Assessment of the FAM174A 11G allele as a risk allele for equine metabolic syndrome.

An 11G nucleotide repeat in the 3' UTR of FAM174A was recently postulated as a risk allele with a dominant mode of inheritance for equine metabolic syndrome (EMS) and laminitis status in Arabian horses. The objective of this project was to evaluate this hypothesis in a large and diverse across-breed population. A total of 301 ponies, 292 Morgans, 64 Arabians, 49 Tennessee Walking Horses and 59 Quarter Horses were genotyped for six observed G repeat alleles in the FAM174A 3' UTR. Phenotype data included laminitis status, baseline insulin, glucose, non-esterified fatty acids, triglycerides, adiponectin, leptin, ACTH, insulin and glucose post oral sugar test, and two proxies for insulin resistance. The 11G allele frequencies were 18.8, 6.9, 1.8, 0.2 and 0.0% in the Arabians, Tennessee Walkers, ponies, Morgans and Quarter Horses respectively. Association analyses between FAM174A genotype and EMS phenotypes, and between allele count and EMS phenotypes, identified no statistically significant associations. When a dominant effect for the 11G allele was evaluated, a statistically significant association with adiponectin levels was identified in the ponies, and pairwise comparisons revealed that the estimated marginal means were higher in ponies with the 11G allele vs. alternative alleles (i.e. the allele had a protective effect). In conclusion, our data do not support the FAM174A 11G allele as a risk allele for EMS in our studied breeds.

High-fructose diet during adolescent development increases neuroinflammation and depressive-like behavior without exacerbating outcomes after stroke.

Diseases, disorders, and insults of aging are frequently studied in otherwise healthy animal models despite rampant co-morbidities and exposures among the human population. Stressor exposures can increase neuroinflammation and augment the inflammatory response following a challenge. The impact of dietary exposure on baseline neural function and behavior has gained attention; in particular, a diet high in fructose can increase activation of the hypothalamic-pituitary-adrenal axis and alter behavior. The current study considers the implications of a diet high in fructose for neuroinflammation and outcomes following the cerebrovascular challenge of stroke. Ischemic injury may come as a "second hit" to pre-existing metabolic pathology, exacerbating inflammatory and behavioral sequelae. This study assesses the neuroinflammatory consequences of a peri-adolescent high-fructose diet model and assesses the impact of diet-induced metabolic dysfunction on behavioral and neuropathological outcomes after middle cerebral artery occlusion. We demonstrate that consumption of a high-fructose diet initiated during adolescent development increases brain complement expression, elevates plasma TNFα and serum corticosterone, and promotes depressive-like behavior. Despite these adverse effects of diet exposure, peri-adolescent fructose consumption did not exacerbate neurological behaviors or lesion volume after middle cerebral artery occlusion.

Pharmacokinetic and pharmacodynamic properties of pergolide mesylate following long-term administration to horses with pituitary pars intermedia dysfunction.

The objective of this study was to gain an understanding of the pharmacokinetic and pharmacodynamic properties of pergolide in horses with PPID after of long-term oral administration. Six horses with confirmed PPID were treated with pergolide (Prascend® ) at 1 mg/horse po q24 h for 2 months, followed by 2 mg/horse po q24 h for 4 months. Following the last dose, plasma samples were collected for measurement of pergolide using an LC/MS/MS method and ACTH measurement using a chemiluminescent immunoassay. Noncompartmental and compartmental pharmacokinetic analyses were performed, as well as pharmacodynamic assessment of the effect of plasma pergolide concentrations on plasma ACTH concentrations. Pergolide effectively decreased plasma ACTH concentration in aged horses with PPID, with similar pharmacokinetic properties as reported in young horses, including an approximate terminal half-life of 24 h. Plasma ACTH concentration increased by 50% in 3/6 horses at 2 days and 6/6 horses 10 days after discontinuing drug administration. Pergolide was quantified in all horses at 2 days and in none at 10 days after last dose. In summary, after discontinuing pergolide treatment, plasma ACTH concentration increased while pergolide was still quantifiable in some horses. Once-daily dosing of pergolide is likely appropriate in most horses with PPID for regulating the plasma ACTH concentration.

