Effects of injectable trace minerals on humoral and cell-mediated immune responses to Bovine viral diarrhea virus, Bovine herpes virus 1 and Bovine respiratory syncytial virus following administration of a modified-live virus vaccine in dairy calves.

Our objective was to evaluate the effect of an injectable trace mineral (ITM) supplement containing zinc, manganese, selenium, and copper on the humoral and cell mediated immune (CMI) responses to vaccine antigens in dairy calves receiving a modified-live viral (MLV) vaccine containing BVDV, BHV1, PI3V and BRSV. A total of 30 dairy calves (3.5 months of age) were administered a priming dose of the MLV vaccine containing BHV1, BVDV1 & 2, BRSV, PI3V, and an attenuated-live Mannheimia-Pasteurella bacterin subcutaneously (SQ). Calves were randomly assigned to 1 of 2 groups: (1) administration of ITM SQ (ITM, n=15) or (2) injection of sterile saline SQ (Control; n=15). Three weeks later, calves received a booster of the same vaccine combination SQ, and a second administration of ITM, or sterile saline, according to the treatment group. Blood samples were collected on days 0, 7, 14, 21, 28, 42, 56, and 90 post-vaccination for determination of antibody titer, viral recall antigen-induced IFN-γ production, and viral antigen-induced proliferation by peripheral blood mononuclear cells (PBMC). Administration of ITM concurrently with MLV vaccination resulted in higher antibody titers to BVDV1 on day 28 after priming vaccination compared to the control group (P=0.03). Calves treated with ITM showed an earlier enhancement in PBMC proliferation to BVDV1 following vaccination compared to the control group. Proliferation of PBMC after BVDV stimulation tended to be higher on day 14 after priming vaccination in calves treated with ITM than in the control group (P=0.08). Calves that received ITM showed higher PBMC proliferation to BRSV stimulation on day 7 after priming vaccination compared to the control group (P=0.01). Moreover, calves in the ITM group also had an enhanced production IFN-γ by PBMC after stimulation with BRSV on day 21 after priming vaccination compared to day 0 (P<0.01). In conclusion, administration of ITM concurrently with MLV vaccination in dairy calves resulted in increased antibody titer to BVDV1, and greater PBMC proliferation to BVDV1 and BRSV recall stimulation compared to the control group, suggesting that ITM might represent a promising tool to enhance the humoral and CMI responses to MLV vaccines in cattle.

Screening of 64 tryptamines at NMDA, 5-HT1A, and 5-HT2A receptors: a comparative binding and modeling study.

Tryptamine (T) and several T derivatives (Ts) inhibit in a voltage-dependent manner the NMDA receptor (NR). This effect is influenced by substituents at various positions, but has not yet been subjected to a detailed SAR study. Here, 64 Ts have been tested as inhibitors of [3H]MK-801 binding to NRs on rat brain membranes. For comparison, they were also tested as inhibitors of [3H]8-OHDPAT binding to 5-HT1A and of [3H]ketanserin binding to 5-HT2A receptors. Since most of these Ts have not been tested before at any of these receptors, we start with a review of the effects of Ts on 5-HT1A and 5-HT2A binding sites. NRs were inhibited with IC50s from 2 to 7 µM by Ts with alkyl or halogen at positions 2, 5, and/or 7. Inhibition by some Ts was attenuated more than 10-fold by 30 µM spermine. The most potent inhibitors at 5-HT1A receptors were 5-carboxamido-T (IC50 0.00015 µM) and serotonin (0.0016 µM), at 5-HT2A receptors 2-Me-4,7-Cl2-T (1.2 µM) and 2,7-Me2-4-Cl-T (2.0 µM). Fujita-Ban modified Free-Wilson analyses pointed to the individual significance of particular substituents. Also QSARs based on molecular operating environment descriptors resulted in sound correlations at all 4 targets. No similarities between the NR and 5-HT receptors could be found. At the NR, only L-Trp-NH2 bound 10 times better than at both 5-HT receptors studied. L-Trp-NH2 may be a structural lead to endogenous non-competitive NR antagonists.

Chronic exposure to manganese decreases striatal dopamine turnover in human alpha-synuclein transgenic mice.

