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[This corrects the article DOI: 10.1371/journal.pone.0228564.].

We aimed to develop radioligands for PET imaging of brain phosphodiesterase subtype 4D (PDE4D), a potential target for developing cognition enhancing or antidepressive drugs. Exploration of several chemical series gave four leads with high PDE4D inhibitory potency and selectivity, optimal lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl cores. They were successfully labeled with carbon-11 ( t 1/2 = 20.4 min) for evaluation with PET in monkey. Whereas two of these radioligands did not provide PDE4D-specific signal in monkey brain, two others, [ 11 C]T1660 and [ 11 C]T1650, provided sizable specific signal, as judged by pharmacological challenge using rolipram or a selective PDE4D inhibitor (BPN14770) and subsequent biomathematical analysis. Specific binding was highest in prefrontal cortex, temporal cortex, and hippocampus, regions that are important for cognitive function. [ 11 C]T1650 was progressed to evaluation in humans with PET, but the output measure of brain enzyme density ( V T ) increased with scan duration. This instability over time suggests that radiometabolite(s) were accumulating in the brain. BPN14770 blocked PDE4D uptake in human brain after a single dose, but the percentage occupancy was difficult to estimate because of the unreliability of measuring V T . Overall, these results show that imaging of PDE4D in primate brain is feasible but that further radioligand refinement is needed, most likely to avoid problematic radiometabolites.

Noncommunicable diseases (NCDs), such as heart disease, cancer, diabetes, and chronic respiratory disease, are responsible for seven out of every 10 deaths worldwide. While NCDs are associated with aging in high-income countries, this representation is often misleading. Over one-third of the 41 million annual deaths from NCDs occur prematurely, defined as under 70 years of age. Most of those deaths occur in low- and middle-income countries (LMICs) where surveillance, treatment, and care of NCDs are often inadequate. In addition to high health and social costs, the economic costs imposed by such high numbers of excess early deaths impede economic development and contribute to global and national inequity. In higher-income countries, NCDs and their risks continue to push health care costs higher. The burden of NCDs is strongly intertwined with economic conditions for good and for harm. Understanding the multiple ways they are connected-through risk factor exposures, access to quality health care, and financial protection among others-will determine which countries are able to improve the healthy longevity of their populations and slow growth in health expenditure particularly in the face of aging populations. The aim of this Special Collection is to provide new evidence to spur those actions., Competing Interests: The authors have declared that no competing interests exist.

Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.

Over the past decade, universal health coverage (UHC) has emerged as a major policy goal for many low- and middle-income country governments. Yet, despite the high burden of cardiovascular diseases (CVD), relatively little is known about how to address CVD through UHC. This review covers three major topics. First, we define UHC and provide some context for its importance, and then we illustrate its relevance to CVD prevention and treatment. Second, we discuss how countries might select high-priority CVD interventions for a UHC health benefits package drawing on economic evaluation methods. Third, we explore some implementation challenges and identify research gaps that, if addressed, could improve the inclusion of CVD into UHC., Competing Interests: Competing interests: DAW and RAN are supported by the Disease Control Priorities Network grant from the Bill and Melinda Gates Foundation to the University of Washington. Additionally, DAW is funded by Medtronic Foundation through support to Rheumatic heart disease Evidence-Advocacy-Communication-Hope (RhEACH) and RHD Action, and RAN is funded by RTI International.