Age- and gender-associated changes in the concentrations of serum TGF-1ß, DHEA-S and IGF-1 in healthy captive baboons (Papio hamadryas anubis).

Age-related changes in the concentration of factors like TGF-1ß, DHEA-S and IGF-1 may increase the risk of disease and illnesses in advanced life. A better understanding of these changes would aid in the development of more appropriate treatments and/or preventative care for many conditions associated with age. Due to their similar immune system and vulnerability to pathogens, baboons are an ideal model for humans. However, little research has been done examining the general effects of age in baboons. Therefore, we wanted to further examine the effects of aging in baboons by determining the age-dependent changes in serum TGF-1ß, DHEA-S and IGF-1 concentrations. Blood samples were collected during routine health checks in 113-118 captive baboons. In addition, longitudinal samples from 23 to 27 adult individuals were collected an average of 10.7years apart. Both age and gender influenced the concentrations of serum TGF-1ß and IGF-1. When both genders were analyzed together, TGF-1ß increased 16.1% as adults, compared to younger and older animals, but male and female baboons showed a slightly different temporal pattern of change. IGF-1 decreased with increasing age and males had a 30% greater concentration of IGF-1 than did females. While there was no effect of gender among our population, serum DHEA-S was negatively correlated with age, decreasing by 51.6% in the oldest animals. There were no effects of age or gender on serum IGFBP-3. In longitudinal samples collected from the same individuals, the concentrations of TGF-1ß, DHEA-S and IGF-1 were reduced with age. The results presented herein provide additional knowledge of the aging process in baboons and further validate the use of this species as an appropriate model for aging in humans.

Markers of muscle atrophy and impact of treatment with pergolide in horses with pituitary pars intermedia dysfunction and muscle atrophy.

Pituitary pars intermedia dysfunction (PPID) is a common endocrine disorder of aged horses, with muscle atrophy as one of the clinical signs. We sought to compare muscle mass and regulation of skeletal muscle proteolysis between horses with PPID and muscle atrophy to older horses without PPID, and to assess the impact of treatment with pergolide (dopaminergic agonist) on PPID horses. We hypothesized that PPID-associated muscle atrophy is a result of increased proteolysis, and that markers of muscle atrophy and proteolysis would improve over time with pergolide treatment. Markers of muscle atrophy, adiposity, insulin regulation, skeletal muscle composition, and proteolysis (muscle atrophy F- box/atrogin 1 [MAFbx1], muscle RING finger 1 [MuRF1], Bcl2/adenovirus EIV 19kD interacting protein 3 [Bnip3], and microtubule-associated light chain 3 [LC3]) were compared between PPID and control horses. PPID horses were treated for 12 weeks with either pergolide or placebo. Dose of pergolide was adjusted based upon monthly measurement of adrenocorticotropin, and markers of muscle atrophy, adiposity, insulin regulation, skeletal muscle composition, and proteolysis were compared after 12 weeks of treatment. Horses with PPID exhibited increased transcript abundance of MuRF1 (P= 0.04) compared to control. However, no difference was observed in transcript abundance of markers of proteolysis with treatment (P ≥ 0.25). Pergolide treated horses lost weight (P = 0.02) and improved fasting insulin (P = 0.02), while placebo treated horses gained weight and rump fat thickness (P = 0.02). Findings from this study suggest that treatment with pergolide may promote weight loss and improve insulin regulation in horses with PPID, but does not impact muscle mass or markers of muscle proteolysis.

Using treated wastewater to save wetlands impacted by climate change and pumping.

