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Purpose: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects., Methods and Materials: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses., Results: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively., Conclusions: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase ( IDH )-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life., Methods and Analysis: PRO-GLIO (PROton versus photon therapy in IDH -mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH -mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints., Ethics and Dissemination: To implement proton therapy as part of standard of care for patients with IDH -mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums., Trial Registration Number: ClinicalTrials.gov Registry (NCT05190172)., 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.)

The introduction of immune checkpoint inhibitors has transformed the treatment landscape of metastatic non-small cell lung cancer. However, challenges remain to increase the fraction of patients achieving durable clinical responses to these drugs and to help monitor the treatment effect. In this phase II trial, we investigated the toxicity, systemic responses and circulating tumour DNA responses in patients (n = 21) with advanced non-small-cell lung cancer treated with atezolizumab and stereotactic body radiotherapy in the second or later line. We found the combined treatment to be safe with grade 3 toxicity reported in three patients. As the best overall response, four patients had a partial response, eight had stable disease and five had progressive disease. Median overall survival time was still not reached after a median follow-up of 26.5 months and 10/15 patients with programmed death-ligand 1 negative tumours were alive >18 months after the start of the study treatment. ctDNA was detectable at baseline in 11 patients. A rapid decline in ctDNA to <30% of baseline levels was seen in three patients, two of which were radiographic responders and one was considered clinically benefiting from therapy for almost 1 year., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Lower-leg injury and knee arthroscopy are both associated with venous thromboembolism (VTE). The mechanism of VTE in both situations is unknown, including the role of procoagulant microparticles. This may provide useful information for individualizing thromboprophylactic treatment in both patient groups., Objective: We aimed to study the effect of (1) lower-leg trauma and (2) knee arthroscopy on procoagulant phospholipid-dependent (PPL) activity plasma levels., Methods: POT-(K)CAST trial participants who did not develop VTE were randomly selected for the current study. Plasma was collected shortly after lower-leg trauma or before and after knee arthroscopy. For aim 1, samples of 67 patients with lower-leg injury were compared with control samples (preoperative samples of 74 patients undergoing arthroscopy). Linear regression was used to obtain mean ratios (natural logarithm retransformed data), adjusted for age, sex, body mass index, infections, and comorbidities. For aim 2, pre- and postoperative samples of 49 patients undergoing arthroscopy were compared using paired t tests. PPL activity was measured using modified activated factor X-dependent PPL clotting assay., Results: For aim 1, PPL activity levels were almost threefold higher in patients with lower-leg injury compared with controls, that is, mean ratio, 2.82 (95% confidence interval [CI], 1.98-4.03). For aim 2, postoperative PPL activity levels did not change significantly, that is, mean change, -0.72 mU/mL (95% CI, -2.03 to 0.59)., Conclusion: Lower-leg trauma was associated with increased plasma levels of PPL activity, in contrast to knee arthroscopy. Lower-leg trauma triggers the release of procoagulant microparticles., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Venous thromboembolism (VTE) is a frequent cardiovascular disease with severe complications, including recurrence and death. There is a great need for alternative prophylactic treatment options as anticoagulation is accompanied by increased bleeding risk. Statins are reported to reduce the risk of incident and recurrent VTE, but the mechanisms are elusive. Procoagulant phospholipids (PPL), and phosphatidylserine in particular, are crucial for efficient coagulation activation, but no studies have investigated the effect of statin treatment on plasma PPL activity., Objectives: To investigate the impact of rosuvastatin treatment on plasma PPL activity and levels of extracellular vesicles (EVs)., Patients/methods: Patients with a history of VTE (≥18 years) allowed to stop anticoagulant treatment were randomized to either 20 mg/day of rosuvastatin treatment or no treatment for 28 days in the Statins Reduce Thrombophilia (NCT01613794) trial. Plasma samples were collected at baseline and study end. PPL activity was measured in samples from 245 participants using a factor Xa-dependent clotting assay and EV levels by flow cytometry., Results: Rosuvastatin treatment yielded an overall 22% (95% confidence interval [CI] -38.2 to -5.8) reduction in PPL activity, and 37% (95% CI -62.9 to -11.2) reduction in PPL activity in participants with a history of pulmonary embolism. The effect of rosuvastatin on plasma PPL activity was not explained by changes in total cholesterol nor change in levels of total- or platelet-derived EVs., Conclusions: Rosuvastatin treatment caused a substantial decrease in plasma PPL activity, suggesting that a PPL-dependent attenuation of coagulation activation may contribute to a reduced VTE risk following statin treatment., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Negatively charged procoagulant phospholipids, phosphatidylserine (PS) in particular, are vital to coagulation and expressed on the surface membrane of extracellular vesicles. No previous study has investigated the association between plasma procoagulant phospholipid clotting time (PPL CT ) and future risk of venous thromboembolism (VTE)., Objectives: To investigate the association between plasma PPL CT and the risk of incident VTE in a nested case-control study., Methods: We conducted a nested case-control study in 296 VTE patients and 674 age- and sex-matched controls derived from a general population cohort (The Tromsø Study 1994-2007). PPL CT was measured in platelet-free plasma using a modified factor Xa-dependent clotting assay. Logistic regression was used to estimate odds ratio (OR) with 95% confidence intervals (CI) for VTE with PPL CT modelled as a continuous variable across quartiles and in dichotomized analyses., Results: There was a weak inverse association between plasma PPL CT and risk of VTE per 1 standard deviation increase of PPL CT (OR 0.93, 95% CI 0.80-1.07) and when comparing those with PPL CT in the highest quartile (OR 0.89, 95% CI 0.60-1.30) with those in the lowest quartile. Subjects with PPL CT >95th percentile had substantially lowered OR for VTE (OR 0.35, 95% CI 0.13-0.81). The inverse association was stronger when the analyses were restricted to samples taken shortly before the event. The risk estimates by categories of plasma PPL CT were similar for deep vein thrombosis and pulmonary embolism., Conclusion: Our findings suggest that high plasma PPL CT is associated with reduced risk of VTE., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Introduction: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity., Methods: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea., Results: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0-10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the "hottest" 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage., Conclusions: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions)., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The present study explores changes in pulmonary function, symptoms and radiological signs of pneumonitis after curatively intended stereotactic body radiation therapy (SBRT)., Methods: All inoperable, early-stage non-small cell lung cancer patients treated with stereotactic body radiation therapy (SBRT) from 2014-2017 were included in this single-centre study. They were followed regularly for 12 months after treatment. The patients were classified into three groups based on radiology and symptomatology: no radiation pneumonitis, asymptomatic and symptomatic radiation pneumonitis., Results: Forty-four patients with stage IA-IIB disease were treated with 45-56 Gy in 3-8 fractions. The median age was 75 years, 43% of the patients were female; 60% of the patients had a COPD in GOLD grade of 2-4, and 95.5% were active or former smokers. Symptomatic radiation pneumonitis occurred in 18% of the patients and asymptomatic pneumonitis as defined by radiology, in 39%. The mean of forced expiratory volume in 1 second (FEV1) and diffusion capacity for carbon monoxide (DLCO) decreases for all patients during the first years were higher than one would expect from physiologic ageing. FEV1 and DLCO in percent decrease 7-8% at 1-1.5 months in the symptomatic radiation pneumonitis group. CT scan findings consistent with radiation pneumonitis occurred after a median of 2.9 months in the symptomatic and 5.4 months in the asymptomatic radiation pneumonitis groups. In the group with symptomatic radiation pneumonitis, symptoms, as measured by the Clinical COPD questionnaire score, significantly increased at 3 and 6 months. Significant higher maximum doses to the critical lung volumes DC1000cm 3 (1000 cm 3 of lung receiving a given dose or less) and DC 1500cm 3 (1500 cm 3 of lung receiving a given dose or less) were observed in patients who developed radiation pneumonitis., Conclusion: Early decrease in measured FEV1 and DLCO occurred before imaging changes and symptoms and might indicate the development of symptomatic radiation pneumonitis. The dose to critical lung volumes of DC1000 cm 3 and DC1500 cm 3 may predict the risk for the development of symptomatic radiation pneumonitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Berg, Ramberg, Haugstvedt, Bengtson, Gabrielsen, Brustugun, Halvorsen and Helland.)