The South African Government recently set targets to reduce cardiovascular disease (CVD) by lowering salt consumption. We conducted an extended cost-effectiveness analysis (ECEA) to model the potential health and economic impacts of this salt policy. We used surveys and epidemiologic studies to estimate reductions in CVD resulting from lower salt intake. We calculated the average out-of-pocket (OOP) cost of CVD care, using facility fee schedules and drug prices. We estimated the reduction in OOP expenditures and government subsidies due to the policy. We estimated public and private sector costs of policy implementation. We estimated financial risk protection (FRP) from the policy as (1) cases of catastrophic health expenditure (CHE) averted or (2) cases of poverty averted. We also performed a sensitivity analysis. We found that the salt policy could reduce CVD deaths by 11%, with similar health gains across income quintiles. The policy could save households US$ 4.06 million (2012) in OOP expenditures (US$ 0.29 per capita) and save the government US$ 51.25 million in healthcare subsidies (US$ 2.52 per capita) each year. The cost to the government would be only US$ 0.01 per capita; hence, the policy would be cost saving. If the private sector food reformulation costs were passed on to consumers, food expenditures would increase by <0.2% across all income quintiles. Preventing CVD could avert 2400 cases of CHE or 2000 cases of poverty yearly. Our results were sensitive to baseline CVD mortality rates and the cost of treatment. We conclude that, in addition to health gains, population salt reduction can have positive economic impacts-substantially reducing OOP expenditures and providing FRP, particularly for the middle class. The policy could also provide large government savings on health care., (© The Author 2015. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Background: The way in which a government chooses to finance a health intervention can affect the uptake of health interventions and consequently the extent of health gains. In addition to health gains, some policies such as public finance can insure against catastrophic health expenditures. We aimed to evaluate the health and financial risk protection benefits of selected interventions that could be publicly financed by the government of Ethiopia., Methods: We used extended cost-effectiveness analysis to assess the health gains (deaths averted) and financial risk protection afforded (cases of poverty averted) by a bundle of nine (among many other) interventions that the Government of Ethiopia aims to make universally available. These nine interventions were measles vaccination, rotavirus vaccination, pneumococcal conjugate vaccination, diarrhoea treatment, malaria treatment, pneumonia treatment, caesarean section surgery, hypertension treatment, and tuberculosis treatment., Findings: Our analysis shows that, per dollar spent by the Ethiopian Government, the interventions that avert the most deaths are measles vaccination (367 deaths averted per $100,000 spent), pneumococcal conjugate vaccination (170 deaths averted per $100,000 spent), and caesarean section surgery (141 deaths averted per $100,000 spent). The interventions that avert the most cases of poverty are caesarean section surgery (98 cases averted per $100,000 spent), tuberculosis treatment (96 cases averted per $100,000 spent), and hypertension treatment (84 cases averted per $100,000 spent)., Interpretation: Our approach incorporates financial risk protection into the economic evaluation of health interventions and therefore provides information about the efficiency of attainment of both major objectives of a health system: improved health and financial risk protection. One intervention might rank higher on one or both metrics than another, which shows how intervention choice-the selection of a pathway to universal health coverage-might involve weighing up of sometimes competing objectives. This understanding can help policy makers to select interventions to target specific policy goals (ie, improved health or financial risk protection). It is especially relevant for the design and sequencing of universal health coverage to meet the needs of poor populations., (Copyright © 2015 Verguet et al. Open access article published under the terms of CC BY-NC-SA. Published by .. All rights reserved.)

Background: In China, there are more than 300 million male smokers. Tobacco taxation reduces smoking-related premature deaths and increases government revenues, but has been criticised for disproportionately affecting poorer people. We assess the distributional consequences (across different wealth quintiles) of a specific excise tax on cigarettes in China in terms of both financial and health outcomes., Methods: We use extended cost-effectiveness analysis methods to estimate, across income quintiles, the health benefits (years of life gained), the additional tax revenues raised, the net financial consequences for households, and the financial risk protection provided to households, that would be caused by a 50% increase in tobacco price through excise tax fully passed onto tobacco consumers. For our modelling analysis, we used plausible values for key parameters, including an average price elasticity of demand for tobacco of -0·38, which is assumed to vary from -0·64 in the poorest quintile to -0·12 in the richest, and we considered only the male population, which constitutes the overwhelming majority of smokers in China., Findings: Our modelling analysis showed that a 50% increase in tobacco price through excise tax would lead to 231 million years of life gained (95% uncertainty range 194-268 million) over 50 years (a third of which would be gained in the lowest income quintile), a gain of US$703 billion ($616-781 billion) of additional tax revenues from the excise tax (14% of which would come from the lowest income quintile, compared with 24% from the highest income quintile). The excise tax would increase overall household expenditures on tobacco by $376 billion ($232-505 billion), but decrease these expenditures by $21 billion (-$83 to $5 billion) in the lowest income quintile, and would reduce expenditures on tobacco-related disease by $24·0 billion ($17·3-26·3 billion, 28% of which would benefit the lowest income quintile). Finally, it would provide financial risk protection worth $1·8 billion ($1·2-2·3 billion), mainly concentrated (74%) in the lowest income quintile., Interpretation: Increased tobacco taxation can be a pro-poor policy instrument that brings substantial health and financial benefits to households in China., Funding: Bill & Melinda Gates Foundation and Dalla Lana School of Public Health., (Copyright © 2015 Verguet et al. Open access article distributed under the terms of CC BY-NC-SA. Published by .. All rights reserved.)

