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Introduction: This study estimated the direct medical and indirect costs associated with coronavirus disease 2019 (COVID-19) diagnoses among U.S. active duty (AD) Army service members (SMs). These cost estimates provide the U.S. Military with a better understanding of the financial burden of COVID-19 and provide a foundation for cost-effectiveness estimates., Materials and Methods: The study was approved as Public Health Practice (#17-605) by the U.S. Army Public Health Center, Public Health Review Board. U.S. AD Army SMs with COVID-19 were identified using an Army COVID-19 testing and surveillance database. Encounters for these SMs were captured from medical record where International Classification of Disease Tenth Revision, Clinical Modification code U07.1 was in the first or second diagnostic position. Analyses were conducted on SMs with COVID-19 who either had no healthcare encounters in the Military Health System (MHS); at least one MHS COVID-19 inpatient hospitalization; or at least one MHS outpatient COVID-19 encounter. Coronavirus disease 2019 (COVID-19) costs captured from the encounters were used to develop direct medical cost estimates. Literature on COVID-19 recovery post-hospitalization, along with the number of COVID-19 hospitalizations and outpatient visits from encounters were used to describe the intensity of COVID-19 care. Estimates of the indirect cost of lost duty were based on SMs salary information, along with recovery time, bed days, or outpatient visit time. The indirect cost of limited duty was estimated using the time associated with the Department of Defense (DoD) COVID-19 pandemic mitigation strategies in place when these SMs were identified as positive for COVID-19., Results: Coronavirus disease 2019 (COVID-19) cost estimates were developed for the Army using data from 19,086 SMs identified as positive for COVID-19 between June 1, 2020, and December 31, 2020. Direct medical costs, or the amount paid by the DoD to facilities for COVID-19 care, averaged $606 per SM with an encounter. Indirect costs for lost duty or the cost for recovery and the time taken to seek care for COVID-19 averaged $319 per SM, while indirect costs for limited duty or isolation associated with COVID-19 averaged $4,111 per SM or $411 per day. Service members (SMs) with an inpatient hospitalization averaged 4.8 bed days (range 1-43) and 266 recovery hours while SMs who sought outpatient care for COVID-19 averaged two outpatient visits (range 1-60 visits)., Conclusions: The direct medical costs of a COVID-19 encounter in the MHS ($606) are a small portion of the costs for a SM with COVID-19. Indirect costs of lost and limited duty associated with COVID-19 averaged seven times higher ($4,331) and accounted for the vast majority of costs. Recognition of these costs is important especially given that soldiers in the hospital or in quarters being quarantined are complete losses of manpower to the Army. While the COVID-19 pandemic is ongoing and prevention, treatment, and mitigation efforts continue to evolve, having reliable estimates of direct medical and indirect costs from this study allows the U.S. Army and MHS to better account for the cost of this pandemic for its population., (© The Association of Military Surgeons of the United States 2022.)

Magnetic fields are fundamental to the evolution of galaxies, playing a key role in the astrophysics of the interstellar medium and star formation. Large-scale ordered magnetic fields have been mapped in the Milky Way and nearby galaxies 1,2 , but it is not known how early in the Universe such structures formed 3 . Here we report the detection of linearly polarized thermal emission from dust grains in a strongly lensed, intrinsically luminous galaxy that is forming stars at a rate more than 1,000 times that of the Milky Way at redshift 2.6, within 2.5 Gyr of the Big Bang 4,5 . The polarized emission arises from the alignment of dust grains with the local magnetic field 6,7 . The median polarization fraction is of the order of 1%, similar to nearby spiral galaxies 8 . Our observations support the presence of a 5-kiloparsec-scale ordered magnetic field with a strength of around 500 μG or lower, oriented parallel to the molecular gas disk. This confirms that such structures can be rapidly formed in galaxies, early in cosmic history., (© 2023. The Author(s).)

Objectives: To examine whether discharge destination is a useful predictor variable for the length of admission within psychiatric intensive care units (PICUs)., Methods: A clinician-led process separated PICU admissions by discharge destination into three types and suggested other possible variables associated with length of stay. Subsequently, a retrospective study gathered proposed predictor variable data from a total of 368 admissions from four PICUs. Bayesian models were developed and analysed., Results: Clinical patient-type grouping by discharge destination displayed better intraclass correlation (0.37) than any other predictor variable (next highest was the specific PICU to which a patient was admitted (0.0585)). Patients who were transferred to further secure care had the longest PICU admission length. The best model included both patient type (discharge destination) and unit as well as an interaction between those variables., Discussion: Patient typing based on clinical pathways shows better predictive ability of admission length than clinical diagnosis or a specific tool that was developed to identify patient needs. Modelling admission lengths in a Bayesian fashion could be expanded and be useful within service planning and monitoring for groups of patients., Conclusion: Variables previously proposed to be associated with patient need did not predict PICU admission length. Of the proposed predictor variables, grouping patients by discharge destination contributed the most to length of stay in four different PICUs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite the existence of a substantial amount of climate-related scientific data, misconceptions about climate change are still prevalent within public opinion. Dissemination of misinformation to the public through subjective media sources is a major challenge that climate scientists face. Implementation of climate policy is crucial for mitigation and adaptation measures required to curtail anthropogenic rooted climate change. This paper will discuss student perspectives on the 2022 United Nations climate summit in Egypt (COP27) related to climate literacy and public opinion as the driving forces behind the enactment and execution of important climate-based policy., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