Anatomical changes during chemoradiation for lung cancer may decrease dose to the target or increase dose to organs at risk. To assess our ability to identify clinically significant anatomical alterations, we followed 67 lung cancer patients by daily cone-beam CT scans to ensure correct patient positioning and observe anatomical alterations. We also re-calculated the original dose distribution on a planned control CT scan obtained halfway during the treatment course to identify anatomical changes that potentially affected doses to the target or organs at risk. Of 66 patients who completed the treatment, 12 patients needed adaptation, two patients were adapted twice. We conclude that daily cone-beam CT and routines at the treatment machine discover relevant anatomical changes during curative radiotherapy for patients with lung cancer without additional imaging., 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., (© 2021 The Author(s).)

Growing evidence supports a role for extracellular vesicles (EVs) in haemostasis and thrombosis due to exposure of negatively charged procoagulant phospholipids (PPL). Current commercial PPL-dependent clotting assays use chemically phospholipid depleted plasma to measure PPL activity. The purpose of our study was to modify the PPL assay by substituting the chemically phospholipid depleted plasma with PPL depleted plasma obtained by ultracentrifugation This in order to get readily access to a sensitive and reliable assay to measure PPL activity in human plasma and cell supernatants. The performance of the assay was tested, including the influence of individual coagulation factors and postprandial lipoproteins and compared to a commercial PPL assay (STA-Procoag-PPL). The two PPL assays displayed similar sensitivity to exogenously added standardized phospholipids. The PPL activity measured by the modified assay strongly correlates with the results from the commercial assay. The intraday- and between-days coefficients of variation ranged from 2-4% depending on the PPL activity in the sample. The modified PPL assay was insensitive to postprandial lipoprotein levels in plasma, as well as to tissue factor (TF) positive EVs from stimulated whole blood. Our findings showed that the modified assay performed equal to the comparator, and was insensitive to postprandial lipoproteins and TF + EVs.

Background and Purpose: Spine stereotactic body radiotherapy (SBRT) requires a high degree of accuracy due to steep dose gradients close to the spinal cord. This study aimed to (1) evaluate intrafractional motion in spine SBRT utilizing flattening filter free (FFF) beam delivery and cone beam computed tomography (CBCT) image guidance and (2) evaluate if adding another CBCT acquisition and corrections prior to treatment improves the overall position accuracy., Materials and Methods: Intrafractional motion was retrospectively analyzed for 78 fractions in 54 patients. All patients were immobilized with an evacuated cushion. Before treatment, a CBCT was acquired, a bony fusion with the planning CT was performed and translational and rotational errors were corrected. For 30 of the patients (39 fractions) acquisition of another CBCT and corrections were performed before treatment. A post treatment CBCT was acquired for all patients, and translational and rotational errors measured by fusion of the post treatment CBCT with the planning CT were recorded to calculate means and standard deviations (SDs)., Results: The positional errors were significantly smaller in 4 out of 6 error values in the patient group treated with verification CBCT. In this group, translational and rotational SDs ranged from 0.5 to 0.6 mm and 0.3°, respectively. Corresponding values in the group treated without verification CBCT were 0.7-1.0 mm and 0.4-0.7°., Conclusion: With proper CBCT image guidance, patient immobilization and FFF-beam delivery, one can obtain very high patient position accuracy in spine SBRT. Inclusion of a verification CBCT prior to treatment increases the overall position accuracy., 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., (© 2019 The Author(s).)