Background: Low fruit and vegetable (FV) intake is a leading risk factor for chronic disease globally, but much of the world's population does not consume the recommended servings of FV daily. It remains unknown whether global supply of FV is sufficient to meet current and growing population needs. We sought to determine whether supply of FV is sufficient to meet current and growing population needs, globally and in individual countries., Methods and Findings: We used global data on agricultural production and population size to compare supply of FV in 2009 with population need, globally and in individual countries. We found that the global supply of FV falls, on average, 22% short of population need according to nutrition recommendations (supply:need ratio: 0.78 [Range: 0.05-2.01]). This ratio varies widely by country income level, with a median supply:need ratio of 0.42 and 1.02 in low-income and high-income countries, respectively. A sensitivity analysis accounting for need-side food wastage showed similar insufficiency, to a slightly greater extent (global supply:need ratio: 0.66, varying from 0.37 [low-income countries] to 0.77 [high-income countries]). Using agricultural production and population projections, we also estimated supply and need for FV for 2025 and 2050. Assuming medium fertility and projected growth in agricultural production, the global supply:need ratio for FV increases slightly to 0.81 by 2025 and to 0.88 by 2050, with similar patterns seen across country income levels. In a sensitivity analysis assuming no change from current levels of FV production, the global supply:need ratio for FV decreases to 0.66 by 2025 and to 0.57 by 2050., Conclusion: The global nutrition and agricultural communities need to find innovative ways to increase FV production and consumption to meet population health needs, particularly in low-income countries.

A novel series of potent benzoxazole mPGES-1 inhibitors has been derived from a hit from a high throughput screen. Compound 37 displays mPGES-1 inhibition in an enzyme assay (0.018 μM) and PGE-2 inhibition in a cell-based assay (0.034 μM). It demonstrates 500- and 2500-fold selectivity for mPGES-1 over COX-2 and 6-keto PGF-1α, respectively. In vivo PK studies in dogs demonstrate 55% oral bioavailability and an 7 h half-life., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A United Nations high-level summit meeting on noncommunicable diseases will set priorities for addressing this major threat to the health of both developing and developed nations.

Chronic diseases present a significant challenge to 21st century global health policy. In developing nations, the growing prevalence of chronic diseases such as chronic kidney disease has severe implications on health and economic output. The rapid rise of common risk factors such as diabetes, hypertension, and obesity, especially among the poor, will result in even greater and more profound burdens that developing nations are not equipped to handle. Attention to chronic diseases, chronic kidney disease in particular, has been lacking, largely due to the global health community's focus on infectious diseases and lack of awareness. There is a critical need for funding in and to developing countries to implement more comprehensive, cost-effective, and preventative interventions against chronic diseases. This paper examines the epidemiology of chronic diseases, the growing prevalence of chronic kidney disease and its implications for global public health, and the associated health and economic burdens. Finally, a summary review of cost-effective interventions and funding needs is provided., (Copyright © 2011 S. Karger AG, Basel.)

A series of C-2 pyrroloquinoline analogs designed to improve aqueous solubility were examined for herpesvirus polymerase and antiviral activity. Several analogs were identified that maintained the antiviral activity of the previous development candidate against HCMV, HSV-1 and VZV, but with significantly improved aqueous solubility., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The integral membrane enzyme fatty acid amide hydrolase (FAAH) hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anxiolytic, and antiinflammatory phenotypes but not the undesirable side effects of direct cannabinoid receptor agonists, indicating that FAAH may be a promising therapeutic target. Structure-based inhibitor design has, however, been hampered by difficulties in expressing the human FAAH enzyme. Here, we address this problem by interconverting the active sites of rat and human FAAH using site-directed mutagenesis. The resulting humanized rat (h/r) FAAH protein exhibits the inhibitor sensitivity profiles of human FAAH but maintains the high-expression yield of the rat enzyme. We report a 2.75-A crystal structure of h/rFAAH complexed with an inhibitor, N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750), that shows strong preference for human FAAH. This structure offers compelling insights to explain the species selectivity of FAAH inhibitors, which should guide future drug design programs.

Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for treatment of pain, inflammation, and other central nervous system disorders. However, the FAAH inhibitors reported to date lack drug-like pharmacokinetic properties and/or selectivity. Herein we describe piperidine/piperazine ureas represented by N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750) and N-phenyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide (PF-622) as a novel mechanistic class of FAAH inhibitors. PF-750 and PF-622 show higher in vitro potencies than previously established classes of FAAH inhibitors. Rather unexpectedly based on the high chemical stability of the urea functional group, PF-750 and PF-622 were found to inhibit FAAH in a time-dependent manner by covalently modifying the enzyme's active site serine nucleophile. Activity-based proteomic profiling revealed that PF-750 and PF-622 were completely selective for FAAH relative to other mammalian serine hydrolases. We hypothesize that this remarkable specificity derives, at least in part, from FAAH's special ability to function as a C(O)-N bond hydrolase, which distinguishes it from the vast majority of metabolic serine hydrolases in mammals that are restricted to hydrolyzing esters and/or thioesters. The piperidine/piperazine urea may thus represent a privileged chemical scaffold for the synthesis of FAAH inhibitors that display an unprecedented combination of potency and selectivity for use as potential analgesic and anxiolytic/antidepressant agents.