A stringent outcome assessment is a key aspect of establishing evidence-based clinical guidelines for anterior cruciate ligament (ACL) injury treatment. To establish a standardized assessment of clinical outcome after ACL treatment, a consensus meeting including a multidisciplinary group of ACL experts was held at the ACL Consensus Meeting Panther Symposium, Pittsburgh, Pennsylvania, USA, in June 2019. The aim was to establish a consensus on what data should be reported when conducting an ACL outcome study, what specific outcome measurements should be used, and at what follow-up time those outcomes should be assessed. The group reached consensus on 9 statements by using a modified Delphi method. In general, outcomes after ACL treatment can be divided into 4 robust categories: early adverse events, patient-reported outcomes (PROs), ACL graft failure/recurrent ligament disruption, and clinical measures of knee function and structure. A comprehensive assessment after ACL treatment should aim to provide a complete overview of the treatment result, optimally including the various aspects of outcome categories. For most research questions, a minimum follow-up of 2 years with an optimal follow-up rate of 80% is necessary to achieve a comprehensive assessment. This should include clinical examination, any sustained reinjuries, validated knee-specific PROs, and health-related quality of life questionnaires. In the midterm to long-term follow-up, the presence of osteoarthritis should be evaluated. This consensus paper provides practical guidelines for how the aforementioned entities of outcomes should be reported and suggests the preferred tools for a reliable and valid assessment of outcome after ACL treatment., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: The ACL Consensus Meeting Panther Symposium at the University of Pittsburgh Medical Center (UPMC) was sponsored by Smith & Nephew, the UPMC, Elizur, Arthrex, Conmed, DJO, Mid-Atlantic Surgical Systems, RTI Surgical, and BlackRhino Medical. K.S. has received consulting fees from the National Football League, Service Excellence, Mitek, Flexion Therapeutics, Samumed, and NovoPedics and royalties from nPhase. C.B.M. has received consulting fees from Linvatec, Medacta, Stryker, Wright Medical, and Zimmer Biomet. V.M. has received educational grants, consulting fees, and speaking fees from Smith & Nephew and educational grants from Arthrex. O.R.A. has received speaking fees from Conmed and honoraria from DJO. S.D. has received personal fees from Zimmer Biomet. A.G. has received grants and personal fees from Smith & Nephew and Ossur and personal fees from Graymont and Olympus. C.C.K. has received grant support from DJO, educational support from CDC Medical, consulting fees from Zimmer Biomet, and nonconsulting fees from Arthrex. R.K. has received grants from Smith & Nephew, Zimmer Biomet, Stryker, and Johnson & Johnson; consulting fees from Medacta, Arthrex, Japan Tissue Engineering, and Hirosaki Life Science Innovation; and speaking fees from Arthrex, Smith & Nephew, Zimmer Biomet, Johnson & Johnson, and Japan Tissue Engineering. B.L. has received royalties from Wolters Kluwer Health–Lippincott Williams & Wilkins. R.G.M. has received stock/stock options from MEND Nutrition and royalties from Springer and Demos Health. L.P. has received research support from the Australian Orthopaedic Association, Friends of the Mater Foundation, and Smith & Nephew; has received speaking fees from Smith & Nephew; has received royalties from Australian Biotechnologies and Signature Orthopaedics; has stock/stock options in Australian Biotechnologies; and has patents with Hip Developments, Smith & Nephew, and Surgical Apps. A.R. has received other support from Enhatch, Conformis, Stryker, Smith & Nephew, Arthrex, Anika Therapeutics, and Bodycad. B.R. has received fellowship support from Smith & Nephew, has received royalties from Elsevier, has stock in Johnson & Johnson and Merck, and is the Editor-in-Chief of The Orthopaedic Journal of Sports Medicine. B.R.W. has received educational support from Wardlow Enterprises, consulting fees from Linvatec, and faculty/speaking fees from Linvatec. M.Z. is the founder of and has stock in Orthocell. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2020.)

Background: We aimed to assess the quality of physical health monitoring following rapid tranquillisation (RT) for acute behavioural disturbance in UK mental health services., Methods: The Prescribing Observatory for Mental Health (POMH-UK) initiated an audit-based quality improvement programme addressing the pharmacological treatment of acute behavioural disturbance in mental health services in the UK., Results: Data relating to a total of 2454 episodes of RT were submitted by 66 mental health services. Post-RT physical health monitoring did not reach the minimum recommended level in 1933 (79%) episodes. Patients were more likely to be monitored (OR 1.78, 95% CI 1.39-2.29, p  < 0.001) if there was actual or threatened self-harm, and less likely to be monitored if the episode occurred in the evening (OR 0.79, 95% CI 0.62-1.0, p  < 0.001) or overnight (OR 0.57, 95% CI 0.44-0.75, p  < 0.001). Risk factors such as recent substance use, RT resulting in the patient falling asleep, or receiving high-dose antipsychotic medication on the day of the episode, did not predict whether or not the minimum recommended level of post-RT monitoring was documented., Conclusions: The minimum recommended level of physical health monitoring was reported for only one in five RT episodes. The findings also suggest a lack of targeting of at-risk patients for post-RT monitoring. Possible explanations are that clinicians consider such monitoring too demanding to implement in routine clinical practice or not appropriate in every clinical situation. For example, physical health measures requiring direct contact with a patient may be difficult to undertake, or counter-productive, if RT has failed. These findings prompt speculation that post-RT monitoring practice would be improved by the implementation of guidance that integrated and refined the currently separate systems for undertaking and recording physical health observations post-RT, determining nursing observation schedules and detecting acute deterioration in physical health. The effectiveness and clinical utility of such an approach would be worth testing., Competing Interests: Conflict of interest statement: CP, CA, SD, OD and CO have nothing to declare. TREB has been a member of scientific advisory boards for Sunovion, Otsuka/Lundbeck and Newron Pharmaceuticals, and received speaker fees from Janssen., (© The Author(s), 2019.)

Transcriptome analyses show a surprisingly large proportion of the mammalian genome is transcribed; much more than can be accounted for by genes and introns alone. Most of this transcription is non-coding in nature and arises from intergenic regions, often overlapping known protein-coding genes in sense or antisense orientation. The functional relevance of this widespread transcription is unknown. Here we characterize a promoter responsible for initiation of an intergenic transcript located approximately 3.3 kb and 10.7 kb upstream of the adult-specific human β-globin genes. Mutational analyses in β-YAC transgenic mice show that alteration of intergenic promoter activity results in ablation of H3K4 di- and tri-methylation and H3 hyperacetylation extending over a 30 kb region immediately downstream of the initiation site, containing the adult δ- and β-globin genes. This results in dramatically decreased expression of the adult genes through position effect variegation in which the vast majority of definitive erythroid cells harbor inactive adult globin genes. In contrast, expression of the neighboring ε- and γ-globin genes is completely normal in embryonic erythroid cells, indicating a developmentally specific variegation of the adult domain. Our results demonstrate a role for intergenic non-coding RNA transcription in the propagation of histone modifications over chromatin domains and epigenetic control of β-like globin gene transcription during development., Competing Interests: The authors have declared that no competing interests exist.

In this work, we consider the pros and cons of using various layers of keyless coding to achieve secure and reliable communication over the Gaussian wiretap channel. We define a new approach to information theoretic security, called practical secrecy and the secrecy benefit, to be used over real-world channels and finite blocklength instantiations of coding layers, and use this new approach to show the fundamental reliability and security implications of several coding mechanisms that have traditionally been used for physical-layer security. We perform a systematic/structured analysis of the effect of error-control coding, scrambling, interleaving, and coset coding, as coding layers of a secrecy system. Using this new approach, scrambling and interleaving are shown to be of no effect in increasing information theoretic security, even when measuring the effect at the output of the eavesdropper's decoder. Error control coding is shown to present a trade-off between secrecy and reliability that is dictated by the chosen code and the signal-to-noise ratios at the legitimate and eavesdropping receivers. Finally, the benefits of secrecy coding are highlighted, and it is shown how one can shape the secrecy benefit according to system specifications using combinations of different layers of coding to achieve both reliable and secure throughput.

Background: A quality improvement programme addressing prescribing practice for acutely disturbed behaviour was initiated by the Prescribing Observatory for Mental Health., Method: This study analysed data from a baseline clinical audit conducted in inpatient mental health services in member trusts., Results: Fifty-eight mental health services submitted data on 2172 episodes of acutely disturbed behaviour. A benzodiazepine alone was administered in 60% of the 1091 episodes where oral medication only was used and in 39% of the 1081 episodes where parenteral medication (rapid tranquillisation) was used. Haloperidol was combined with lorazepam in 22% of rapid tranquillisation episodes and with promethazine in 3%. Physical violence towards others was strongly associated with receiving rapid tranquillisation in men (odds ratio 1.74, 1.25-2.44; p<0.001) as was actual or attempted self-harm in women (odds ratio 1.87, 1.19-2.94; p=0.007). Where physical violence towards others was exhibited, a benzodiazepine and antipsychotic was more likely to be prescribed than a benzodiazepine alone (odds ratio 1.39, 1.00-1.92; p=0.05). The data suggested that 25% of patients were at least 'extremely or continuously active' in the hour after rapid tranquillisation was administered., Conclusion: The current management of acutely disturbed behaviour with parenteral medication may fail to achieve a calming effect in up to a quarter of episodes. The most common rapid tranquillisation combination used was lorazepam and haloperidol, for which the randomised controlled trial evidence is very limited. Rapid tranquillisation prescribing practice was not wholly consistent with the relevant National Institute for Health and Care Excellence guideline, which recommends intramuscular lorazepam on its own or intramuscular haloperidol combined with intramuscular promethazine. Clinical factors prompting the use of rapid tranquillisation rather than oral medication may differ between the genders.