Optimal pre-analytical handling is essential for valid measurements of plasma concentration and size distribution of extracellular vesicles (EVs). We investigated the impact of plasma preparation, various anticoagulants (Citrate, EDTA, CTAD, Heparin), and fasting status on concentration and size distribution of EVs measured by Nanoparticle Tracking Analysis (NTA). Blood was drawn from 10 healthy volunteers to investigate the impact of plasma preparation and anticoagulants, and from 40 individuals from a population-based study to investigate the impact of postprandial lipidemia. Plasma concentration of EVs was measured by NTA after isolation by high-speed centrifugation, and size distribution of EVs was determined using NTA and scanning electron microscopy (SEM). Plasma concentrations and size distributions of EVs were essentially similar for the various anticoagulants. Transmission electron microscopy (TEM) confirmed the presence of EVs. TEM and SEM-analyses showed that the EVs retained spherical morphology after high-speed centrifugation. Plasma EVs were not changed in postprandial lipidemia, but the mean sizes of VLDL particles were increased and interfered with EV measurements (explained 66% of the variation in EVs-concentration in the postprandial phase). Optimization of procedures for separating VLDL particles and EVs is therefore needed before NTA-assessment of EVs can be used as biomarkers of disease.

Readiness and motivation for change were examined in 32 women with broadly defined eating disorders who took part in a 10-week Cognitive Behavioral Therapy (CBT)-based group intervention. Readiness for change and eating disorder psychopathology were assessed before and after the intervention. The results revealed significant negative associations between degree of eating disorder symptoms and degree of readiness for change before the intervention started. In particular, higher levels of eating concern, shape concern, and body dissatisfaction were associated with lower motivation for change. No significant associations between degree of readiness for change before the intervention started and changes in eating disorder symptoms at the end of intervention were found. Readiness for change increased from the beginning to the end of the intervention, indicating that group CBT may be a cost-effective and time-efficient way of enhancing readiness and motivation for change in individuals with eating psychopathology.

Introduction: Technological innovations have taken stereotactic body radiotherapy (SBRT) from frame-based strategies to image-guided strategies. In this study, cone beam computed tomography (CBCT) images acquired prior to SBRT of patients with lung tumors was used to study the dosimetric impact of a pure frame-based strategy., Material and Methods: Thirty patients with inoperable lung tumors were retrospectively analyzed. All patients had received CBCT-guided SBRT with 3 fractions of 15 Gy to the planning target volume (PTV) margin including immobilization in a stereotactic body frame (SBF). Using the set-up corrections from the co-registration of the CBCT with the planning CT, all individual dose plans were recalculated with an isocenter position equal to the initial set-up position. Dose Volume Histogram (DVH) parameters of the recalculated dose plans were then analyzed., Results: The simulated plans showed that 88% of all fractions resulted in minimum 14.5 Gy to the internal target volume (ITV). For the simulated summed treatment (3 fractions per patient), 83% of the patients would minimum receive the prescription dose (45 Gy) to 100% of the ITV and all except one would receive the prescription dose to more than 90% of the ITV., Conclusions: SBRT including SBF, but without image guidance, results in appropriate dose coverage in most cases, using the current margins. With image guidance, margins for SBRT of lung tumors could possibly be reduced.

Managing P on dairy farms requires the assessment and monitoring of P status of the animals so that potential overfeeding may be minimized. Numerous published studies have demonstrated that for lactating dairy cows, increasing P concentrations in diets led to greater P excretion in feces. More recent work reported that inorganic P (P(i)) in 0.1% HCl extracts of feces (fecal extract P(i), g/kg) closely reflects dietary P changes. This has led to the proposal that 0.1% HCl fecal extract P(i) may serve as an indicator of the animal's P status (adequate or excessive) when compared with a benchmark value. Here, we present the results of an extensive evaluation of the proposed fecal P indicator test. With samples (n=575) from >90 farms, fecal total P (TP, g/kg) and fecal extract P were positively correlated with dietary P (X, g/kg): TP=1.92X - 0.17 (R2=0.36); fecal extract P=1.82X - 2.54 (R2=0.46). Fecal extract P was responsive to dietary P changes, whereas the remaining P, calculated as TP minus fecal extract P, was not. A provisional benchmark value of fecal extract P representing near-adequate P status was set at 4.75g/kg. Assessment of the farm data using the benchmark indicated that 316 out of 575 data points were associated with possible P overfeeding. Advantages of the fecal-based test over feed-based analysis to assess P status are discussed. The fecal extract P method is a simple and practical test that can be used as an assessment tool for helping dairy producers improve P management and reduce their environmental footprint., (Copyright 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

A survey of 715 Holstein dairy farms in Pennsylvania was used to construct demographics for the average Holstein dairy farm. The average Holstein dairy farm was composed of 69 lactating cows; 11 nonlactating, pregnant cows; 44 heifers; and 18 calves. Milk production averaged 27.3 kg (60.0 lb). Crop area averaged 73.6 ha. Milk production, crop area and type, average county yields, and herd animal groups were used to construct a typical feeding program for these farms. Typical rations were constructed for six feeding groups (three milk production groups, one nonlactating group, two heifer groups) to meet milk production, pregnancy, and growth requirements. Rations were constructed based on three forage qualities (excellent, average, and poor) typically observed on Pennsylvania dairy farms. Data for animal description (milk production, body weight, growth, and pregnancy status) and ration components and amounts consumed for each animal group were input into the excretion model of the Dairy Nutrient Planner computer program (DNP). Excretion of fecal N and dry matter (DM), urinary N, and total P and K were produced for each animal group and used to assess potential volatile losses of N. Work at the Marshak Dairy, New Bolton Center, indicates the majority of urinary N is rapidly lost as ammonia from dairy facilities. Based on this observation, the losses of N as ammonia were estimated to be 4.63, 4.62, and 4.28 tonne/year for the farm with excellent, average, and poor quality forages, respectively. Volatile losses of N may be reduced most by controlling levels of urea in urine. Urinary N may be reduced through dietary manipulation of protein and carbohydrate sources. Conversion of urea to ammonia may be reduced by altering the pH of barn floors and gutters. Entrapment of ammonia may be accomplished by acidification of manure slurry. Atmospheric ammonia contributes to acid rain, eutrophication of estuaries and lakes, and particulate air pollution. Reduction of ammonia emissions from dairy barns can significantly reduce atmospheric pollution and improve air and water quality.