Intracranial calcifications may represent calcified cerebral emboli. Calcified emboli may be overlooked even though cerebral CT is widely used as a stroke assessment. We report 4 cases of calcified cerebral emboli and demonstrate the value of CT in the diagnosis and temporal evaluation of such emboli.

Balo concentric sclerosis is a rare demyelinating disease. Pathognomonic features have been previously described. Diffusion-wighted imaging findings have not been previously described in Balo concentric sclerosis. We describe the diffusion-weighted imaging findings in a 45-year-old lady with Balo concentric sclerosis. Diffusion-weighted imaging offers insight into the possible pathophysiology of this rare disease.

Background/aims: Adult xanthogranulomatous disease involving the ocular tissues is rare and poorly understood. Adult onset xanthogranuloma (AOX), adult onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX), and Erdheim-Chester disease (ECD) are the four syndromes within this disorder, which is diagnosed by characteristic histopathology. Experience with eight cases prompted a multi-institutional effort to study the histopathology, immunohistochemistry, clinical findings, and systemic associations in this disorder., Methods: 22 cases, including histopathological slides, were compiled. Published reports were identified by an English language Medline search (1966-2005) and review of reference citations. Each case in this series and the literature was classified as one of four syndromes and then analysed for age onset, sex, skin xanthoma, orbital location, immune dysfunction, internal organ and bone lesions, treatment, and outcome. The histopathology in each of these cases was reviewed by two pathologists. Immunhistochemical stains (CD3, CD4, CD8, L26) were performed in 14 cases where unstained slides were available., Results: 137 cases were compiled. There was no sex or age difference between syndromes. AOX, AAPOX, NBX affect the anterior orbit, ECD tends to be diffuse and intraconal. Skin lesions are found in all the syndromes. Immune dysfunction was noted in all cases of AAPOX and NBX; 11% of NBX and all ECD patients had internal organ disease. Treatment included surgery, corticosteroids, other chemotherapeutic agents, radiotherapy, and combinations of these. No AOX or AAPOX deaths occurred; 66% of ECD patients died. All 22 cases had xanthoma cells; most had Touton giant cells. Lymphocytes were present in all cases and occurred as aggregates (mostly in AAPOX) or diffuse populations mixed with fibroblasts (mostly in ECD). Immunohistochemistry revealed the majority of these to be CD8+. Necrosis was most marked in NBX., Conclusion: Adult xanthogranuloma of the orbit is rare, making prospective evaluation or meta-analysis impossible. The best treatment is unknown but seems to be with multiagent chemotherapy guided by histopathological, immunohistochemical, and systemic findings.

A novel series of nonnucleoside HCV NS5B polymerase inhibitors were prepared from (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid, a high throughput screening lead. SAR studies combined with structure based drug design focusing on the southern heterobiaryl region of the template led to the synthesis of several potent and orally bioavailable lead compounds. X-ray crystallography studies were also performed to understand the interaction of these inhibitors with HCV NS5B polymerase.

We present the case of a scuba diver who experienced acute ear pain during ascent from a dive. CT imaging was performed because of severe unrelenting headache. Blood and gas was identified within the epidural space of the middle fossa and over the petrous bone, as well as hemorrhage within the adjacent temporal lobe. To the best of our knowledge, this is the first case of CT-documented barotrauma affecting the brain as a result of middle-ear gas rupturing through the tegmen tympani.

Objective: Hodgkin lymphoma (HL) risk has been linked with higher social class and lower parity, but our prior population-based case-control study in adult women had unexpected null findings for these variables. Because subject participation was 87% for cases but 65% for random digit-dialing (RDD) controls, we examined representativeness of our controls and the impact of detected bias on prior results., Methods: Using data from RDD enumeration, abbreviated interviews with nonparticipating controls, and the US census, we compared participating and nonparticipating RDD controls across several age groups and then recomputed odds ratios for risk factor associations adjusted for bias., Results: The 325 RDD control participants were younger, more likely to be white, better educated, and of lower birth order and lower parity than the nonparticipants. Adjustment of odds ratios for bias strengthened previously null findings for education and for parity, breast-feeding and miscarriages in young adult women; these latter changes eliminated previously apparent age modification of risks., Conclusions: Selection bias in female RDD controls resulted from differential participation by socioeconomic factors, varied with age, and produced underestimations of several associations in young women, including reproductive factors. Thus, our prior conclusions of etiologic irrelevance for some study variables may have been inaccurate.

Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.

