteocalcin levels. Alendronate treatment by itself decreased osteocalcin by day 28 and resulted in a marginal decrease in serum total calcium on day 14. The histomorphometry findings reconfirmed that the administration of CsA induces a state of high-turnover osteopenia. Alendronate prevented CsA's adverse effects, particularly in maintaining trabecular bone volume, presumably by decreasing bone remodeling. Alendronate would seem to hold therapeutic promise in post-transplantation bone disease.

The purpose of our study was to determine the effects of GH and insulin-like growth factor I (IGF-I) administration singly and in combination on vertebral, tibial, and femoral bone in aged female monkeys as well as the various treatment effects on serum hormone levels and osteocalcin gene expression. Twenty-one ovulating female monkeys (rhesus macaque), aged 16-20 yr (5-6 kg), were divided into four groups to receive the following treatment for 7 weeks via Alzet pumps inserted sc: A, eluant (control group); B, recombinant human IGF-I (rhIGF-I; 120 micrograms/kg.day); C) rhGH (100 micrograms/kg.day); D, combination of rhIGF-I (120 micrograms/kg.day) and rhGH (100 micrograms/kg.day). Serum was assayed serially for glucose, IGF-I, GH, and IGF-binding protein-3 levels. All groups received double labeling with calcein. On the day of death, the primates' second lumbar vertebrae, tibiae, and femora were carefully dissected, fixed in 70% ethanol, and subjected to histomorphometric analysis. Ribonucleic acid was extracted from contralateral tibiae for the purpose of osteocalcin gene expression analysis. Serum glucose was unaffected by treatment. Serum GH was significantly elevated in groups C and D, whereas serum IGF-I and IGFBP-3 were only significantly increased in group D. Histomorphometric analysis showed no significant differences or trends for bone volume in any treatment group. Bone formation rate, surface and/or bone volume referent were significantly higher in both groups treated with GH (C and D) in tibia and femur, with a similar trend in vertebrae. The increase in bone formation rate was due mainly to a significant increase in mineral apposition rate, but there was also an increase in tibial mineralizing surface by GH by factorial analysis (P < 0.05). There were significant treatment effects on osteoid surface and osteoclastic surface in femur in the combination treatment group vs. the controls. Osteocalcin gene expression analysis supported an enhanced expression in both groups treated with GH. These findings are consistent with a short term effect of GH to increase bone remodeling and predominantly osteoblastic activity in the appendicular skeleton. In contrast, other than an isolated increase in osteoclastic surface in femoral bone, IGF-I, when administered alone, was unable to significantly influence bone formation or resorption activity in this short term study.

Our laboratory has demonstrated that the immunosuppressants Cyclosporin A (CsA) and tacrolimus (FK506), in vivo in the rat, produce a high-turnover osteopenia. CsA is known to decrease serum testosterone (Test) levels both in the rat and in human transplant patients. Less is known of FK506's effect on androgens. CsA-induced hypogonadism may contribute to the aforementioned bone loss because hypogonadism itself is a risk factor for osteoporosis and fracture. The aim of this study was to assess serum androgen levels following CsA and FK506 therapy and to see wether Test replacement therapy, in the form of 28-day controlled release subcutaneous pellet implants, could prevent CsA-induced osteopenia. Two experiments were conducted. In experiment I, four groups of 6-month-old male Sprague-Dawley rats received the following: (A) CsA vehicle and placebo pellet, (B) Test 15 mg pellet and CsA vehicle, (C) CsA 10 mg/kg and placebo pellet, (D) Test 15 mg pellet and CsA 10 mg/kg. In experiment II, two groups of rats received (E) FK506 vehicle and (F) FK506 4 mg/kg. CsA, FK506, and vehicles were given for 28 days by daily oral gavage. The rats were weighted and bled on days 0, 14, and 28. All rats received double fluorescent labeling, and on day 28 the tibiae were removed for histomorphometry. Whole blood was assayed for CsA and FK506 levels. Serum was assayed for total and free Test as well as for osteocalcin (BGP), blood urea nitrogen (BUN), creatinine, and calcium. Whole blood monoclonal CsA levels measured by fluorescent immunoassay were in the therapeutic range, while a drug concentration profile showed good absorption of FK506. Those rats receiving Test and FK506 lost weight, while those receiving CsA remained constant. BUN was only marginally elevated in the CsA-treated groups on day 28 (p < 0.05), while creatinine was unchanged. On day 28, total and free Test was significantly reduced in the CsA-treated rats versus control (p < 0.05), while Test replacement therapy maintained total Test levels above vehicle (p < 0.01) and free Test levels similar to vehicle on day 28. FK506 did not lower total or free Test levels. BGP levels were significantly increased in the CsA (p < 0.01) and FK506 (p < 0.001) groups on day 28. BGP in the groups receiving Test alone and in combination with CsA remained similar to vehicle. Histomorphometry confirmed CsA- and FK506-induced high-turnover osteopenia. The Test alone group marignally increased bone formation. Test replacement failed to prevent the CsA-induced bone loss. In conclusion, immunosuppressive doses of CsA, but not FK506, lowers serum total and free Test. Hypoandrogenemia does not seem to be a major factor in CsA-induced osteopenia because bone loss occurs despite Test replacement.