Wetlands occur where the watertable which underlies much of Perth intersects the land surface. Regional groundwater levels have been falling since the 1970s as a result of lower rainfall and increased extraction causing a loss of environmental and social values. This paper examines a scheme to add almost 2 GL/yr of treated wastewater to infiltration galleries immediately down-gradient of Perry Lakes so that the wetlands may be restored. Modelling suggest that groundwater levels would be raised up-gradient of the galleries, increasing both lake levels and groundwater supplies in the vicinity. It is not envisaged that wastewater will enter the lakes. Adding treated wastewater to nearby trial galleries has shown that phosphorus, pathogens and organic carbon are greatly reduced within 5 to 50 m. Nitrogen levels are less reduced but are similar to those in the lakes and nearby aquifer. It is estimated that the wetlands add about $54 m to land prices near the lakes and would add more than $24M to the sale price of proposed nearby land if they contain water. If successful, the proposal could be a test case for the use of treated wastewater to create hydraulic barriers against salt water intrusion into coastal areas.

Heritability of metabolic traits associated with equine metabolic syndrome in Welsh ponies and Morgan horses.

BACKGROUND: Equine metabolic syndrome (EMS) is a complex clinical disorder with both environmental and genetic factors contributing to EMS phenotypes. Estimates of heritability determine the proportion of variation in a trait that is attributable to genetics. OBJECTIVES: To provide heritability estimates for nine metabolic traits associated with EMS in two high-risk breeds. STUDY DESIGN: Retrospective cohort study. METHODS: High-density single-nucleotide polymorphism (SNP) genotype data was used to estimate the heritability (h2 SNP ) of nine metabolic traits relevant to EMS in a cohort of 264 Welsh ponies and 286 Morgan horses. Traits included measurements of insulin, glucose, non-esterified fatty acids (NEFA), triglycerides, leptin, adiponectin, ACTH, and glucose (GLU-OST) and insulin (INS-OST) following an oral sugar challenge. RESULTS: In Welsh ponies, seven of the nine traits had statistically significant h2 SNP estimates that were considered moderately to highly heritable (h2 SNP >0.20) including: triglycerides (0.313; s.e. = 0.146), glucose (0.408; s.e. = 0.135), NEFA (0.434; s.e. = 0.136), INS-OST (0.440; s.e. = 0.148), adiponectin (0.488; s.e. = 0.143), leptin (0.554; s.e. = 0.132) and insulin (0.808; s.e. = 0.108). In Morgans, six of the nine traits had statistically significant h2 SNP estimates that were also determined to be moderately to highly heritable including: INS-OST (0.359; s.e. = 0.185), leptin (0.486; s.e. = 0.177), GLU-OST (0.566 s.e. = 0.175), insulin (0.592; s.e. = 0.195), NEFA (0.684; s.e. = 0.164), and adiponectin (0.913; s.e. = 0.181). MAIN LIMITATIONS: Insufficient population size may have limited power to obtain statistically significant h2 SNP estimates for ACTH (both breeds), glucose and triglycerides in Morgans and GLU-OST in Welsh ponies. CONCLUSIONS: This study provides the first concrete evidence of a genetic contribution to key phenotypes associated with EMS. Eight of these nine traits had moderate to high h2 SNP estimates in this cohort. These data demonstrate that continued research for identification of the genetic risk factors for EMS phenotypes within and across breeds is warranted.

Cytokine dysregulation in aged horses and horses with pituitary pars intermedia dysfunction.

BACKGROUND: Equine pituitary pars intermedia dysfunction (PPID) is the result of a loss of dopaminergic inhibition of the pars intermedia secondary to neurodegeneration of periventricular hypothalamic neurons. The pathologic events contributing to development of neurodegeneration or clinical signs in equids with PPID are unknown. Chronic inflammation may contribute to initiation or progression of PPID. HYPOTHESIS: Horses with PPID have a distinct systemic cytokine profile compared with that of normal adult or aged horses. The cytokine profile of healthy aged horses differs from that of adult horses. ANIMALS: Aged horses with PPID, healthy aged-matched controls, and adult controls (n = 14 per group). METHODS: Total leukocyte cytokine expression was determined by quantitative polymerase chain reaction (PCR), and tumor necrosis factor (TNF)-alpha plasma concentration was determined by enzyme-linked immunosorbent assay (ELISA). Peripheral blood mononuclear cell (PBMC) TNF-alpha response after endotoxin (lipopolysaccharide [LPS]) treatment was assessed by ELISA. RESULTS: Aged healthy horses had increased expression of interleukin (IL)-6, IL-8, and interferon-gamma as well as PBMC TNF-alpha release after LPS stimulation compared with healthy adult horses. In contrast, aged horses with PPID had increased IL-8 expression, but expression of other cytokines was similar to that of healthy adult horses, not age-matched controls. CONCLUSIONS AND CLINICAL IMPORTANCE: Aged horses show evidence of a proinflammatory state that may contribute to development of age-associated diseases. Horses with PPID have increased expression of IL-8, which may influence the ability of horses with PPID to respond to bacterial pathogens. The general decrease in proinflammatory cytokine expression observed in horses with PPID may be the outcome of high plasma concentrations of anti-inflammatory hormones.