Background/aim: To describe the characteristic constellation of historical, clinical, radiographic, and histopathological findings of localised invasive sino-orbital aspergillosis based on the authors' recent experience of four consecutive cases presenting over a 6 month period. Treatment and outcome are reviewed., Methods: A case series of four patients with review of the English language literature., Results: There have been 17 reported cases of invasive sino-orbital aspergillosis in healthy individuals over the past 33 years. The authors report four patients who presented during a 6 month period with persistent and significant pain followed by progressive ophthalmic signs-clinical histories reflecting the literature. Similar imaging findings were also noted: focal hypodense areas within apical infiltrates on contrasted computed tomography correspond to abscesses seen at surgery, and sinus obliteration or involvement of the adjacent sinus lining was noted on magnetic resonance imaging. Bone erosion (often focal) was also seen. There is frequently a delay in making the correct diagnosis, and often disease progression occurs despite treatment., Conclusions: The authors encountered four cases of invasive sino-orbital aspergillosis, three of which occurred in otherwise healthy individuals. The clinician must be aware of the characteristic presentation so that earlier diagnosis, management, and improved outcomes can be achieved.

Purpose: To study the natural history and growth of optic nerve sheath meningiomas and evaluate their management outcome., Design: Clinicopathologic retrospective noncomparative case series., Methods: A retrospective study of 88 patients who were treated between 1976 and 1999 at the University of British Columbia and the University of Amsterdam. Clinical reports, imaging studies, and histopathologic findings were reviewed., Results: The mean age at onset of symptoms was 40.3 years, and most were seen in middle-aged females. Patients typically presented with visual loss, frequently associated with optic atrophy or papilledema and occasionally optociliary shunt vessels. On imaging, the optic nerve demonstrated segmental or diffuse thickening of the sheath or globular growth. Calcification was seen in 31% of cases and was associated with slower tumor growth. Tumors with posterior components in the orbit had more frequent intracranial involvement. Intracranial extension was more frequent and had a greater growth rate in younger patients. Irregular margins in the orbit implied local invasion. A presenting visual acuity better than 20/50 correlated with longer preservation of vision. Patients who underwent radiotherapy showed improvement in their visual acuity, and tumor growth was halted. Optic sheath decompression did not preserve vision. En bloc tumor excision was associated with no detectable recurrence in contrast to debulked tumors that recurred., Conclusions: Meningiomas show characteristic indolent growth. Management therefore should be conservative in most cases. Radiotherapy is indicated in patients with progressive visual deterioration. Surgery, when indicated, should be an en bloc excision.

Reproductive factors have been suggested to have an impact on the development of Hodgkin's disease (HD) in women. In the San Francisco Bay Area, the authors conducted a population-based case-control study addressing the effects of reproductive experience and hormone use on HD risk. Cases were 370 women with HD diagnosed at ages 19-79 years between July 1988 and December 1994. Controls were 450 community women found through random digit dialing. Among the 312 cases and 325 controls interviewed, HD risk was related to parity versus nulliparity but only among never nursers (odds ratio (OR)=2.2, 95% confidence interval (CI): 1.0, 5.0). Risk was marginally related to having uterine fibroids (OR=0.6, 95% CI: 0.5, 1.0) and long-term versus short-term hormone use (OR=0.7, 95% CI: 0.4, 1.0) and was significantly related to recurrent miscarriage (OR=2.8, 95% CI: 1.1, 7.4). Among women aged 35-54 years, for whom the sex difference in incidence is largest, nursing decreased risk; among never nursers, a parity of 1 lowered risk and higher parity increased risk; long-term hormone use lowered risk; and recurrent miscarriage increased risk. Among women under age 35 years, endometriosis lowered HD risk; the lack of significant findings for most other variables may reflect selection bias in controls. Among older women, no significant associations were observed, although hormone use appeared to be protective. These data suggest that steroid hormones may affect HD development.

The objective of this study was to estimate heritability for body length (LEN) at the end of performance testing and to estimate genetic correlations with backfat (BF) thickness and loin muscle area (LMA) in Landrace, Yorkshire, Duroc, and Hampshire breeds of swine. Also examined were two measures of body density involving body length and weight and their relationships to backfat and loin muscle area. Data consisted of performance test records collected in a commercial swine operation from 1992 to 1999. Boars from 60% of the litters were culled at weaning based on a maternal breeding value of the dam. Remaining boars and all females were grown to 100 d of age (15,594, 55,497, 12,267, and 9,782 Landrace, Yorkshire, Duroc, and Hampshire pigs, respectively). At this time, all pigs were weighed (WT100) and selected for performance testing based on a combination of maternal and performance indexes, which differed by breed. All pigs were weighed at the end of the 77 d performance test (WT177) when BF, LMA, and LEN were measured. Two measures of body density involving length were calculated: Body mass index (BMI) = WT177/LEN2 and body density (DENSITY) = WT177/LEN. For each breed, genetic parameters were estimated using an animal model with random litter effects and multiple-trait REML procedures. A series of three-trait models including WT100 and combinations of two other traits in each analysis was conducted. Fixed effects included contemporary group and age as a covariate. Average estimates of heritability were 0.16 to 0.32 for LEN (unadjusted for WT177), 0.12 to 0.26 for LEN (adjusted for WT177), 0.23 to 0.33 for DENSITY, and 0.16 to 0.25 for BMI. Genetic correlations between LEN and LMA were low. Genetic correlations between LEN (unadjusted for WT177) and BF were 0.10 to 0.41. Adjusting LEN for WT177 gave correlations of 0.11 for Landrace and Hampshire and negative correlations (-0.06 and -0.19, respectively) for Yorkshire and Duroc. Genetic correlations between LMA and DENSITY and between LMA and BMI were comparable and ranged from 0.44 to 0.54. Genetic correlations between BF and DENSITY were slightly higher (0.53 to 0.68) than those between BF and BMI (0.37 to 0.67). In these data, not much relationship between BF and body length at a constant weight and age was found. There was a negative relationship between LMA and LEN at a constant weight and age, implying that longer pigs had smaller LMA.