Spatial patterns in major dissolved solute concentrations were examined to better understand impact of surface coal mining in headwaters on downstream water chemistry. Sixty sites were sampled seasonally from 2012 to 2014 in an eastern Kentucky watershed. Watershed areas (WA) ranged from 1.6 to 400.5 km 2 and were mostly forested (58%-95%), but some drained as much as 31% surface mining. Measures of total dissolved solutes and most component ions were positively correlated with mining. Analytes showed strong convergent spatial patterns with high variability in headwaters (<15 km 2 WA) that stabilized downstream (WA > 75 km 2 ), indicating hydrologic mixing primarily controls downstream values. Mean headwater solute concentrations were a good predictor of downstream values, with % differences ranging from 0.55% (Na + ) to 28.78% (Mg 2+ ). In a mined scenario where all headwaters had impacts, downstream solute concentrations roughly doubled. Alternatively, if mining impacts to headwaters were minimized, downstream solute concentrations better approximated the 300 μS/cm conductivity criterion deemed protective of aquatic life. Temporal variability also had convergent spatial patterns and mined streams were less variable due to unnaturally stable hydrology. The highly conserved nature of dissolved solutes from mining activities and lack of viable treatment options suggest forested, unmined watersheds would provide dilution that would be protective of downstream aquatic life.

Roughly 40% of the Earth's total heat flow is powered by radioactive decays in the crust and mantle. Geo-neutrinos produced by these decays provide important clues about the origin, formation and thermal evolution of our planet, as well as the composition of its interior. Previous measurements of geo-neutrinos have all relied on the detection of inverse beta decay reactions, which are insensitive to the contribution from potassium and do not provide model-independent information about the spatial distribution of geo-neutrino sources within the Earth. Here we present a method for measuring previously unresolved components of Earth's radiogenic heating using neutrino-electron elastic scattering and low-background, direction-sensitive tracking detectors. We calculate the exposures needed to probe various contributions to the total geo-neutrino flux, specifically those associated to potassium, the mantle and the core. The measurements proposed here chart a course for pioneering exploration of the veiled inner workings of the Earth.

Aims and method Two police liaison and section 136 schemes were developed alongside police services at different sites within the same NHS trust. In one, a mental health nurse worked with frontline police attending incidents related to mental health. The other involved nurses providing advice from the police control room. Section 136 detentions were measured over two 6-month periods (6 months apart) before and after practice change. Data analysed included total numbers of section 136 assessments, outcomes following subsequent assessment, and relevant diagnostic and demographic factors. Association of any change in section 136 total numbers and proportion subsequently admitted was investigated in both sites. Results The model involving a nurse alongside frontline police showed significant reduction in section 136 numbers (38%, P < 0.01) as well as greater admission rates ( P = 0.01). The scheme involving support within the police control room did not show any change in section 136 detention but showed a non-significant ( P = 0.16) decrease in subsequent admission. Clinical implications Mental health nurses working alongside frontline police officers can help improve section 136 numbers and outcomes., Competing Interests: Declaration of interest None.

Recently, the term 'locked rehabilitation' has spread from commissioning to now also clinical parlance. This is without any clear service description or category of patient which this service manages. Differences between this new term and an established definition of low secure services are examined and reasons for the introduction of this terminology are discussed. This is contextualised within service development, payment by results and measures of quality. It is argued that there is a need for ongoing measurements of types of patients admitted to, and treatments offered by, this 'new' ward, as well as those within psychiatric intensive and low secure care services.

Every second greater than 10(25) antineutrinos radiate to space from Earth, shining like a faint antineutrino star. Underground antineutrino detectors have revealed the rapidly decaying fission products inside nuclear reactors, verified the long-lived radioactivity inside our planet, and informed sensitive experiments for probing fundamental physics. Mapping the anisotropic antineutrino flux and energy spectrum advance geoscience by defining the amount and distribution of radioactive power within Earth while critically evaluating competing compositional models of the planet. We present the Antineutrino Global Map 2015 (AGM2015), an experimentally informed model of Earth's surface antineutrino flux over the 0 to 11 MeV energy spectrum, along with an assessment of systematic errors. The open source AGM2015 provides fundamental predictions for experiments, assists in strategic detector placement to determine neutrino mass hierarchy, and aids in identifying undeclared nuclear reactors. We use cosmochemically and seismologically informed models of the radiogenic lithosphere/mantle combined with the estimated antineutrino flux, as measured by KamLAND and Borexino, to determine the Earth's total antineutrino luminosity at . We find a dominant flux of geo-neutrinos, predict sub-equal crust and mantle contributions, with ~1% of the total flux from man-made nuclear reactors.

Glial cell line-derived neurotrophic factor (GDNF) exerts neurotrophic and neuroprotective effects on substantia nigra (SN) dopamine neurons and has great therapeutic potential for Parkinson's disease (PD). Hindering this potential is the fact that GDNF cannot cross the blood-brain barrier. The aim of this study was to assess the effects of GDNF administered by the intranasal route in normal rats, and in the unilateral 6-hydroxydopamine (6-OHDA) model of PD. In the first study, rats received single intranasal doses of 50-μg GDNF in phosphate-buffered saline (PBS) or cationic liposomes, but no 6-OHDA. In the second study, rats were nasally administered 10, 50 or 150 μg of GDNF in PBS or cationic liposomes 1h before injection of 6-OHDA. All groups were sacrificed 3-4 weeks later. Both intranasal GDNF treatments induced a neurotrophic effect in the SN insofar as the number of tyrosine hydroxylase (TH)-positive neurons was significantly higher than in controls given intranasal PBS liposomes. Dopamine cell counts were also higher in the intact SN of 6-OHDA-lesioned rats compared to controls given PBS liposomes. Most importantly, intranasal GDNF provided significant neuroprotective efficacy indicated by greater TH immunostaining density in the lesioned versus intact SN of rats given single 50-μg doses of GDNF in PBS, or 150-μg doses of liposomal GDNF, compared to lesioned rats given PBS liposomes. Three 50-μg doses given at daily intervals (1 day before, 1h before, and 1 day after 6-OHDA) provided even greater protection than single 150-μg doses. Multiple doses at short intervals may therefore provide greater neuroprotection than single bolus doses. These results demonstrate both a neurotrophic effect of intranasal GDNF in the intact SN as well as neuroprotective efficacy in the unilateral 6-OHDA model, supporting pursuit of this approach as a potential treatment for PD., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expelling the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.