The effect of age on serum antibody titers after rabies and influenza vaccination in healthy horses.

BACKGROUND: The proportion of geriatric horses within the equine population has increased in the past decade, but there is limited information on the immune function of these animals. HYPOTHESIS: Aged horses will have a lesser increase in serum antibody response to vaccination. ANIMALS: Thirty-four aged healthy horses (> or = 20 years) and 29 younger adult horses (4-12 years) of various breeds. METHODS: All horses were vaccinated with vaccines of killed rabies and influenza virus. Horses in each age group were allocated to receive either rabies or influenza booster vaccine 4 weeks after the initial vaccination. Serum samples were taken at 0, 4, 8, and 24 weeks. Rabies serum neutralization titers and equine influenza virus specific antibody sub-isotypes (IgGa, IgGb, IgG(T), and IgA) as well as single radial hemolysis (SRH) titers were determined. RESULTS: Rabies antibody titers were similar in the 2 age groups at all sampling times. Aged horses had higher IgGa and IgGb influenza antibody titers before vaccination than younger horses but similar titers after vaccination (P= .004 and P= .0027, respectively). Younger horses had significantly greater increases in titer than aged horses at all sampling times for IgGa (P= .001) and at 8 and 24 weeks for IgGb (P= .041 and .01, respectively). There was no detectable serum IgG(T) at any time point. A significant booster vaccine effect was seen for both antirabies and anti-influenza titers. Anti-influenza titer before vaccination also had a significant effect on subsequent antibody response. CONCLUSIONS AND CLINICAL IMPORTANCE: Healthy aged horses generated a primary immune response to a killed rabies vaccine similar to that of younger adult horses. Aged horses had a significantly reduced anamnestic response to influenza vaccine.

Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses.

BACKGROUND: Increased free cortisol fraction is associated with insulin dysregulation (ID) in people with Metabolic Syndrome and Cushing's Disease. Free cortisol has not been investigated in equine endocrine disorders. HYPOTHESES: (1) In healthy horses, sex, age, body condition score (BCS), and season impact free cortisol; (2) free cortisol is increased in horses with Pituitary Pars Intermedia Dysfunction (PPID) or Equine Metabolic Syndrome (EMS). ANIMALS: Fifty-seven healthy horses; 40 horses and ponies with PPID (n = 20) or EMS (n = 20). METHODS: Prospective study. Serum collected seasonally from healthy animals and archived serum from PPID and EMS animals was analyzed for insulin, total and free cortisol concentrations, and free cortisol fraction (FCF). Linear mixed models were used to determine effects of age, sex, season, and BCS on hormones in controls. Hormone measurements were compared between disease groups and age- and season-matched controls with t-tests. EMS and hyperinsulinemic PPID animals were combined in an ID (hyperinsulinemia) group. RESULTS: Free cortisol concentrations were increased in overweight/obese controls (0.3 ± 0.1 µg/dL) compared to lean controls (0.2 ± 0.1 µg/dL; P = .017). Mean FCF was significantly higher in animals with PPID (8.8 ± 5.8 µg/dL, P = .005) or ID (8.8 ± 10.2 µg/dL, P = .039) than controls (5.0 ± 0.9 µg/dL), but total cortisol concentrations were similar (P ≥ .350) (PPID: 4.2 ± 4.3 µg/dL; ID: 5.0 ± 4.5 µg/dL; controls: 4.6 ± 1.7 and 5.1 ± 2.1 µg/dL). CONCLUSIONS AND CLINICAL IMPORTANCE: Increased FCF is associated with obesity in healthy horses and with ID (hyperinsulinemia) in horses and ponies with endocrine disease. Decreased plasma cortisol-binding capacity could be a component of these endocrine disorders in horses.