The objective of this study was to investigate the importance of maternal genetic effects on postweaning performance traits of Yorkshire, Landrace, Duroc, and Hampshire breeds of swine. Data consisted of performance test records collected in a commercial swine operation from 1992 to 1999. Boars from 60% of the litters were culled at weaning based on a combination of maternal and performance indexes that differed by breed. Remaining boars and all females were grown to 100 d of age. At this time all pigs were weighed (WT100) and selected for testing using recalculated breed-specific indexes (n = 15,594, 55,497, 12,267, and 9,782 for Landrace, Yorkshire, Duroc, and Hampshire, respectively). All pigs were weighed at the end of the 77-d test, and backfat (BF) and loin eye area (LEA) were measured over the 12th rib by ultrasound. Average daily feed intake was calculated for boars, and ADG was calculated for all animals. Genetic parameters were estimated for each breed and trait using multiple-trait DFREML procedures. Fixed effects were contemporary groups and either initial or final test age as a covariate. Four models were examined. Model 1 included only the additive genetic effect of the animal. Model 2 added the common litter environmental effect; Model 3 added the maternal genetic value assumed to be uncorrelated with additive genetic effects. Model 4 was the same as Model 3 with additive and maternal genetic effects assumed to be correlated. All models were two-trait models with WT100 as the second trait. Ratios of likelihoods were used to compare models. Maternal effects were important (P < 0.05) for WT100, ADG, ADFI, LEA, and BF in Landrace; for WT100, ADG, LEA, and BF in Yorkshire; for WT100 and ADG in Duroc, and for WT100 in Hampshire. Estimates of heritabilities for direct additive effects using the appropriate model for ADG, ADFI, LEA, and BF were 0.28, 0.34, 0.48, and 0.63 for Landrace; 0.26, 0.31, 0.39, and 0.65 for Yorkshire; 0.14, 0.20, 0.26, and 0.35 for Duroc; and 0.17, 0.23, 0.25, and 0.31 for Hampshire, respectively. Heritability estimates for maternal genetic effects for ADG, ADFI, LEA, and BF were 0.02, 0.05, 0.06, and 0.07 for Landrace and 0.02, 0, 0.04, and 0.06 for Yorkshire, respectively. They were zero for all traits except ADG (0.03) in Duroc and for all traits in Hampshire. Maternal effects may need to be considered in genetic evaluation of performance traits in some breeds of swine.

Hodgkin's disease (HD) risk in young adults has been associated with higher childhood social class. Although recent decades have witnessed increases in both young-adult HD incidence rates and the socioeconomic affluence reported to influence risk, social class risk factors have not been reexamined. For 204 cases and 254 controls aged 19-44 years from a population-based case-control study of HD diagnosed in 1988-94 in San Francisco area females, we evaluated social class predictors of HD overall and for subgroups defined by age and by ethnicity. HD was associated weakly with a few childhood social class markers but more strongly with combinations of these variables. Risk was higher for women with family-owned than rented childhood homes; for US-born women with single vs. shared bedrooms at age 11; and for women with 2+ births who were from smaller than larger childhood households. These patterns differed by age, with risk appearing to increase over the young-adult years for some factors and to decrease for others. In whites, risk was additionally associated with having a single childhood bedroom in larger households, and with tall adult height in women from smaller childhood households. In nonwhites, risk was higher for single bedrooms at age 11 in smaller childhood households, taller height and higher maternal education. Most study findings support the hypothesis that HD development in young adults follows protection from early exposure to other children. Variation in risk by age suggests differing etiologies across young adulthood, or the importance of birth cohort-appropriate social-class measures. Negative findings for previously reported risk factors may reflect their insufficient heterogeneity of exposure or their failure to measure cohort-relevant exposures in this population., (Copyright 2001 Wiley-Liss, Inc.)