The intergalactic medium was not completely reionized until approximately a billion years after the Big Bang, as revealed by observations of quasars with redshifts of less than 6.5. It has been difficult to probe to higher redshifts, however, because quasars have historically been identified in optical surveys, which are insensitive to sources at redshifts exceeding 6.5. Here we report observations of a quasar (ULAS J112001.48+064124.3) at a redshift of 7.085, which is 0.77 billion years after the Big Bang. ULAS J1120+0641 has a luminosity of 6.3 × 10(13)L(⊙) and hosts a black hole with a mass of 2 × 10(9)M(⊙) (where L(⊙) and M(⊙) are the luminosity and mass of the Sun). The measured radius of the ionized near zone around ULAS J1120+0641 is 1.9 megaparsecs, a factor of three smaller than is typical for quasars at redshifts between 6.0 and 6.4. The near-zone transmission profile is consistent with a Lyα damping wing, suggesting that the neutral fraction of the intergalactic medium in front of ULAS J1120+0641 exceeded 0.1.

Gravitational lensing is a powerful astrophysical and cosmological probe and is particularly valuable at submillimeter wavelengths for the study of the statistical and individual properties of dusty star-forming galaxies. However, the identification of gravitational lenses is often time-intensive, involving the sifting of large volumes of imaging or spectroscopic data to find few candidates. We used early data from the Herschel Astrophysical Terahertz Large Area Survey to demonstrate that wide-area submillimeter surveys can simply and easily detect strong gravitational lensing events, with close to 100% efficiency.

Aim: To evaluate the effect of a residential retreat on promoting lifestyle modification for the health-related quality of life (HRQOL) of people with multiple sclerosis (MS)., Methods: A longitudinal cohort study of adults with self-reported MS who voluntarily attended a five-day residential retreat in rural Victoria, Australia. Participants were asked to complete the MSQOL-54 questionnaire just prior to the retreat, and at one year and 2.5 years post-retreat., Results: Of 188 participants 109 (58%) completed the questionnaire. The cohort showed a significant improvement in HRQOL at one year and 2.5 year follow-up. After one year, overall quality of life (QOL) domain had increased from 73.4 to 81.7 (P<0.001), physical health composite from 66.2 to 76.4 (P=0.001) and mental health composite from 73.7 to 83.6 (P<0.001) in the subset of 76 with data at both time points. After 2.5 years, overall QOL had increased from 68.4 to 71.7 (P=0.03), physical health 59.7 to 70.0 (P=0.01), and mental health 66.9 to 76.6 (P<0.01) in the subset of 44 with data at both time points., Conclusions: HRQOL usually deteriorates over time in people with MS. Attendance at a residential retreat promoting lifestyle modification appears to have a significant short-medium term positive effect on QOL for people with MS. General practitioners caring for people with MS should consider the potential benefits of this approach in overall management.

The oceans play a key role in climate regulation especially in part buffering (neutralising) the effects of increasing levels of greenhouse gases in the atmosphere and rising global temperatures. This chapter examines how the regulatory processes performed by the oceans alter as a response to climate change and assesses the extent to which positive feedbacks from the ocean may exacerbate climate change. There is clear evidence for rapid change in the oceans. As the main heat store for the world there has been an accelerating change in sea temperatures over the last few decades, which has contributed to rising sea-level. The oceans are also the main store of carbon dioxide (CO2), and are estimated to have taken up approximately 40% of anthropogenic-sourced CO2 from the atmosphere since the beginning of the industrial revolution. A proportion of the carbon uptake is exported via the four ocean 'carbon pumps' (Solubility, Biological, Continental Shelf and Carbonate Counter) to the deep ocean reservoir. Increases in sea temperature and changing planktonic systems and ocean currents may lead to a reduction in the uptake of CO2 by the ocean; some evidence suggests a suppression of parts of the marine carbon sink is already underway. While the oceans have buffered climate change through the uptake of CO2 produced by fossil fuel burning this has already had an impact on ocean chemistry through ocean acidification and will continue to do so. Feedbacks to climate change from acidification may result from expected impacts on marine organisms (especially corals and calcareous plankton), ecosystems and biogeochemical cycles. The polar regions of the world are showing the most rapid responses to climate change. As a result of a strong ice-ocean influence, small changes in temperature, salinity and ice cover may trigger large and sudden changes in regional climate with potential downstream feedbacks to the climate of the rest of the world. A warming Arctic Ocean may lead to further releases of the potent greenhouse gas methane from hydrates and permafrost. The Southern Ocean plays a critical role in driving, modifying and regulating global climate change via the carbon cycle and through its impact on adjacent Antarctica. The Antarctic Peninsula has shown some of the most rapid rises in atmospheric and oceanic temperature in the world, with an associated retreat of the majority of glaciers. Parts of the West Antarctic ice sheet are deflating rapidly, very likely due to a change in the flux of oceanic heat to the undersides of the floating ice shelves. The final section on modelling feedbacks from the ocean to climate change identifies limitations and priorities for model development and associated observations. Considering the importance of the oceans to climate change and our limited understanding of climate-related ocean processes, our ability to measure the changes that are taking place are conspicuously inadequate. The chapter highlights the need for a comprehensive, adequately funded and globally extensive ocean observing system to be implemented and sustained as a high priority. Unless feedbacks from the oceans to climate change are adequately included in climate change models, it is possible that the mitigation actions needed to stabilise CO2 and limit temperature rise over the next century will be underestimated.

Recent studies of galaxies approximately 2-3 Gyr after the Big Bang have revealed large, rotating disks, similar to those of galaxies today. The existence of well-ordered rotation in galaxies during this peak epoch of cosmic star formation indicates that gas accretion is likely to be the dominant mode by which galaxies grow, because major mergers of galaxies would completely disrupt the observed velocity fields. But poor spatial resolution and sensitivity have hampered this interpretation; such studies have been limited to the largest and most luminous galaxies, which may have fundamentally different modes of assembly from those of more typical galaxies (which are thought to grow into the spheroidal components at the centres of galaxies similar to the Milky Way). Here we report observations of a typical star-forming galaxy at z = 3.07, with a linear resolution of approximately 100 parsecs. We find a well-ordered compact source in which molecular gas is being converted efficiently into stars, likely to be assembling a spheroidal bulge similar to those seen in spiral galaxies at the present day. The presence of undisrupted rotation may indicate that galaxies such as the Milky Way gain much of their mass by accretion rather than major mergers.

Alternaria is a saprophytic fungus that is widespread in the environment; it is an opportunistic pathogen and causes disease in human beings and domestic animals. Fungal spores gain entry to the host through skin lesions and cause slow-growing, soft to firm, subcutaneous swellings, either with or without ulcers. An indirect ELISA was developed for the detection of anti-Alternaria immunoglobulin G (IgG) antibodies in serum to determine the prevalence of Alternaria exposure in domestic cats. Fifty-two of 63 cats had detectable levels of anti-Alternaria IgG antibody. There were no correlations between the concentration of antibody and the sex, breed or living environment of the cats, but cats less than two years of age had significantly lower concentrations than older cats. The cats with disease caused by culture-confirmed Alternaria infections did not have significantly higher concentrations of antibody than the healthy cats or cats with other diseases.