Reliable estimation of nutrient concentrations is required to manage animal manure for protecting waters while sustaining crop production. This study was conducted to investigate sample variability and reliable nutrient analysis for several manure types and handling systems. Serial samples were collected from dairy, swine, and broiler poultry operations while manure was being loaded onto hauler tanks or spreaders for field application. Samples were analyzed for total solids (TS), total nitrogen (N), ammoniacal nitrogen (NH4-N), total phosphorus (P), and potassium (K). The least number of samples needed for reliable testing of total N and P, defined as +/- 10% of the experimental means with 99% probability, was obtained for each farm using a computer-intensive random resampling technique. Sample variability within farms, expressed as the coefficient of variation (CV), was mostly 6 to 8% for farms that used agitation of manure storages but several times higher (20-30%) on farms where no agitation was applied during the sampling period. Results from the random resampling procedure indicated that for farms that used agitation, three to five samples were adequate for a representative composite for reliable testing of total N and P; whereas for farms without agitation, at least 40 samples would be required. Data also suggest that using book values for manure nutrient estimations could be problematic because the discrepancies between book standards and measured farm data varied widely from a small amount to several fold.

A survey was conducted to collect information on nutrient management practices on dairy farms in south-central Pennsylvania. Of the 994 responding farms, the average farm consisted of 64 lactating cows, 10 dry cows, 41 heifers, and 17 calves with 69.7 ha of tillable land. Manure from lactating cows was mainly collected on a daily basis (84% of the farms) and stored as slurry or liquid (73%), while dry cow and heifer manure was collected weekly or less frequently (69 and 85% of the farms) and stored as solid stack or bedded pack (67 and 82%). Manure utilization featured consistent use of on-farm spreading, with limited incorporation, to corn or small grain fields before planting. Spreading on perennial forages or pasture was also common. Irrigation or injection of manure occurred on less than 5% of the farms. Only 20% of the farms reported manure nutrient testing, contrasting to over 90% for soil testing. Farm advisors and their services can be of vital importance in helping producers make conscientious management decisions for enhanced nutrient utilization. For example, ration balancing involved the services of feed and mineral sales representatives (85% of the farms), independent consultants (12%), and veterinarians (5%). Manure nutrient crediting to determine manure application rates was made by fertilizer dealers (40%), crop advisors and independent consultants (31%), and others. Nutrient management strategies and efforts must address the specific needs of farms with different animal densities and nutrient balances in order to be effective and applicable on the majority of farms.

The clinical outcome after successful conventional coronary balloon angioplasty is compared with that of stent implantation after 30 days and 12 months. The study took place at the Divisions of Cardiology and Thoracic Radiology, Norrland University Hospital, Umeå, a referral centre for northern Sweden. The first 100 consecutive patients with stable or unstable angina undergoing successful percutaneous transluminal coronary angioplasty (PTCA) in 1994 and the first 100 consecutive patients undergoing successful coronary stent implantation in 1995 were included. The cardiac endpoints studied were death, myocardial infarction, need for repeat PTCA or coronary artery bypass grafting (CABG). Significantly more adverse cardiac events were observed in the PTCA group compared with the stent group. Event-free 12 months' follow-up (no deaths, myocardial infarction or re-intervention) was 64% in the PTCA group and 86% in the stent group (p < 0.005). The main explanation for the observed difference was a reduction in the need for a repeat PTCA (7 vs 18, p < 0.05) or CABG (4 vs 12, p < 0.05) in the stent group. Patients with stable or unstable angina who can be treated with a stent have a better clinical outcome than those treated with coronary balloon angioplasty only.

Changes in Se metabolism were studied in ewes fed hay containing normal or inadequate levels of Se. After intravenous injection of 75Se-sodium selenite, blood, feces and urine were collected at different times, and the concentrations of labeled and unlabeled Se were determined. Ewes were killed 1, 5, 9 or 14 d after tracer injection, and tissues were obtained for determination of radioactivity and Se concentration. The data were fitted to a compartmental model using the SAAM/CONSAM computer program, and kinetic parameters and steady-state transport rates were estimated. Daily Se intake (Vi) and fecal excretion (VF) were significantly (P < 0.001) higher in the ewes fed normal hay (6.06 +/- 1.09 and 3.36 +/- 0.88 mumol/d, respectively) than in those fed Se-deficient hay (0.64 +/- 0.18 and 0.26 +/- 0.15 mumol/d). The net absorption (Va) of Se was significantly higher in ewes fed normal hay [3.19 +/- 0.82 mumol/d by the balance method, Va = Vi-(VF -Vf) (Vf = endogenous fecal Se) and 1.05 +/- 0.38 mumol/d by using the model (plasma entry rate, U(1))] than in those fed hay deficient in Se [0.57 +/- 0.33 mumol/d (balance) and 0.28 +/- 0.08 mumol/d (model)]. The efficiency of absorption [alpha = U(1) divided by Vi] was significantly higher (0.46 +/- 0.19) in ewes fed Se-deficient hay than in those fed normal hay (0.18 +/- 0.09). Simultaneous fitting of the tracer data of both the groups showed that changes in hepatic extraction and urinary and fecal excretion were sufficient and necessary to account for the kinetic differences observed between treatments.