Baló's concentric sclerosis is a demyelinating disorder in which bands of demyelination alternate with concentric bands of myelin preservation. The pathogenesis of the lesion is unknown. Previous reports using modern histopathologic techniques have shown the bands of myelin preservation to be comprised of remyelinated or partially demyelinated myelin. Here we report a case of Baló's concentric sclerosis in a 24-year-old East Indian patient with a previous history of relapsing-remitting multiple sclerosis (MS). Pathologically, the bands of myelin preservation showed myelin sheaths of normal thickness, with focal areas of demyelination. The findings, taken together with those of previously reported cases, suggest that Baló's concentric sclerosis is a variant of MS, and the concentric lesion may be an intermediary form in evolution of a chronic active MS plaque. The pathogenesis of this concentric lesion may be explained by periodic suppression of demyelination in the rapidly expanding border, allowing remyelination or only transient incomplete demyelination to occur.

Objective: During the pallidotomy procedure, is pre-operative localization with MRI more accurate than CT and does it result in a significant difference in surgical outcome?, Methods: Twenty-four Parkinson's Disease patients received a unilateral pallidotomy for their motor symptoms. Dyskinesia was scored pre- and six weeks postoperatively. All patients had a pre-operative CT scan and MRI to calculate the target co-ordinates. Patients were then randomly selected to proceed with either the CT or MRI coordinates. The final position for the lesion was determined with intraoperative macrostimulation and impedance measurements. The percentage improvement of dyskinesia was noted for each patient and the two groups compared by the Mann-Whitney test. The distance from the final target to the MRI and CT pre-operative co-ordinates were calculated for each patient. The mean distance for each modality was then compared by Student's t-test. The number of electrode repositionings was also recorded for each patient and the two groups compared by the nonparametric Mann-Whitney test., Results: Although the MRI co-ordinates were significantly (p<0.023) closer to the final target, this did not translate into a significant reduction in electrode repositionings. There was no significant difference in the improvement in dyskinesia between the two groups., Conclusions: The pre-operative MRI co-ordinates were significantly (p=0.023) closer to the final target than those from the CT. The potential advantages and disadvantages of both imaging modalities are reviewed. There was no significant difference in surgical outcome using either MRI or CT for pre-operative localization in pallidotomy.

The purpose of this study was to estimate genetic parameters for ADG, backfat thickness and loin eye area (LEA), and measures of feed intake and efficiency for purebred Large White boars born from 1990 to 1997. Boars from 60% of the litters were culled at weaning based on a maternal breeding value (index) of the dam, and remaining boars (n = 26,706) were grown to 100 d of age. Selection of boars for individual pen testing was based on a combination of growth and maternal indices. Boars were fed a corn-soybean meal diet that was 1.14% lysine, 19% protein, and 3,344 kcal/kg ME for approximately 77 d. Boars were weighed at the beginning and end of the test, and feed intake was recorded. Daily feed intake (DFI), ADG, and feed:gain ratio (FG) were computed. Four measures of residual feed intake (RFI) were estimated as the difference between actual feed intake and that predicted from models that included 1) initial test age and weight and test ADG (RFI1); 2) initial test age and weight, test ADG, and backfat (RFI2); 3) initial test age and weight, test ADG, and LEA (RFI3); and 4) initial test age and weight, test ADG, backfat, and LEA (RFI4). Genetic parameters were estimated using an animal model and single- or multiple-trait DFREML procedures. Models included fixed effects of contemporary groups and initial test age as a covariate and random animal and litter effects. Heritability estimates for test ADG, DFI, FG, backfat, LEA, RFI1, RFI2, RFI3, and RFI4 were .24, .23, .16, .36, .24, .17, .11, .15, and .10, respectively. Genetic correlations between ADG and backfat, ADG and LEA, ADG and DFI, and ADG and FG were .37, .36, .82, and -.32, respectively. Genetic correlations between ADG and measures of residual feed intake ranged from .11 to .18. Genetic correlations of backfat with LEA, DFI, and FG were -.27, .64, and .40, respectively. Genetic correlations of backfat with RFI measures were higher when backfat was not included in the estimation of RFI. Genetic correlations for LEA with DFI and FG were 0 and -.52, respectively. Genetic correlations for LEA with RFI measures were all negative and ranged from -.31 to -.51. Genetic correlations indicate that selection for reduced RFI could be made without adversely affecting ADG. Backfat should also decrease, and LEA should increase. The amount of change in backfat or LEA would depend on the measure of RFI used.

A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1IIIB-WT and retain good activity against a laboratory-derived HIV-1MF delavirdine-resistant variant.