This study examined the effects of long-term exposure to the endocrine-disrupting compounds (EDCs) Bisphenol-A (BPA) and Octylphenol (OP) on gonadotrophin secretion in pre-pubertal female sheep. Four-week-old, female lambs were randomly allocated to four groups (n=6), and twice each week treated with i.m. injections of either corn oil (vehicle controls), diethylstilbestrol (DES; 0.175mg/kg), BPA (3.5mg/kg) or OP (3.5mg/kg). After 5 weeks of treatment, animals were ovariectomized (ovx) and ovary weights recorded. Two weeks later, blood samples were collected from lambs every 15min for 6h, for LH pulse analysis. Animals were then euthanased and adrenal and kidney weight recorded. An age-related increase in tonic LH secretion was noted in Control, BPA- and OP-treated lambs, but was absent in DES-treated lambs. Following ovx, LH secretion increased in all except DES-treated lambs; FSH concentrations increased in all groups. BPA and DES significantly suppressed LH pulse frequency (C: 6.7+/-0.3pulses/6h, DES: 1.5+/-0.8pulses/6h, BPA: 2.3+/-0.8pulses/6h) and amplitude (C: 7.1+/-1.0ng/ml, DES: 1.9+/-0.6ng/ml, BPA: 1.6+/-0.4ng/ml). OP had no effect on LH secretion (Frequency: 5.8+/-0.5pulses/6h, amplitude: 8.0+/-2.0ng/ml). Ovary weight was similar among all groups. Results show that chronic in vivo exposure of prepubertal female lambs to BPA, at levels lower than those reported previously, can have significant effects on LH secretion that are comparable to those seen following exposure to the known xenoestrogen, DES. Exposure to an equal dose of the EDC OP, over the equivalent period of time was without effect on gonadotropin secretion in the prepubertal ewe lamb. These results indicate that exposure of prepubertal female lambs to the EDC BPA can induce significant effects on gonadotropin secretion, the potential long-term effects of exposure and the effects of these changes on reproductive performance and efficacy, therefore, merit further study.

This study investigates the development of visuo-spatial memory in school-aged children, as measured by the Nine Box Maze Test Child Version (NBMT-CV). This task, originally developed for adults by, utilises an allocentric framework to assess the complexities of spatial memory. Sixty children participated in this study (aged 5-12 years), which also involved administration of traditional 'non-verbal' memory tests. Results indicate that visuo-spatial memory develops across childhood and that the NBMT-CV taps distinct skills compared to other 'non-verbal' memory tasks. The theoretical, assessment and developmental issues raised by these findings are discussed.

The overflow and descent of cold, dense water from the sills of the Denmark Strait and the Faroe Shetland channel into the North Atlantic Ocean is the principal means of ventilating the deep oceans, and is therefore a key element of the global thermohaline circulation. Most computer simulations of the ocean system in a climate with increasing atmospheric greenhouse-gas concentrations predict a weakening thermohaline circulation in the North Atlantic as the subpolar seas become fresher and warmer, and it is assumed that this signal will be transferred to the deep ocean by the two overflows. From observations it has not been possible to detect whether the ocean's overturning circulation is changing, but recent evidence suggests that the transport over the sills may be slackening. Here we show, through the analysis of long hydrographic records, that the system of overflow and entrainment that ventilates the deep Atlantic has steadily changed over the past four decades. We find that these changes have already led to sustained and widespread freshening of the deep ocean.

The absolute amount of microbial biomass and relative contribution of fungi and bacteria are expected to vary among types of organic matter (OM) within a stream and will vary among streams because of differences in organic matter quality and quantity. Common types of benthic detritus [leaves, small wood, and fine benthic organic matter (FBOM)] were sampled in 9 small (1st-3rd order) streams selected to represent a range of important controlling factors such as surrounding vegetation, detritus standing stocks, and water chemistry. Direct counts of bacteria and measurements of ergosterol (a fungal sterol) were used to describe variation in bacterial and fungal biomass. There were significant differences in bacterial abundance among types of organic matter with higher densities per unit mass of organic matter on fine particles relative to either leaves or wood surfaces. In contrast, ergosterol concentrations were significantly greater on leaves and wood, confirming the predominance of fungal biomass in these larger size classes. In general, bacterial abundance per unit organic matter was less variable than fungal biomass, suggesting bacteria will be a more predictable component of stream microbial communities. For 7 of the 9 streams, the standing stock of fine benthic organic matter was large enough that habitat-weighted reach-scale bacterial biomass was equal to or greater than fungal biomass. The quantities of leaves and small wood varied among streams such that the relative contribution of reach-scale fungal biomass ranged from 10% to as much as 90% of microbial biomass. Ergosterol concentrations were positively associated with substrate C:N ratio while bacterial abundance was negatively correlated with C:N. Both these relationships are confounded by particle size, i.e., leaves and wood had higher C:N than fine benthic organic matter. There was a weak positive relationship between bacterial abundance and streamwater soluble reactive phosphorus concentration, but no apparent pattern between either bacteria or fungi and streamwater dissolved inorganic nitrogen. The variation in microbial biomass per unit organic matter and the relative abundance of different types of organic matter contributed equally to driving differences in total microbial biomass at the reach scale.

How progesterone blocks the E2-induced GnRH surge in females is not known. In this study we assessed whether the endogenous opioid peptides (EOPs) that mediate progesterone negative feedback on pulsatile GnRH secretion also mediate the blockade of the GnRH surge. We treated ovariectomized ewes with physiological levels of E2 and progesterone to stimulate and block the GnRH surge, respectively, using LH secretion as an index of GnRH release. A pilot study confirmed that blocking opioidergic neurotransmission with the opioid receptor antagonist, naloxone (NAL; 1 mg/kg.h, i.v.), could prevent the suppression of pulsatile LH secretion by progesterone in our model. By contrast, antagonizing EOP receptors with NAL did not restore LH surges in ewes in which the E2-induced GnRH surge was blocked by progesterone treatment during the E2-dependent activation stage (Exp 1) of the GnRH surge induction process. However, in ewes treated with progesterone during the E2-independent transmission stage (Exp 2), NAL partially restored blocked LH surges, as indicated by increased fluctuations in LH that, in some cases, resembled LH surges. We conclude, therefore, that the EOPs that mediate progesterone negative feedback on pulsatile GnRH secretion are not involved in blockade of activation of the E2-induced GnRH surge by progesterone, but do appear to be part of the mechanism by which progesterone disrupts the transmission stage.

Background: Positron emission tomography (PET) studies have revealed functional left superior temporal gyrus (STG) abnormalities in symptomatic schizophrenia during word generation., Aims: To discover if this dysfunction is present in asymptomatic schizophrenia. To determine whether, without concurrent symptomatology, schizophrenia and bipolar affective disorder (BPD) are distinguishable by differing regional cerebral blood flow (rCBF) patterns during word generation., Method: A PET verbal fluency protocol was applied to six patients with BPD in remission and six patients with asymptomatic schizophrenia. Analysis included 10 control subjects from a contemporaneous study., Results: All groups showed relative reduction of rCBF in both superior temporal cortices. There were no quantitative differences in any group comparison. All groups exhibited negative covariation between rCBF in left prefrontal and right (but not left) temporal regions., Conclusions: Abnormal patterns of left STG function cannot be regarded as a trait marker for schizophrenia. Functional abnormalities may reflect aspects of mental state.