Our laboratory has previously demonstrated that the T-lymphocyte is critical in the development of cyclosporin A-induced osteopenia in the rat model. A similar state of osteopenia is induced by estrogen depletion in the ovariectomized (OVX) rat, which is the animal model of postmenopausal bone loss. However, the role of the immune system, and particularly the T-lymphocyte, in estrogen deplete osteopenia has not been elucidated. We used the Rowett athymic nude rat as our model of T-lymphocyte deficiency. In this study, the experimental rats were divided into four groups as follows: (1) sham-operated Rowett heterozygous (rnu/+) euthymic rats (control group); (2) OVX Rowett heterozygous (rnu/+) euthymic rats; (3) sham-operated Rowett homozygous (rnu/rnu) athymic nude rats, which are T-lymphocyte deficient; and (4) ovariectomized Rowett homozygous (rnu/rnu) rats. Rats were weighed, and venous blood was taken in weeks 2, 4, and 6 for determination of serum osteocalcin. Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) was determined on the day of sacrifice. Following sacrifice, histomorphometry was performed on double-labeled proximal tibial metaphyses. Flow cytometric analysis of splenic mononu-clear cell isolates stained for OX19-positive (CD5) T-lymphocytes was performed. T-lymphocyte analysis revealed significant reductions in both athymic nude groups, while OVX euthymic rats demonstrated a diminished number of T-cells relative to their sham-operated counterparts. Histomorphometric data indicated that both OVX groups exhibited a significant loss of trabecular volume, with associated increases in indices for bone formation and resorption, with resorption likely outstripping formation, resulting in osteopenia. Serum osteocalcin was significantly elevated in the ovariectomized euthymic group throughout the experimental period compared with the control group (p < 0.01); it was elevated in the ovariectomized athymic group on week 4 only (p < 0.01 vs. control). It appears that the T-lymphocyte may not be an essential component in the pathogenesis of estrogen deficiency osteopenia. The contribution of circulating T-lymphocytes as well as other T-lymphocyte-rich organs needs to be explored further.

Cyclosporin A (CsA) administered to the oophorectomized (Ox) rat exacerbates the high turnover osteopenia associated with estrogen deficiency. 17 beta-estradiol replacement therapy prevent this bone loss. The aim of this study was to see whether an estrogen-like compound, Raloxifene analog (LY117018 HCL, Ral) could likewise ameliorate CsA-induced osteopenia in the Ox rat. Sixty 6-month-old Sprague-Dawley rats, divided into five groups, underwent oophorectomy. One group acted as a basal group and the others received either vehicle (group B), CsA 15 mg/kg/day (group C), Ral 3 mg/kg/day (group D), or CsA 15 mg/kg/day and Ral 3 mg/kg/day (group E) for 28 days by gavage. A sixth sham operated group of 12 rats received vehicle only (group A). Rats were weighed and bled on days 0, 14, and 28 for measurement of ionized calcium, glucose, osteocalcin (BGP), 17 beta-estradiol, and 1,25-dihydroxyvitamin D3 (1,25[OH]2D3). Tibiae were removed on day 28 for bone histomorphometry after double tetracycline and calcein labeling. Oophorectomy caused a significant gain in weight in groups B and C which was prevented by Ral in groups D and E. Randomized blood glucose levels and 1,25(OH)2D3 levels were elevated in both CsA-treated groups. Blood ionized calcium levels were lower in vehicle (group B) compared with sham (group A) on day 28. Ox (group B) had significantly higher serum BGP levels compared with sham-operated rats. Serum BGP levels were further elevated in group C compared with vehicle and were lowered in both Ral-treated groups to vehicle levels by day 28. Bone histomorphometry revealed a high turnover osteopenia with increased parameters of bone formation and resorption and loss of cancellous bone volume postoophorectomy (group B). CsA (group C) exacerbated the effects of oophorectomy. Ral (group D) completely prevented the high turnover osteopenia caused by oophorectomy and was able to attenuate substantially the effects of CsA in the Ox rat (group E). Ral therapy ameliorated CsA-induced osteopenia in the Ox rat and might prove a useful agent in preventing bone loss in postmenopausal women receiving CsA.