Bisphosphonates (BP) are synthetic pyrophosphates with a stable P-C-P bond replacing the more labile P-O-P bond. This structural class has been used extensively for the treatment of bone diseases, such as osteoporosis and hypercalcemia due to the propensity of BP to bind mineralized tissues and prevent bone resorption. Rheumatoid arthritis (RA) is characterized by chronic inflammatory synovitis, pannus tissue formation and erosion of bone and cartilage, which is a major, disabling, pathogenic feature poorly managed with existing disease modifying anti-rheumatic drugs (DMARDs). A few investigators have used BP in combination with anti-arthritic therapy to treat the bone erosion component of RA, reports of which are mainly anecdotal. We review data suggesting that BP possess novel anti-inflammatory properties which may also be of benefit for the treatment of the chronic inflammatory component of RA, thus modifying the subsequent destructive disease process by mechanisms unrelated to direct inhibition of bone resorption. The rationale for pursuing this therapeutic approach to demonstrate BP anti-inflammatory activity will be reviewed. The subsequent design and synthesis of new BP chemical entities and their altered pharmacokinetic properties will also be discussed.

Bisphosphonate ester 2 is an inhibitor of inflammation, but is devoid of antiarthritic effects. SAR studies on a series of related bisphosphonate esters resulted in compounds 6e, 6i, 6j, and 6m, which exhibited excellent inhibition of an arthritis model, in addition to potent anti-inflammatory effects.

The objective of this study was to determine whether serum concentrations of growth hormone (GH), IGF-I, IGF binding proteins (IGFBP), and glucose at wk 2 and 10 postpartum were associated with the ability of postpartum beef cows to resume cycling when maintained on a limited nutrient environment. Cows (n = 29) were individually fed either 130 or 170 kcal ME x BW-75 x d-1 during nonlactation and 170 or 210 kcal ME x BW-75 x d-1 during lactation for an average of 4.1 yr before sample collection. The proportion of cows that resumed estrus within 20 wk after parturition was less (P < .05) at the lower feeding rate (5 of 14) than at the higher feeding rate (11 of 15). Concentrations of IGF-I increased from wk 2 to 10 in cows that resumed cycling but not in cows that remained anestrous and were less (P < .05) at wk 2 and 10 in cows that remained anestrous compared to cows that resumed cycling. Circulating amounts of IGFBP-2 at wk 2 were greater (P < .05) and IGFBP-3 concentrations were lower (P < .05) in cows that remained anestrous compared to cows that resumed cycling. Cows on the lower feeding rate that did not cycle had lower body condition scores and greater concentrations of GH compared (P < .05) to other cows. At the higher feeding rate, body condition score and concentrations of GH did not differ between cows that did or did not resume cycling. Circulating concentrations of IGF-I and IGFBP-2 and -3 at wk 2 postpartum were indicators of the capacity of energy-restricted cattle to resume cycling after parturition.

Using a 32-echo imaging pulse sequence, T2 relaxation decay curves were acquired from five white- and six gray-matter brain structures outlined in 12 normal volunteers. The water contents of white and gray matter were 0.71 (0.01) and 0.83 (0.03) g/ml, respectively. All white-matter structures had significantly higher myelin water percentages (signal percentage with T2 between 10 and 50 ms) than all gray-matter structures. The range in geometric mean T2 of the main peak for both white and gray matter was from 70 to 86 ms. T2 distributions from the posterior internal capsules and splenium of the corpus callosum were significantly wider (width is related to water environment inhomogeneity) than those from any other white- or gray-matter structures. Thus, quantitative measurement and analysis of T2 relaxation reveals differences in brain tissue water environments not discernible on conventional MR images. These differences may make short T2 components reliable markers for normal myelin.

A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.

Diphosphonates (DP) are synthetic pyrophosphates with a P-C-P backbone and are predominantly used for the treatment of bone diseases. Several DP have also been shown to exert significant antiarthritic effects in the rat adjuvant-induced polyarthritis model; however, there is no direct evidence for the anti-inflammatory effects of these compounds. We therefore tested the effects of dichloromethylene diphosphonate on delayed-type hypersensitivity granuloma elicited by s.c. implantation of antigen-soaked hydroxyapatite disks in antigen-sensitized mice. Dichloromethylene diphosphonate induced a dose-related inhibition of the delayed-type hypersensitivity granuloma response (38-64% at 25-100 mg/kg/day s.c. or p.o.); novel DP analogs, U-81581, U-82579 and U-84849 were also effective in the same dose range. In contrast, all DP failed to suppress 24-hr delayed-type hypersensitivity paw edema in mice. In addition to rat adjuvant-induced polyarthritis, mouse antigen-induced erosive arthritis was also significantly suppressed by s.c. administration of all four DP. Toxicity was minimal for each DP (> 600 mg/kg p.o. or s.c.). We conclude that DP represent a novel class of anti-inflammatory agents with excellent therapeutic potential for chronic inflammatory diseases including rheumatoid arthritis.