The preovulatory GnRH/LH surge in the ewe is stimulated by a rise in the circulating estradiol concentration that occurs in conjunction with preovulatory ovarian follicle development. In the presence of high levels of progesterone, such as during the luteal phase of the estrous/menstrual cycle, the stimulatory effects of elevated estradiol on GnRH/LH secretion are blocked. Recent work in the ewe has shown that a relatively short period of estradiol exposure can stimulate a GnRH/LH surge that begins after estrogenic support has been removed. This result suggests that surge generation is characterized by an estradiol-dependent period (during which the signal is read) and an estradiol-independent period (during which a cascade of neuronal events transmits the stimulatory signal to the GnRH neurosecretory system, which releases a surge of GnRH). In this series of studies, we addressed the hypothesis that progesterone can block transmission of the stimulatory estradiol signal after it has been read. Nine ovariectomized ewes were run through repeated artificial estrous cycles by sequential addition and removal of exogenous steroids. In study one, ewes received three treatments in a randomized cross-over design. Exposure to a follicular phase estradiol concentration for 10 h (positive control treatment) stimulated an LH surge in all ewes, as determined in hourly jugular blood samples. Maintenance of luteal phase progesterone concentrations throughout the artificial follicular phase (2 x CIDR-G devices, negative control) blocked the stimulatory effects of a 10-h estradiol signal, and no ewes that received this treatment expressed an LH surge. In the experimental group, exposure to luteal phase levels of progesterone, during the period after the surge generating system had been activated by estradiol, blocked the LH surge in six of nine ewes. This result demonstrates that progesterone can block the surge, even when applied after the surge-generating system has been activated and, therefore, that it inhibits either the transmission of the estradiol signal and/or the release of the GnRH/LH surge. In study 2, we assessed whether sensitivity to the inhibitory effects of progesterone was confined to a specific stage of the transmission of the estradiol signal. Eight ewes were exposed to four treatments, over successive artificial estrous cycles. Positive and negative controls were similar to those described in Study 1, except the duration of the stimulatory estradiol signal was reduced to 8 h. The two experimental groups consisted of an EARLY P (progesterone) treatment, in which progesterone was given from hours 8-13 after estradiol insertion (immediately after estradiol removal), and a LATE P treatment, in which progesterone was given from hours 13-18 (immediately before LH surge secretion). As expected, LH surges were stimulated and blocked, in response to the positive and negative controls, respectively. Whereas the EARLY P treatment blocked the LH surge in seven of eight ewes, the LATE P treatment was only successful in inhibiting a surge in one of eight animals. This result demonstrates that progesterone can block the estradiol-induced surge-generating signal soon after the onset of signal transmission (immediately after estradiol removal) but not during the later stages of signal transmission (at the time of GnRH/LH surge onset).

The conscious neurosensory characteristics of the internal components of the human knee were documented by instrumented arthroscopic palpation without intraarticular anesthesia. With only local anesthesia injected at the portal sites, the first author (SFD) had both knees inspected arthroscopically. Subjectively, he graded the sensation from no sensation (0) to severe pain (4), with a modifier of either accurate spatial localization (A) or poor spatial localization (B). The nature of the intraarticular sensation was variable, ranging from 0 on the patellar articular cartilage to 4A on the anterior synovium, fat pad, and joint capsule. The sensation arising from the cruciate ligaments ranged from 1 to 2B in the midportion, and from 3 to 4B at the insertion sites. The sensation from the meniscal cartilages ranged from 1B on the inner rim to 3B near the capsular margin. Innervation of most intraarticular components of the knee is probably crucial for tissue homeostasis. Failure of current intraarticular soft tissue reconstructions of the knee may be due, in part, to the lack of neurosensory restoration. Research studies of the knee designed to delineate factors that restore neurosensory characteristics of the musculoskeletal system may lead to techniques that result in true restoration of joint homeostasis and function.

Oxytocin neurone terminals display a powerful opioid-mediated auto-inhibitory mechanism which restrains secretory activity. In pregnancy, upregulation of this mechanism may underlie the accumulation of large stores of oxytocin in the pituitary. In the present study, conscious pregnant rats were cannulated to allow blood samples to be taken for measurement of oxytocin secretion in response to intravenous administration of cholecystokinin (CCK). In each rat, we measured the secretory response to CCK before and after administration of norbinaltorphine (norBNI), a selective kappa-opioid antagonist, or of naloxone, a relatively mu-selective antagonist. Throughout pregnancy, the stimulatory effect of CCK was enhanced by prior administration of norBNI. In pregnant rats norBNI also consistently increased basal oxytocin secretion, while naloxone had no effect, suggesting that in pregnancy there is active restraint of oxytocin secretion by endogenous opioids acting at kappa-receptors. However, in late pregnancy, between days 17 and 20, there was a significant reduction in the efficacy of norBNI in potentiating the oxytocin release in response to CCK, compared to its efficacy either in non-pregnant rats or in rats between days 8 and 13 of pregnancy. This suggests that in late pregnancy, endogenous kappa-opioid restraint is downregulated. In addition, the present results demonstrate an attenuation in the potency with which CCK evoked oxytocin release in late pregnancy. The attenuation was unrelated to opioid restraint at the level of the pituitary since it coincided with apparent desensitization of this auto-inhibitory mechanism.

We have previously demonstrated that a specific anti-IGF-I antibody will enhance the growth-promoting activity of IGF-I in vivo (Stewart et al. 1993). Since the antibody had a modest affinity for IGF-I we suggested that the antiserum might protect IGF-I from degradation whilst maintaining it in a bioavailable form. The aim of this investigation was to test that hypothesis by determining the plasma clearance and tissue distribution of tracer IGF-I in the presence of the enhancing anti-IGF-I immunoglobulin (anti-IGF-I Ig) or non-immune immunoglobulin (NI Ig). Dwarf rats were treated with saline, NI Ig or anti-IGF-I Ig for 4 days. On day 4, 125I-IGF-I (1.6 x 10(7) c.p.m.) was injected into the jugular vein and blood sampled over the next 330 min when the rats were killed: samples of liver, kidney and skeletal muscle were quickly dissected out. Mean plasma trichloroacetic acid (TCA)-precipitable 125I-IGF-I was always significantly greater (P < 0.001 for each time point) from anti-IGF-I Ig rats versus the NI Ig or saline groups (which exhibited practically identical decay curves), implying increased binding capacity for IGF-I in the anti-IGF-I Ig rats. Pharmacokinetic parameters were calculated by resolution of the decay curves using a two-phase model. The total clearance rate of 125I-IGF-I was significantly decreased (P < 0.001) by almost twofold in the anti-IGF-I versus the two control groups, consistent with the increased binding capacity in the anti-IGF Ig rats. The half-lives of the faster-decaying phase were not significantly different between treatment groups but, surprisingly, that for the slower-decaying phase was significantly decreased (P < 0.001) in the anti-IGF-I Ig rats versus the two control groups; this may reflect the low affinity of the anti-IGF-I Ig for IGF-I and its enhancing properties. The degradation of 125I-IGF-I was significantly decreased in animals receiving the anti-IGF-I Ig. In support of this, kidney TCA-precipitable radioactivity (c.p.m.) was seven-fold less (P < 0.001) in the anti-IGF-I Ig groups versus the controls, indicative of reduced excretion. Liver TCA-precipitable radioactivity was increased (P < 0.001) in the anti-IGF-I Ig rats, probably due to reticuloendothelial clearance of non-self antibodies: skeletal muscle TCA-precipitable radioactivity tended to increase in the anti-IGF-I Ig group versus the controls which might indicate increased targeting of IGF-I to muscle. Size exclusion chromatography of plasma 15 and 120 min after administration of 125I-IGF-I demonstrated a broad peak of radioactivity with a molecular mass of 150-300 kDa in the anti-IGF-I Ig-treated rats, which was responsible for more than 90% of the eluted radioactivity. This suggests that: (1) 125I-IGF-I was bound to the anti-IGF-I Ig and might also be able to associate with IGFBPs or (2) the polyclonal antibody might recognise more than one antigenic site on IGF-I. These data indicate that the anti-IGF-I Ig was protecting IGF-I from degradation, leading to a large plasma pool of IGF-I but that IGF-I could be transferred readily from the plasma pool to tissues. We suggest that administration of IGF-I in conjunction with a binding molecule similar to the antibody described here could provide the basis for effective IGF-I treatment strategy.