Interaction of genetic and environmental factors is likely involved in Parkinson's disease (PD). Mutations and multiplications of alpha-synuclein (α-syn) cause familial PD, and chronic manganese (Mn) exposure can produce an encephalopathy with signs of parkinsonism. We exposed male transgenic C57BL/6J mice expressing human α-syn or the A53T/A30P doubly mutated human α-syn under the tyrosine hydroxylase promoter and non-transgenic littermates to MnCl2-enriched (1%) or control food, starting at the age of 4 months. Locomotor activity was increased by Mn without significant effect of the transgenes. Mice were sacrificed at the age of 7 or 20 months. Striatal Mn was significantly increased about three-fold in those exposed to MnCl2. The number of tyrosine hydroxylase positive substantia nigra compacta neurons was significantly reduced in 20 months old mice (-10%), but Mn or transgenes were ineffective (three-way ANOVA with the factors gene, Mn and age). In 7 months old mice, striatal homovanillic acid (HVA)/dopamine (DA) ratios and aspartate levels were significantly increased in control mice with human α-syn as compared to non-transgenic controls (+17 and +11%, respectively); after Mn exposure both parameters were significantly reduced (-16 and -13%, respectively) in human α-syn mice, but unchanged in non-transgenic animals and mice with mutated α-syn (two-way ANOVA with factors gene and Mn). None of the parameters were changed in the 20 months old mice. Single HVA/DA ratios and single aspartate levels significantly correlated across all treatment groups suggesting a causal relationship between the rate of striatal DA metabolism and aspartate release. In conclusion, under our experimental conditions, Mn and human α-syn, wild-type and doubly mutated, did not interact to induce PD-like neurodegenerative changes. However, Mn significantly and selectively interacted with human wild-type α-syn on indices of striatal DA neurotransmission, the neurotransmitter most relevant to PD.

The effect of age and bone mineral density on the absolute, excess, and relative risk of fracture in postmenopausal women aged 50-99: results from the National Osteoporosis Risk Assessment (NORA).

INTRODUCTION: This study evaluates the effect of age and bone mineral density (BMD) on the absolute, excess, and relative risk for osteoporotic fractures at the hip, wrist, forearm, spine, and rib within 3 years of peripheral BMD testing in postmenopausal women over a wide range of postmenopausal ages. METHODS: Data were obtained from 170,083 women, aged 50-99 years, enrolled in the National Osteoporosis Risk Assessment (NORA) following recruitment from their primary care physicians' offices across the United States. Risk factors for fracture and peripheral BMD T-scores at the heel, forearm, or finger were obtained at baseline. Self-reported new fractures at the hip, spine, rib, wrist, and forearm were obtained from questionnaires at 1- and 3-year follow-ups. Absolute, excess (attributable to low BMD), and unadjusted and adjusted relative risks of fracture were calculated. RESULTS: At follow-up, 5312 women reported 5676 fractures (868 hip, 2420 wrist/forearm, 1531 rib, and 857 spine). Absolute risk of fracture increased with age for all fracture sites. This age-effect was most evident for hip fracture--both the incidence and the excess risk of hip fracture for women with low BMD increased at least twofold for each decade increase in age. The relative risk for any fracture per 1 SD decrease in BMD was similar across age groups (p>0.07). Women with low BMD (T-score <-1.0) had a similar relative risk for fracture regardless of age. CONCLUSIONS: At any given BMD, not only the absolute fracture risk but also the excess fracture risk increased with advancing age. Relative risk of fracture for low bone mass was consistent across all age groups from 50 to 99 years.

Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment.

CONTEXT: Large segments of the population at risk for osteoporosis and fracture have not been evaluated, and the usefulness of peripheral measurements for short-term prediction of fracture risk is uncertain. OBJECTIVES: To describe the occurrence of low bone mineral density (BMD) in postmenopausal women, its risk factors, and fracture incidence during short-term follow-up. DESIGN: The National Osteoporosis Risk Assessment, a longitudinal observational study initiated September 1997 to March 1999, with approximately 12 months of subsequent follow-up. SETTING AND PARTICIPANTS: A total of 200 160 ambulatory postmenopausal women aged 50 years or older with no previous osteoporosis diagnosis, derived from 4236 primary care practices in 34 states. MAIN OUTCOME MEASURES: Baseline BMD T scores, obtained from peripheral bone densitometry performed at the heel, finger, or forearm; risk factors for low BMD, derived from questionnaire responses; and clinical fracture rates at 12-month follow-up. RESULTS: Using World Health Organization criteria, 39.6% had osteopenia (T score of -1 to -2.49) and 7.2% had osteoporosis (T score

Autoradiography with [3H]PK11195 of spinal tract degeneration in amyotrophic lateral sclerosis.