This study examined group differences in language and pragmatic functions across sex-, age- and IQ-matched samples of Asperger syndrome (N = 22), high-functioning autism (N = 11), deficits in attention, motor control and perception (DAMP) (N = 11), and speech and language disorder (SLD) (N = 11) groups. The purpose was to explore possible differentiating features in the fields of vocabulary, comprehension and pragmatics and, in addition, to determine whether Asperger syndrome could be reliably separated from high-functioning autism on these variables. The findings suggest that Asperger syndrome may be associated with higher full-scale and verbal IQ than high-functioning autism; Asperger syndrome may not be associated with better pragmatic skills (as defined in this context) than high-functioning autism; language comprehension may not clearly separate Asperger syndrome and high-functioning autism once the effects of very low IQ are partialled out; both DAMP and SLD can be distinctly separated from Asperger syndrome and autism.

Multicompartmental analysis was applied to study the kinetics of D-xylose distribution after its intragastric administration to healthy mares deprived of food for 12, 36, 72, and 96 hours. Disposition of D-xylose was described by a 5-compartment model. Maximal plasma D-xylose concentration was similar for 12 and 36 hours of food deprivation and was greater (P = 0.0001) than the values for 72 and 96 hours. Peak concentration of D-xylose appeared progressively later as food deprivation proceeded (P = 0.0001). Fractional rate of transfer (k1,6) was less after 96 hours of food deprivation, compared with 12 hours (P = 0.0001), and percentage of D-xylose absorbed was reduced (P = 0.0441) after food deprivation. Fractional rate of transfer (k6,5), representing gastric emptying, tended to progressively decrease with food deprivation. Results indicated that formal kinetic analysis can be applied to D-xylose absorption kinetics in horses. Reduction in the extent of D-xylose absorption after food deprivation may be partly caused by decreased rate of D-xylose absorption across the small intestinal mucosa, but other factors, such as gastric emptying and nonabsorptive losses, may also be involved.

Chylomicrons transport fat and cholesterol via lymphatic vessels from the intestine into the bloodstream. The understanding of the metabolism of chylomicrons in man has been slowed by the difficulty of obtaining lymph chylomicrons for experimental studies. Acceptable methods for the study of chylomicron clearance in man are required, because the metabolism of chylomicrons may be abnormal in diseases such as diabetes mellitus. Metabolism of chylomicrons may also play a role in the development of atherosclerosis. In the present work, lipid emulsions were used as a physical model of chylomicrons. Triacylglycerol-rich lipid emulsions labelled with tracer amounts of radioactive triolein and cholesteryl oleate were prepared by sonication and purified by density gradient ultracentrifugation, then injected into unanaesthetized rats and normal human subjects. Plasma radioactivities were measured for 30 min in rats and 90 min in human subjects. Rat lymph chylomicrons were also injected into rats for comparison with the clearance of the lipid emulsions. The plasma clearance data for triacylglycerols and cholesteryl esters were fitted with a kinetic model using the SAAM/CONSAM programs. Multiple studies analysis of the individual studies in each group was used to obtain estimates of the parameter average values and variabilities. The plasma residence times of the lipid labels were obtained from the fitted clearance data. Our results suggest that information about chylomicron metabolism in man can be obtained by analysis of the plasma clearance data following the injection of suitably labelled chylomicron-like lipid emulsions. Our data provide a baseline for comparisons with individuals having abnormalities of lipid metabolism or risk factors for arteriosclerosis.

Multicompartmental analysis was applied to study the kinetics of D-xylose distribution after IV administration to healthy mares deprived of food for 12 and 96 hours. Urinary excretion of D-xylose was measured over a 15-hour period after administration. The plasma D-xylose concentrations in this study were in the range found after oral tolerance testing. The disposition of D-xylose was described by a two-compartment model with linear kinetic characteristics. Total volume of distribution decreased significantly (P < 0.025) from 0.270 L/kg of body weight after the 12-hour period of food deprivation to 0.235 L/kg after the 96-hour period. Fractional rate of transfer between the central and peripheral compartments did not change after 96 hours without food. Approximately a third of the D-xylose administered was recovered in the urine. Difference in urinary elimination between the 12- and 96-hour periods was not significant. Nonrenal elimination rate was determined to be twice the renal elimination rate. The results indicated that formal kinetic analysis can provide useful information about D-xylose distribution in horses. The decreased D-xylose space found after a 96-hour period of food deprivation would tend to increase the plasma D-xylose concentration, and this may help in the interpretation of the D-xylose absorption test applied to anorectic horses.

Vancomycin hydrochloride was infused intravenously (i.v.) over a 30-min period in five horses at doses of 6.6, 11.0 and 15.4 mg/kg. Vancomycin concentration in plasma and synovial fluid samples was measured using a polarization immunoassay. A pharmacokinetic model was developed to accommodate the special features of the present study. The data were described by a two compartment open model with synovial fluid as an additional compartment in exchange with plasma. Minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) were measured for Staphylococcus aureus and Enterococcus sp. using isolates from hospital patients. Based on the pharmacokinetic model and MIC/MBC data, a practical therapeutic protocol for vancomycin administration was established at doses of 4.3-7.5 mg/kg given as a 1-h infusion every 8 h.

This paper concerns some issues involved in the design of tracer experiments for the development of whole-body compartmental models of nutrient metabolism. It focuses on tracer administration protocol, use of multiple tracers, sampling strategy, measurement types and experiment duration in a pragmatic approach to obtaining data suitable for analysis and interpretation with use of models.

A general application of portfolio analysis for herd decision tree analysis is described. In the herd environment, this methodology offers a means of employing population-based decision strategies that can help the producer control economic variation in expected return from a given set of decision options. An economic decision tree model regarding the use of prostaglandin in dairy cows with undetected estrus was used to determine the expected return of the decisions to use prostaglandin and breed on a timed basis, use prostaglandin and then breed on sign of estrus, or breed on signs of estrus. The risk attributes of these decision alternatives were calculated from the decision tree, and portfolio theory was used to find the efficient decision combinations (portfolios with the highest return for a given variance). The resulting combinations of decisions could be used to control return variation.