The Aberdeen Area Indian Health Service, South Dakota Department of Health, and the Centers for Disease Control and Prevention have collaborated since 1985 to investigate hepatitis A in Indian communities in the Northern Plains and to implement clinical trials of hepatitis A vaccine. After licensure of the hepatitis A vaccine in February 1995, community wide immunization programs have been implemented effectively in several communities experiencing hepatitis A outbreaks. The state health department, tribal health departments, Indian Health Service facilities, Head Start programs and schools have provided hepatitis A immunizations to children aged 2-12 years in each of these communities after obtaining parental consent. Culturally-specific educational materials were developed and extensive health education efforts were provided by IHS and tribal programs. Hepatitis A contacts age 2-12 were offered the hepatitis A vaccine at the same time they were offered passive immunization with immune globulin. To date over 70% of parents contacted by letter or in person have returned consent forms to have their children immunized. Higher response rates were obtained in communities where home visits were made to explain this program in more detail. The outbreaks appear to have stopped after 70% or more of the children aged 2-12 years were immunized. Immunization programs are being implemented in all Northern Plains Indian communities utilizing hepatitis. A vaccine from the Vaccine For Children Program. These efforts will likely eliminate hepatitis A as a health problem for Indian communities.

In situ hybridization was used to measure the expression of members of the Fos/Jun family of immediate-early genes in hypothalamic neurons in vivo following defined stimuli that utilize different afferent pathways. Only c-jun messenger RNA was expressed in the hypothalamic supraoptic and paraventricular nuclei of control animals. Intravenous infusions of sodium chloride solutions of different tonicity produced a range of plasma osmolalities within physiological limits. While the induction of c-fos and jun B messenger RNAs followed the stimulus intensity, the expression of c-jun was repressed at low levels of stimulation. A higher level of osmotic stimulation was able to co-induce c-jun with the c-fos, jun B and fos B genes, suggesting that other signalling pathways may then be activated. Parturition or systemic administration of cholecystokinin, that activate supraoptic and paraventricular neurons via ascending afferent pathways from the brainstem, both induced c-fos, but not the other genes, in the magnocellular nuclei. Use of double in situ hybridization confirmed that, unlike with osmotic stimulation, induction of c-fos only occurred in oxytocin neurons. These two stimuli did not cause a concomitant repression of c-jun messenger RNA expression in magnocellular oxytocin neurons. These patterns of induction provide evidence for the differential regulation of members of this family of genes in a physiological context.

Advancements in the understanding of anatomy, kinematics, and physiology should improve future treatment of anterior cruciate ligament injured knees. The ultimate goal of full restoration of an anterior cruciate ligament injured knee to preinjury status, may be possible in the distant future through genetic manipulation inducing regeneration of tissues. In the midterm future, resorbable stents with incorporated bioactive growth factors have the potential of inducing normal anterior cruciate ligament anatomy without the need for detrimental harvesting of the patient's tissues, or risk of microbial transmission with the use of an allograft. In the near future, the development of more benign autografts and allografts is possible along with methods of resorbable fixation of the graft to bone. Future development of 3-dimensional arthroscopic visualization and robotic surgical techniques have the potential for improvement in graft placement. Advancements in treatment of anterior cruciate ligament deficient knees also can be expected from nonsurgical areas, such as control of muscle atrophy, enhancing cerebellar-proprioceptive rehabilitation, and better bracing techniques. The basic principle of therapy should be to maximize the functional load acceptance and transference capacity of the knee with the least degree of risk to the patient.

The knee can be characterized as a complex set of asymmetrical moving parts acting together as a living biologic transmission. The purpose of this system is to accept, transfer, and dissipate loads generated at the ends of the long mechanical lever arms of the femur and tibia. In this analogy, the various ligaments represent sensate adaptive linkages, the articular cartilages represent bearings, and the menisci, mobile sensate bearings within the transmission. The muscles represent both living engines providing motive forces, and brakes and dampening systems under complex neurologic control mechanisms. The range of load that can be applied across an individual joint in a given period without supraphysiologic overload or structural failure can be termed the envelope of function. This range of homeostatic loading can be graphed with increasing applied loads on the vertical axis and the frequency of loading on the horizontal axis. At least 4 categories of factors together determine the envelope of function for a given joint including anatomic, kinematic, physiologic, and treatment factors. This theory of joint function can result in a more rational clinical approach to treating patients with knee injuries and other orthopaedic conditions. Orthopaedic therapy should be designed to maximize the envelope of function of musculoskeletal systems with the least degree of risk.