The diagnostic hallmarks of amyotrophic lateral sclerosis (ALS) are degeneration of upper and lower motor neurons and of corticospinal tracts. Here, we demonstrate the suitability of the gliosis marker [3H]PK11195 for quantitative evaluation of tract degeneration in ALS in vitro. Binding of [3H]PK11195 was increased in lateral and ventral white matter of ALS spinal cords but not in the anterior horn, in spite of a dramatic loss in muscarinic binding sites and a high level of oxidatively modified protein. Labeling of activated microglia with [11C]PK11195 may also allow tract degeneration in ALS to be visualized in vivo.

Indirect cost of ischemic heart disease to employers.

BACKGROUND: The management of healthcare programs by employers requires accurate information about the indirect and direct costs of important chronic diseases. OBJECTIVE: To determine the indirect costs of ischemic heart disease from the perspective of the employer in private industry in the United States. DESIGN: Indirect cost of illness analysis using the human capital approach, taking the perspective of the employer rather than that of society. METHODS: Ischemic heart disease was identified in a proprietary claims database of 3.1 million insured persons using an algorithm based on administrative codes. Economic data were derived from the Bureau of Labor Statistics, the Employment Management Association, and published sources. Work-loss data were taken from the National Center for Health Statistics' Health Interview Survey. The indirect cost was calculated as the sum of the costs due to morbidity and mortality. From the perspective of the employer, morbidity costs come from lost productivity, idle assets, and nonwage factors resulting from absenteeism and mortality costs are expenditures for replacing and retraining workers. This differs from calculations from the societal perspective, in which indirect costs are the value of an individual's lost income--both current and potential. RESULTS: The total indirect cost of ischemic heart disease to employers in private industry was $182.74 per enrollee. Ninety-five percent of the indirect cost was the consequence of work loss due to morbidity rather than of mortality costs. CONCLUSION: From the perspective of the employer, the indirect cost of ischemic heart disease is overwhelmingly due to morbidity costs.

Alternative valuations of work loss and productivity.

In this article, we examine the indirect costs (i.e., work loss and productivity costs) of employee illness from the employer's perspective. We provide a conceptual framework to help employers consider alternative views with regard to assessing indirect costs and valuing the health care they purchase. First, we discuss the matter of perspective and how an employer should view and assess indirect costs. We briefly review current models of measuring indirect costs, and we critique these models. Then we introduce a simple, conceptual framework based on the ideas of health capital and labor productivity, and we lay out the effects of health investment on indirect costs while considering what employees desire and employers can provide. Finally, we offer an agenda for further research.

Tryptamine derivatives as non-competitive N-methyl-D-aspartate receptor blockers: studies using [(3)H]MK-801 binding in rat hippocampal membranes.

Derivatives of phenylethylamine and tryptamine share structural features with the non-competitive N-methyl-D-aspartate (NMDA) receptor blockers phencyclidine, ketamine, and MK-801. Tryptamine and phenylethylamine inhibited the specific binding of [(3)H]MK-801 to rat hippocampal membranes with IC(50)'s 190 and 905 microM, respectively. The corresponding amino acids phenylalanine and tryptophan were inactive, their methyl esters, however, were slightly more potent than the amines. The methyl ester of the naturally occurring L-tryptophan was 12 times more potent than the methyl ester of the D-isomer, whereas the corresponding isomers derived from phenylalanine exhibited no stereoselectivity. The potency of tryptamine was increased by substitutions as, e.g. in 5-methyltryptamine (IC(50) 12 microM) and tryptophan octylester (IC(50) 5.2 microM). Compounds formed in vivo from L-tryptophan and a lipophilic counterpart may function as endogenous non-competitive NMDA receptor blockers.