Several suspect causes of chronic zinc/cadmium toxicosis in horses near a zinc smelter were investigated following observations of lameness, swollen joints, and unthriftiness, particularly in foals. Two foals born and raised near the smelter were lame and had joint swellings that were attributable to severe generalized osteochondrosis. Zinc and cadmium concentrations were markedly increased in the pancreas, liver, and kidney. The serum of 1 foal, zinc and potassium concentrations were high, whereas calcium and magnesium concentrations were low. Marked nephrocalcinosis and osteoporosis were observed in this foal. Nephrocalcinosis also was observed in his dam, who died of a punctured lung following rib fractures, though there was no history of trauma. The joint cartilage lesions were similar to those induced experimentally in animals fed high-zinc diets and may have been the result of zin-induced abnormality of copper metabolism. The osteoporosis and nephrocalcinosis were consistent with chronic cadmium toxicosis.

The purpose of this study was to investigate the effect of stabilization on the maximal isokinetic torque generated by the quadriceps femoris muscle during concentric and eccentric contractions at different velocities using the KIN/COM isokinetic dynamometer. Fifteen female volunteers between the ages of 18 and 32 years were trained to perform maximal isokinetic concentric and eccentric contractions. Each subject participated in two testing sessions. In one testing session, subjects were stabilized maximally, and in the other testing session, subjects were stabilized minimally. Subjects were tested both concentrically and eccentrically at velocities of 30 degrees, 60 degrees, 90 degrees, 120 degrees, 150 degrees, 180 degrees, and 200 degrees/sec. The velocity sequence and stabilization procedure used were randomly assigned. Two nested model analyses of variance followed by post hoc comparisons were used to analyze the data. Results revealed no significant difference between the maximal stabilization procedure and the minimal stabilization procedure for concentric and eccentric contractions. The results of this study should aid rehabilitation specialists in the development of testing and rehabilitation procedures when using the KIN/COM.

The kinetics of glucose cycling in 24 ewes bearing twins were studied 1 month before term by bolus injections of [6-3H]- and [U-14C]glucose. The function representing glucose carbon recycling was determined by deconvolution of the [3H]glucose from the [14C]glucose decay curves in plasma by using the SAAM and CONSAM programs, and a model for kinetics of glucose cycling was developed. The [3H]glucose data were fitted by four compartments, and an additional three compartments were required to explain recycling. The results show that labelled carbon was still recycling to plasma 2 days after the injection of tracer. By contrast, a similar analysis on a non-pregnant sheep, with data taken from the literature, showed that no more material was recycled after 1 day. It appears that a larger fraction (20 v. 5%) of the carbon 6 of glucose recycles in pregnant than in non-pregnant sheep. This presumably reflects the metabolism by the feto-placental unit and the increased rate of glucose metabolism during pregnancy.

Kinetic analysis of radiocalcium data was combined with radioimmunoassays of plasma parathyroid hormone in nonpregnant nonlactating cows 4.5 to 7.8 years of age whose calcium intake was varied from 0.05% to 1.4% of the diet. Calcium intake had no significant effect on plasma concentration of calcium or parathyroid hormone. It had a slight but significant effect on the plasma phosphorus concentration. As calcium intake increased, calcium absorption increased but calcium removal from bone decreased so that total calcium transport into the exchangeable pool remained fairly constant. A decline in calcium clearance with age was accompanied by a fall in plasma parathyroid hormone concentration, and a decrease in calcium transport into the pool. These observations are consistent with feedback controls between plasma calcium, parathyroid hormone and calcium transport operating to maintain plasma calcium homeostasis as calcium clearance declined with advancing age.

The kinetics of selenium metabolism in three nonpregnant ewes were studied by the intravenous injection of 75Se-sodium selenite and measurement of radioactivity responses in blood, tissues and excreta. Stable selenium measurements were also made to determine selenium intake, excretion in feces and urine, and mass of selenium in tissues. Immediately following tracer injection, there was a rapid disappearance of radioactivity from plasma reflecting the uptake of the element by the liver and blood cells. The decrease in plasma radioactivity ceased abruptly by 30-45 min, and was followed by an increase to a peak by 3-4 h and a more gradual biphasic decline thereafter. A kinetic model of selenium metabolism in the whole animal was constructed employing the SAAM/CONSAM computer program. The multiphasic response of plasma radioactivity during a physiological steady state was explained on the basis of rapid hepatic uptake of selenium and its subsequent reappearance in the circulation in protein-bound form followed by further metabolism and excretion of the element. The model provides reference parameter values for 75Se-sodium selenite kinetics in selenium-replete, mature nonpregnant ewes for comparison with the kinetics in animals whose selenium status may be altered.

Effects of mild and severe hypervitaminosis A on retinol transport and clearance were studied in mature ewes. Excessive vitamin A intake was assoicated with high concentrations of vitamin A in plasma and liver, with elevated serum enzymes, with decreased feed consumption and packed cell volume, and with epithelial hyperplasia. Retinol transport in plasma increased 6- to 8-fold with excessive dietary vitamin A, was greater with mild hypervitaminosis A, and increased exponentially with vitamin A concentration in plasma. Clearance of retinol from plasma increased 2-fold with hypervitaminosis A, exhibited a greater response in the mild group, and increased linearly with vitamin A concentration in plasma. The relationship of clearance to vitamin A concentration in liver was described best by a power function. Retinol clearance represents a mechanism to maintain vitamin A concentration in plasma and may be most effective below vitamin A concentrations of 135 microgram/dl plasma. With severe hypervitaminosis A, massive vitamin A accumulates in liver leading to hepatic dysfunction and a resultant decrease in retinol clearance from plasma.