The functional relationship between sexually dimorphic neural populations and sex differences in reproductive functioning is unclear. The present study has investigated the function of the sexually dimorphic, estrogen-receptive, calcitonin gene-related peptide (CGRP) neurones in the female preoptic area by examining patterns of Fos immunoreactivity within these cells in relation to the luteinizing hormone surge and lordosis behaviour. In the first experiment, ovariectomized rats were treated with estradiol alone or estradiol plus progesterone to induce the luteinizing hormone surge. The percentage of CGRP neurones with Fos-positive nuclei was not different in estradiol alone (18 +/- 4%) and estradiol/progesterone-treated (24 +/- 3%) rats although the number of Fos-immunoreactive cells in the medial preoptic nucleus was increased 2-fold (P < 0.01) in estrogen/progesterone-treated rats and 40 +/- 5% of luteinizing hormone-releasing hormone neurones were found to express Fos in this group. In the second experiment, ovariectomized rats were treated with estradiol and progesterone and either, mated with a single male or placed in an empty cage, for 30 min. The number of Fos-immunoreactive cells in the medial preoptic nucleus was increased 4-fold in mated rats (P < 0.01) and the percentage of CGRP neurones with Fos-positive nuclei increased from 24 +/- 3% to 38 +/- 2% (P < 0.01) in mated animals. No differences were detected in the number of luteinizing hormone-releasing hormone neurones with Fos-positive nuclei in mated and non-mated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The physiological importance of oxytocin for the initiation and maintenance of labour and delivery is controversial. We investigated the effects of two novel peptide oxytocin antagonists on the onset and the progress of delivery in rats implanted with a jugular vein cannula one day before term. During delivery rats were given either an oxytocin antagonist (OVT16, n = 10, or F382, n = 7, 30 micrograms/kg) or vehicle (n = 10, 9) after the birth of the second pup and the time to deliver five more pups was recorded. Other rats were given an injection of F382 (30 micrograms/kg, n = 7) or vehicle (n = 9) after the birth of the fourth pup and the time to deliver three more pups was recorded. In another experiment rats were given repeated injections of F382 (30 or 60 micrograms/kg, n = 13, 11) or vehicle (n = 32) prepartum on the day of expected term and the time of onset and the progress of delivery was recorded. Rats given an antagonist after the second pup delivered the next five pups in 100 +/- 8 min (F382) and 83 +/- 12 min (OVT16), significantly slower than the respective controls (51 +/- 6 and 49 +/- 6 min, U-test, P < 0.05). Four of the 7 rats given F382 after the fourth pup showed no prolongation of delivery (time between pups 4-7: 24.7 +/- 2.9 vs 27.5 +/- 3.1 min in controls), while in the other three rats delivery was prolonged (time between pups 4-7: 86 +/- 4.3 min).(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously shown that a polyclonal anti-IGF-I antiserum administered together with IGF-I potentiates IGF-I activity in vivo. The anti-IGF-I antiserum has a modest affinity for IGF-I, similar to that for enhancing IGFBPs, and treated animals have significantly higher circulating IGF-I concentrations than their controls. Our recent findings have demonstrated that the anti-IGF-I activity decreases the clearance of IGF-I by at least 2-fold and that it abolishes the acute hypoglycaemic action of a single subcutaneous dose of IGF-I. Interestingly, we have been unable to demonstrate potentiation of the growth-promoting activity of the potent non-IGFBP binding IGF-I analogue LR3IGF-I, even though the analogue binds to the antiserum in vitro; rather native IGF-I/antibody complexes perform even better than LR3IGF-I. In IGF-I/antibody-treated dwarf rats, most IGF-I may be found in an uncharacterised high molecular weight antibody complex which is probably responsible for improved IGF-I performance. Thus, the anti-IGF-I antibody may be behaving in a similar manner to a high molecular weight IGFBP and is effective in potentiating IGF-I action in vivo.

We studied the results of bone scans in 50 consecutive patients with symptomatic, unilateral, chronic anterior cruciate ligament (ACL) tears. All patients had failed conservative therapy and underwent radionuclide imaging of the knee prior to arthroscopic ACL reconstruction. The scintigraphic activity in each of the three knee compartments was quantitatively scaled from 1 (normal scintigraphic activity) to 4 (marked activity). Quantitative activity in each of the three compartments was correlated with plain radiographic, arthroscopic, and clinical findings. All but four of the scans (92%) showed abnormal scintigraphic activity. The quantitative activity was highest overall in the medial compartment (2.9), followed by the lateral (2.4) and patellofemoral compartments (1.9). In the subgroup of patients with normal menisci (10 patients), most of the abnormal activity was in the lateral compartment (2.9), implying that when the medial meniscus remains competent in the presence of a torn ACL, there is increased stress on the lateral compartment. There was little correlation with scintigraphy and roentgenographic changes, except in the presence of moderate or severe radiographic degenerative arthritis. Similarly, there was little correlation between increased scintigraphic activity and chondromalacia. These results provide a baseline for future studies that use scintigraphic imaging in monitoring restoration of bone homeostasis following ACL reconstruction.

1. Intravenous administration of cholecystokinin (CCK) results in a transient activation of oxytocin neurones in the rat, and hence to oxytocin secretion: this activation is followed by expression of c-fos mRNA and of Fos-like immunoreactivity (Fos-LI) in magnocellular oxytocin neurones. Fos-like immunoreactivity is also induced in the regions of the brainstem that are thought to relay information from the periphery to the hypothalamus. 2. Administration of the selective CCKA receptor antagonist MK-329, but not the CCKB receptor antagonist L-365,260, prior to CCK injection, prevented oxytocin release as measured by radioimmunoassay and oxytocin neuronal activation as measured by electrophysiology and by the lack of induction of c-fos mRNA. 3. MK-329 abolished the release of adrenocorticotrophic hormone (ACTH) following injection of CCK. 4. MK-329 prevented the expression of Fos-LI in the hypothalamic magnocellular nuclei and in the area postrema and dorsal vagal complex of the brainstem. 5. L-365,260 had no effect on the expression of Fos-LI in the brainstem, but attenuated that seen in the hypothalamic magnocellular nuclei. 6. We conclude that CCK acts on CCKA receptors, either in the area postrema or on peripheral endings of the vagus nerve, to cause the release of hypothalamic oxytocin and ACTH. Information may be carried to the hypothalamus in part by CCK acting at CCKB receptors.

Pregnant rats were ovariectomized (or sham-ovariectomized) on days 17, 18 or 21 of pregnancy and oestradiol-17 beta and progesterone were replaced. Prepartum oxytocin concentrations were significantly lower in ovariectomized steroid-treated rats than in intact controls, and on day 21 of pregnancy injection of relaxin into acutely ovariectomized rats significantly increased plasma oxytocin concentrations. During parturition, injection of the opioid antagonist naloxone induced significant increases in plasma oxytocin concentration compared with saline-injected rats. The naloxone-induced increase was significantly less in ovariectomized steroid-treated rats than in rats with intact ovaries, indicating that endogenous opioid activity is less in ovariectomized rats than in intact rats. The progress of parturition in the ovariectomized steroid-treated rats was severely disrupted compared with sham-ovariectomized rats despite similar plasma oxytocin levels at the birth of pup number 2; this disruption was not overcome by injection of naloxone or by the consequent increase in oxytocin secretion, indicating deficient preparation of the uterus and birth canal in the absence of relaxin. We conclude that the decreased oxytocin concentrations prepartum, the prolongation of parturition and the decrease in opioid tone in ovariectomized steroid-treated rats may be partly due to a lack of relaxin produced by the ovary.

Neurons containing calcitonin gene-related peptide in the medial preoptic nucleus exhibit the largest neurochemically defined sex difference in the rat preoptic area with a 20-fold difference in cell numbers. The gonadal steroid hormones responsible for this sexual dimorphism have been investigated by examining calcitonin gene-related peptide immunoreactivity in the preoptic area of adult rats receiving a variety of perinatal and adult gonadal steroid manipulations. Cells immunoreactive for calcitonin gene-related peptide were examined in two populations within the preoptic area, one in its ventrolateral aspect and the other located in the lateral division of the medial preoptic nucleus. Cell profile counts estimate numbers of calcitonin gene-related peptide-containing cells in the medial preoptic nucleus of the female to be 22.2 +/- 3.0 cells/section compared with 1.0 +/- 0.2 in the male (P < 0.01). No sex differences existed in the preoptic ventrolateral population of calcitonin gene-related peptide cells (males 4.3 +/- 0.2, females 4.4 +/- 0.6 cells/section). Gonadectomy of male rats on postnatal day 2 resulted in the appearance of a calcitonin gene-related peptide-containing cell population in the medial preoptic nucleus which was indistinguishable from intact female rats (19.3 +/- 2.2 cells/section). Gonadectomy of adult male rats resulted in a modest increase in calcitonin gene-related peptide cell numbers within the medial preoptic nucleus (8.8 +/- 0.4 cells/section) and this was fully reversed by replacement of testosterone (0.7 +/- 0.2 cells/section).(ABSTRACT TRUNCATED AT 250 WORDS)