Survey of migraineurs referred to headache specialists: care, satisfaction, and outcomes.

The authors report a survey of 281 migraineurs recently referred to headache specialists by primary care physicians. Compared with care before referral, specialists spent substantially more time with patients and were more likely to ask patients to take a prophylactic drug and to keep a headache diary, to discuss migraine triggers, and to prescribe 5-hydroxytryptamine1B/1D agonists (triptans). After referral, patients reported improved satisfaction with care and significant decreases in frequency, duration, and severity of attacks.

Quality-of-life questionnaire for patients taking antihypertensive medication.

This study was undertaken to construct a health-related quality-of-life (QOL) questionnaire for hypertensive patients from preexisting instruments and to validate its use in full form and in a shortened version. Two hundred seventy hypertensive patients who were stable while taking antihypertensive medication (control group), changing medication because of side effects, or newly treated for hypertension were enrolled in a prospective, observational, longitudinal study. At baseline and at months 1, 2, and 3, patients completed a questionnaire covering 7 domains of QOL. The criteria for evaluating the scales were internal consistency, test-retest reliability, construct validity, and responsiveness to change. Data were analyzed for the full questionnaire and the shortened version. Internal consistency and test-retest correlation values were 0.69 to 0.95 for scales in the full questionnaire and 0.57 to 0.92 in the shortened version. Construct validity was supported by statistically significant, positive correlations with a global QOL item for all but 1 scale in both versions. Responsiveness to change was supported by increases in scores between baseline and month 3 for all scales in patients changing their medication because of side effects; scores remained unchanged (on all but 1 scale) in the stable (control) group. By uniformly applying standard validation criteria to a set of preexisting instruments, we created a new QOL questionnaire. Results were similar in both the full form and shortened version.

Efficient patient identification strategies for women with osteoporosis.

The purpose of this analysis was to identify efficient (highest sensitivity at each level of cost) strategies to detect osteoporosis in postmenopausal women. Our study sample consisted of 392 women (age >/=50 yr) who were retirees or active employees of a corporation. The Simple Calculated Osteoporosis Risk Estimation (SCORE) questionnaire was completed, and bone mineral density levels were collected at the forearm using peripheral dual X-ray absorptiometry (pDXA), and at the femoral neck and lumbar spine using central DXA. Osteoporotic women were those with a T-score of -2.5 or less at any one of the three skeletal sites tested. Assumed costs were $5 for SCORE, $35 for pDXA, $120 for DXA at either the hip or spine, and $200 for DXA at both the hip and spine. The analysis indicated that the current "gold standard" is inefficient relative to other strategies investigated. By comparison, a tiered strategy consisting of SCORE, pDXA, and then selective use of DXA at both the hip and spine identified 90% of the women with osteoporosis at a cost of only $106 per woman tested. In choosing among the efficient strategies, decision makers must determine the extent to which they are willing to trade off higher program cost for greater sensitivity.

The once and future application of cost-effectiveness analysis.

BACKGROUND: Cost-effectiveness analysis (CEA) is used by payers to make coverage decisions, by providers to make formulary decisions, and by large purchasers/employers and policymakers to choose health care performance measures. However, it continues to be poorly utilized in the marketplace because of overriding financial imperatives to control costs and a low apparent willingness to pay for quality. There is no obvious relationship between the cost-effectiveness of life-saving interventions and their application. Health care decision makers consider financial impact, safety, and effectiveness before cost-effectiveness. WHY IS CEA NOT MORE WIDELY APPLIED? Most health care providers have a short-term parochial financial perspective, whereas CEA takes a long-term view that captures all costs, benefits, and hazards, regardless of to whom they accrue. In addition, a history of poor standardization of methods, unrealistic expectations that CEA could answer fundamental ethical and political issues, and society's failure to accept the need for allocating scarce resources more judiciously, have contributed to relatively little use of the method by decision makers. HOW WILL CEA FIND GREATER UTILITY IN THE FUTURE? As decision makers take a longer-term view and understand that CEA can provide a quantitative perspective on important resource allocation decisions, including the distributional consequences of alternative choices, CEA is likely to find greater use. However, it must be embedded within a framework that promotes confidence in the social justice of health care decision making through ongoing dialogue about how the value of health and health care are defined.