The response of plasma parathyrin (PT) in cattle fetuses to changes in plasma calcium was investigated in utero. Resting plasma calcium levels for 4 fetuses averaged 3.1 mg/dl higher than for their mothers. Fetal PT levels (0.67 ng/ml) were half those of the mother (1.40 ng/ml). Hypocalcemia induced by EDTA infusion evoked a rise in plasma PT in 2 or 3 fetuses. The relationship between plasma PT and calcium levels in these fetuses was curvilinear, PT rising from about 0.7 ng/ml at 13 mg calcium/dl to a plateau of about 1.6 ng/ml below 10 mg calcium/dl. This contrasted with one of the mothers in which PT rose above 3 ng/ml when plasma calcium fell from 9 to 7 mg/dl. During infusion of EDTA to mother or fetus there were no changes in plasma calcium or PT levels in the respective fetus or mother.

The D-xylose absorption test was applied to clinically normal horses and to horses with signs of gastrointestinal disease. A dosage of 0.5 grams of xylose per kilogram of bodyweight was useful in detecting horses that absorbed the pentose abnormally. The clinical findings were correlated with gross and microscopic findings by biopsy and at necropsy. Gastrointestinal lesions associated with abnormal xylose absorption were classified as: 1) villous atrophy; 2) edema of the lamina propria or 3) necrosis of the lamina propria.

Studies on the discrimination between ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) by chickens have led to conflicting conclusions. To investigate this problem in more detail, radiolabeled vitamin D and vitamin D metabolites were administered intravenously, which allowed determination of their relative plasma clearance rates. The study involved three groups of adult male chickens (five per group). Birds in group 1 were co-dosed with [3H]vitamin D2 and [3H]vitamin D3. Birds in group 2 were co-dosed with [3H]25-dihydroxyvitamin D2 and [3H]25-dihydroxyvitamin D3 and birds in group 3 were co-dosed with [3H]1,25-dihydroxyvitamin D3 and [3H]1,25-dihydroxyvitamin D2. The results indicated that the plasma turnover rate of [3H]vitamin D2 is 1.5 times faster than that of [3H]vitamin D3. Plasma turnover of the 25-hydroxylated metabolites differed, with [3H]25-dihydroxyvitamin D2 clearing faster (11 times) than [3H]25-dihydroxyvitamin D3. The largest difference appeared in the 1,25-dihydroxyvitamin D2 turnover rates with 1,25-dihydroxyvitamin D2 clearing approximately 33 times faster then [3H]1,25-dihydroxyvitamin D3. These data, therefore, indicate that discrimination against vitamin D2 sterols in the chick occurs primarily between steps in the metabolism of vitamin D and not at the point of metabolism or excretion of the parent vitamin.

Five clinically normal, mature horses and 11 with chronic diarrhea were given 51Cr-tagged Cohn fraction V equine albumin intravenously. All urine and feces were collected separately, and blood for plasma analysis was taken periodically for 5 to 8 days after injection of the isotope. Plasma clearance of albumin into the intestinal tract of normal horses was calculated as 0.67 +/- 0.23 (SD) ml/kg of body weight/day, with 1.33 +/- 0.69% of the 51Cr dose appearing in the feces in 5 days. Of the 11 diarrheal horses, 8 had a plasma clearance of 0.49 +/- 0.21 ml/kg/day with 1.12 +/- 0.68% of the dose of 51Cr in a 5-day fecal collection, suggesting that excessive losses of plasma protein into the bowel was not a component of their intestinal disease. The 3 other diarrheal horses had a marked protein-losing enteropathy; 1 of these horses had granulomatous enteritis due to Mycobacterium avium infection; another had severe intercellular edema of small and large intestinal mucosa, cause unknown; and intestinal biopsies were not obtained from the 3rd horse. The results suggest that: (1) as with other species that have been studied, daily loss of plasma protein into the bowel of horses is small; (2) most horses with chronic diarrhea do not have protein-losing enteropathy.

In a 28 week study, 18 racing sled dogs were trained to maximal fitness in 12 weeks, sustained through a racing season of 12 weeks, followed by gradual of training of 4 weeks. The dogs were fed a predominantly cereal diet prior to the study; experimental diets containing more chicken and meat by products were introduced from the 2nd to the 4th week of training. On an energy basis, the diets contained protein, fat, and carbohydrate in the proportions of 39:61:0 (diet A), 32:45:23 (diet B), and 28:34:38 (diet C). Blood samples were taken at rest just before the start of training, at 6, 12,24 and 28 weeks; 33 variables were measured on most samples. The results were subjected to analysis of variance. No adverse effects were observed in dogs fed the extreme diet A. Significant relationships to training were shown by serum glutamic oxaloacetic transaminase, creatinine, packed cell volume, calcium, hemoglobin, and globulin. Serum cholesterol concentration increased with the introduction of the higher protein-fat diets; the high concentrations attenuated with time but rose again when training was abated. Dogs on diet A maintained higher serum concentrations of albumin, calcium, magnesium, and free fatty acids during the racing season than did dogs fed diets B or C. They also exhibited the greatest increases in red cell count, hemoglobin concentration, and packed cell volume during training. High values of red cell indices were not sustained through the racing season in dogs fed diet C. In addition to attributes already widely appreciated, viz. a higher energy density an digestibility, the carbohydrate-free, high-fat diet A appeared to confer advantages for prolonged strenuous running in terms of certain metabolic responses to training.

To study the effects of environmental exposure to zinc and cadmium in immature foals, five pregnant ponies were raised within 2.9 km of the New Jersey Zinc Smelter in Palmerton, Pennsylvania. The mares and their foals were kept outdoors on timothy hay and orchard grass. The foals were examined daily for signs of illness and blood samples were taken monthly for estimation of serum zinc, copper, and ceruloplasmin levels. The foals were sacrificed at 2.5, 4.5, 8.5, 13.5, and 18.5 months of age. Necropsy revealed generalized osteochondrosis in joints of the limbs and cervical vertebrae, lymphoid hyperplasia, and eosinophilia. Two of the foals had developed mild lameness. The concentrations of zinc, cadmium, copper, lead, magnesium, and calcium were determined in liver, kidney cortex, and pancreas. The concentration of cadmium and zinc were the only elements that were greatly elevated in all three tissues as compared to control animals. The concentration of cadmium was directly correlated with age in the three tissues (e.g., 23.9 to 212.7 micrograms/g wet wt in kidney cortex), whereas zinc was significantly increased (range 132 to 954 micrograms/g wet wt in liver) but there was no correlation with age. It was concluded that the development of osteochondrosis is associated with increased exposure to zinc and possibly cadmium. The classical signs of cadmium toxicosis, such as renal damage and osteomalacia, were not observed.