Zinc and ifenprodil allosterically inhibit two separate polyamine-sensitive sites at N-methyl-D-aspartate receptor complex.

In this study, we investigated the hypothesis that inhibition of the N-methyl-D-aspartate (NMDA) receptor complex by zinc involves a polyamine-sensitive regulatory site. We found that the specific binding of the open channel ligand [3H]MK-801 to rat hippocampal membranes 1) was inhibited by low concentrations of Zn2+ (IC50 = 5.5 microM) by 65%. 2) This high-affinity component of inhibition was reversed by the polyamine spermine to an extent that could be reconciled with competitive interaction between Zn2+ and spermine. 3) Partial inhibition by Zn2+ was additive with partial inhibition by ifenprodil, an inhibitor of the NMDA receptor complex supposed to act at a polyamine-sensitive regulatory site, and 4) in membranes prepared from several other brain regions, inhibition of [3H]MK-801 binding by Zn2+ and by ifenprodil was either less than additive, or superadditive. Our observation that ifenprodil, at concentrations saturating its high-affinity component of inhibition, prevented spermine from reversing the inhibition by Zn2+ indicates that spermine did not increase [3H]MK-801 binding by competition with Zn2+ but rather via another polyamine regulatory site not sensitive to zinc but sensitive to ifenprodil. We conclude that Zn2+ reduces channel opening of the NMDA receptor complex by allosteric inhibition of a polyamine-sensitive regulatory site different from that inhibited by ifenprodil and that these two allosteric sites influence each other in a manner dependent on the brain region investigated. The different proportions of zinc/ifenprodil inhibition in different regions could reflect different percentages of various NMDA receptor subtypes.

Burden of migraine in the United States: disability and economic costs.

BACKGROUND: Migraine is a common disabling disease but its economic burden has not been adequately quantified. OBJECTIVE: To estimate the burden of migraine in the United States with respect to disability and economic costs. METHODS: The following data sources were used: published data, the Baltimore County Migraine Study, MEDSTAT's MarketScan medical claims data set, and statistics from the Census Bureau and the Bureau of Labor Statistics. Disability was expressed as bedridden days. Charges for migraine-related treatment were used as direct cost inputs. The human capital approach was used in the estimation of indirect costs. RESULTS: Migraineurs required 3.8 bed rest days for men and 5.6 days for women each year, resulting in a total of 112 million bedridden days. Migraine costs American employers about $13 billion a year because of missed workdays and impaired work function; close to $8 billion was directly due to missed workdays. Patients of both sexes aged 30 to 49 years incurred higher indirect costs compared with younger or older employed patients. Annual direct medical costs for migraine care were about $1 billion and about $100 was spent per diagnosed patient. Physician office visits accounted for about 60% of all costs; in contrast, emergency department visits contributed less than 1% of the direct costs. CONCLUSIONS: The economic burden of migraine predominantly falls on patients and their employers in the form of bedridden days and lost productivity. Various screening and treatment regimens should be evaluated to identify opportunities to reduce the disease burden.

Effectiveness of antihyperlipidemic drug management in clinical practice.

Although randomized clinical trials have convincingly shown the efficacy of antihyperlipidemic drugs, both discontinuation of antihyperlipidemic drugs and failure to achieve goal lipid levels would be expected to attenuate the effect of these drugs on reducing the rates of hospitalization for coronary events. This study compares the rates of hospitalization and low-density lipoprotein cholesterol (LDL-C) levels during and after discontinuation of antihyperlipidemic drug therapy. A retrospective cohort study was conducted among 2369 patients at 2 health maintenance organizations (HMOs) during the period 1988 to 1994. Rates of coronary heart disease (CHD)-related hospitalization and non-CHD-related hospitalization and the LDL-C levels between 14 and 180 days after the initiation or discontinuation of drug therapy were compared for periods of antihyperlipidemic drug use and nonuse. The rate ratio for CHD hospitalization during periods of antihyperlipidemic drug use compared with periods of nonuse was 1.02 (95% CI, 0.74 to 1.40), excluding the first 6 months after initiation or discontinuation and controlling for patient sex, age, history of CHD, hypertension, diabetes, and HMO site. By contrast, the adjusted rate ratio was 0.70 (95% CI, 0.61 to 0.80) for non-CHD hospitalization. The percentage of patients with a history of CHD who achieved LDL-C levels <130 mg/dL was 27% < or =6 months after initiation of antihyperlipidemic drug therapy compared with 18% during gaps in drug therapy (P = 0.04). This study failed to demonstrate the effectiveness of lipid-lowering therapy in reducing CHD hospitalizations in community settings, apparently because most recipients either discontinued therapy or failed to achieve the desired LDL-C reduction while receiving therapy. These results indicate the need for interventions to improve patient compliance and management of lipid disorders.

Compliance with prescribed drugs: challenges for the elderly population.

Compliance with prescribed drug regimens is particularly important among the elderly because of their increased vulnerability and greater burden of chronic disorders. This narrative review discusses the factors that are important to compliance, with particular reference to the elderly. These factors are the patient's perceptions of his disease and it's treatment, the physician's perceptions, the manner the physician assumes and the language he uses to communicate with the patient, the patient's living situation, regular medication review, and a continuity of health care provision. Since it is the patient who decides how to use the therapy, his or her involvement in the process of explaining and understanding it is the key to improved compliance.

The labor productivity effects of chronic backache in the United States.

OBJECTIVES: Back pain afflicts approximately 31 million Americans, and is the number one cause of activity limitation in young adults. Little is known about the labor productivity costs associated with this chronic disease. Such information could provide useful input to employers considering alternative health benefits plans for managing their employees' health care needs. The goals of this study were to generate employee-level as well as national estimates of the labor productivity losses associated with chronic back ache. METHODS: Multivariate methods were used to isolate the effects of chronic backache on employment status and disability days. These results were combined with information on earnings to generate labor productivity cost estimates associated with chronic backache. The study used data from the National Medical Care Expenditure Survey (NMES), which provides information on health status, health care utilization and cost, work, disability, and sociodemographic characteristics for a nationally representative sample of the noninstitutionalized civilian population of the United States in 1987. RESULTS: Average annual productivity losses per worker due to chronic backache were $1,230 for male workers, measured in 1996 dollars, and $773 per female worker. These figures translated into aggregate annual productivity losses from chronic backache of approximately $28 billion in the United States. CONCLUSION: The labor productivity losses from chronic backache differed by gender and other sociodemographic characteristics. The aggregate labor productivity losses associated with chronic backache were quite large and comparable to estimates of the direct medical costs associated with treating this chronic illness.

Leukotrienes in ulcerative colitis: results of a multicenter trial of a leukotriene biosynthesis inhibitor, MK-591.

BACKGROUND & AIMS: Leukotrienes (LTs) are believed to be important in the pathogenesis of ulcerative colitis (UC). The aim of this study was to determine whether inhibition of LT biosynthesis with a 5-lipoxygenase inhibitor (MK-591) induces remission in patients with mild to moderate UC. METHODS: One hundred eighty-three patients with mild to moderately active UC enrolled in this randomized parallel group, double-blind study. Patients received placebo or MK-591 at a dose of 12.5, 50, or 100 mg twice daily for 8 weeks. A subset of patients underwent rectal dialysis to determine LTB4 concentration. RESULTS: MK-591 reduced LTB4 concentrations in rectal dialysate at the final determination. The median percent of baseline LTB4 concentration for 100 mg taken twice daily was 1.4% (n = 4); for 50 mg taken twice daily, 16.5% (n = 6); for 12.5 mg taken twice daily, 12% (n = 6); and for placebo, 78% (n = 6). There was no correlation between reduction of LTB4 and remission. Patients in remission at week 8 were as follows: placebo, 9 of 44 (20.5%); 100 mg taken twice daily, 11 of 43 (25.6%); 50 mg taken twice daily, 8 of 49 (16.3%); and 12.5 mg taken twice daily, 4 of 47 (8.5%) (P > 0.10). CONCLUSIONS: MK-591 markedly inhibited LT biosynthesis, but it did not differ significantly from placebo in clinical efficacy. Inhibition of LT biosynthesis was not effective as a single therapeutic modality in active UC.