1,24,25-Trihydroxyergocalciferol was isolated from bovine kidney homogenates incubated with 1,25-dihydroxyergocalciferol and from chick kidney homogenates incubated with 24,25-dihydroxyergocalciferol. The identity was established by ultraviolet absorbance, sensitivity to periodate, nuclear magnetic resonance, and mass spectrometry. The new metabolite had an affinity equal to 1,24,25-trihydroxycholecalciferol for the bovine-thymus and chick-intestinal 1,25-dihydroxyvitamin D receptor and had an affinity twice that of 1,24,25-trihydroxycholecalciferol for the rat-intestinal receptor. It was 3- and 6-fold less competitive than either 1,25-dihydroxycholecalciferol or 1,24,25-trihydroxycholecalciferol, respectively, for the rat plasma vitamin D transport protein. 1,24,25-Trihydroxyergocalciferol was at least 10-fold less active than 1,25-dihydroxycholecalciferol, 1,25-dihydroxyergocalciferol, and 1,24,25-trihydroxycholecalciferol at stimulating intestinal-calcium transport and was also relatively ineffective at stimulating bone-calcium resorption in rats. Moreover, in rats, [3H]1,24,25-trihydroxyergocalciferol was cleared from plasma approximately 40% faster than [3H]1,24,25-trihydroxycholecalciferol. These data suggest that C-24 hydroxylation of 1,25-dihydroxyergocalciferol represents a significant in vivo deactivation step, whereas equivalent deactivation of 1,25-dihydroxycholecalciferol seems to involve metabolic steps subsequent to C-24 hydroxylation (C-24 ketonization). C-24 ketonization of 1,25-trihydroxyergocalciferol would not be anticipated due to the presence of the 24(S)-methyl group. These results reveal further dissimilarities between ergocalciferol and cholecalciferol metabolism in mammals and suggest a mechanism for the lesser tendency of ergocalciferol to cause hypercalcemia relative to cholecalciferol.

Plasma antithrombin-III (AT-III) values were determined in 74 healthy horses by an automated spectrophotometric assay. The mean plasma AT-III value was 218% +/- 18% of normal human plasma. Plasma AT-III values did not differ significantly (P less than 0.05) among Thoroughbred, Standardbred, Quarter Horse, and other breeds or among mares, geldings, or stallions.

Calcium homeostasis is described in terms of controlled, disturbing, and controlling signals. Plasma calcium concentration [( Ca]p) and bone calcium mass (Mb) are the two main controlled signals. Disturbing signals include calcium intake (Vi) and clearance of plasma calcium to feces ( Clf ), bone (Clo+), placenta (Clp), and milk ( Clm ). Clo+ is a disturbing signal for [Ca]p and a controlling signal for Mb. Homeostasis is maintained by input control. Fractional renal calcium reabsorption (alpha r) decreases when calcium entry into plasma is excessive, but usually calcium entry rate (VT) responds effectively to small changes in [Ca]p associated with changes in disturbing signals. With increases in Vi, both fractional calcium absorption (alpha d) and fraction of bone calcium removed (lambda b) decrease to maintain VT at an appropriate level. As Clo+ declines with advancing age, [Ca]p rises slightly but VT decreases: a 1% change in [Ca]p would lead to a 13% change in VT. In heavily lactating cows, this response of VT may be enhanced. Parturient hypocalcemia may be the result of delayed negative feedback responses of lambda b (1 wk) and alpha d (1 day). Positive feedback between [Ca]p and gut motility may lead to transient suppression of VT during hypocalcemia, despite high plasma parathyroid hormone and 1,25-dihydroxyvitamin D3 concentrations. Parturient paresis is an example of a disordered accelerative response in a complex control system amenable to a variety of physiologically rational management procedures.

Scatchard analyses of 1,25-dihydroxyvitamin D receptors (VDR) from chick and rat intestine, bovine thymus, pig kidney cells (LLC-PK1), and human breast cancer cells (T-47D) demonstrated that 1,25-dihydroxyvitamin D3 (1,25-D3) and 1,25-dihydroxyvitamin D2 (1,25-D2) had equal affinities for VDR. 24-Epi-1,25-dihydroxyvitamin D2 (24-epi-1,25-D2) exhibited affinities for VDR equal to that of 1,25-D2 and 1,25-D3 in most of these tissues. Scatchard analysis with 24-epi-[3H]1,25-D2 underestimated total VDR by 50-70% in rat intestine, LLC-PK1, and T-47D cells. The biological activity of 24-epi-1,25-D2 was found to be only 30-70% of 1,25-D3 and 1,25-D2 as determined by in vivo induction of intestinal calcium transport and bone calcium resorption in the rat and in vitro induction of 23- and 24-hydroxylase activities in T-47D cells. In vivo tracer kinetic studies demonstrated that in the rat 1,25-D3 and 1,25-D2 kinetics were similar, whereas 24-epi-1,25-D2 had a 25% shorter plasma half-life and was cleared from the body 2.8 times faster than the natural hormones. This more rapid clearance of 24-epi-1,25-D2 along with reduced VDR binding appears to explain the reduced biological activity of 24-epi-1,25-D2. Our data clearly demonstrate that although there are differences in side chain structure between 1,25-D2 and 1,25-D3, the VDR binding, biological activity, and whole body tracer kinetics of these two metabolites are virtually identical. However, movement of the 28 methyl of 1,25-D2 from its natural S configuration to the R configuration significantly alters the activity of this hormone.