Lamellar pathology in horses with pituitary pars intermedia dysfunction.

REASONS FOR PERFORMING STUDY: Hoof lamellar pathology in horses with pituitary pars intermedia dysfunction (PPID) has not been described previously. OBJECTIVES: To describe the histomorphometry and pathological lesions in hoof lamellar tissue of animals that had PPID with or without concurrent laminitis, with reference to age-matched controls. We hypothesised that lamellar lesions consistent with laminitis would be associated with PPID, even in animals without current or historical laminitis. STUDY DESIGN: Prospective case-control study. METHODS: Mid-dorsal hoof histological sections were obtained post mortem from the forelimbs of 16 PPID-affected animals either with (n = 6) or without laminitis (n = 10) and 10 age- and breed-matched controls. Sections were examined by a blinded veterinary pathologist. The length and width of 10 primary epidermal lamellae were measured using image analysis software. The morphology and pathology of primary and secondary epidermal lamellae were then typed or graded in axial, middle and abaxial regions. Fasting serum insulin, plasma adrenocorticotropin and blood glucose concentration were measured from blood samples taken prior to euthanasia. RESULTS: All animals with PPID and laminitis had fasting hyperinsulinaemia (median 74.1 miu/l, interquartile range 49.9-349.5 miu/l) whereas PPID animals without laminitis had serum insulin concentrations below the upper limit of the reference range (<20 miu/l). Lamellar pathology in PPID animals with laminitis was variable in severity and unrelated to the reported duration of laminitis (range 2 months-5 years). Most lesions were located abaxially within the lamellar tissue and included increased length and width of the lamellae, chronic abnormal keratinisation, interlamellar epidermal bridging and cell death with more acute lamellar tearing in some cases. The lamellae of PPID animals without laminitis were normal referent to the relevant control group. CONCLUSIONS: Whether PPID and hyperinsulinaemia have a causal inter-relationship or not, it may only be the hyperinsulinaemia that is associated with lamellar morphological alteration and pathology consistent with laminitis.

FTIR spectroscopy study of PTHrP(1-34) involved in humoral hypercalcaemia of malignancy.

The components of secondary structure of the biologically-active N-terminal domain of human parathyroid-hormone-related protein (residues 1-34) and several truncated species were examined using Fourier transform infrared (FTIR) spectroscopy. The major structural features include a segment of alpha-helix within the N-terminal segment probably extending from Glu-4 to Lys-11 with three beta-turns localized to the segments Gly-12 to Ile-15, Gln-16 to Arg-20 and His-25 to Ala-29. Some beta-sheet was detected in the full-length peptide, but not in any of the C-terminal truncated samples. These structural features were studied in the smaller peptides for the purpose of localization of the various components and with a view to describing the region likely to form the bulk of the receptor binding site.

Nitration and increased alpha-synuclein expression associated with dopaminergic neurodegeneration in equine pituitary pars intermedia dysfunction.

Equine pituitary pars intermedia dysfunction (PPID) is a spontaneously occurring progressive disease affecting aged horses and ponies. The pathogenesis of PPID is poorly understood, but the available evidence supports a loss of dopaminergic inhibition of the melanotropes of the pars intermedia. Horses with PPID have increased plasma concentrations of pars intermedia pro-opiomelanocortin-derived peptides that decrease in response to dopamine or dopamine agonist administration. Dopamine and dopamine metabolite concentrations are decreased in the pars intermedia of affected horses compared to age-matched control horses. Horses with disease that are treated with the dopamine agonist pergolide show improvement in clinical signs and normalisation of diagnostic test results. In the present study, immunohistochemical evaluation of pituitary and hypothalamic tissue demonstrated reduced tyrosine hydroxylase immunoreactivity in affected horses compared to age-matched and young controls, supporting the role of dopaminergic neurodegeneration in PPID. In addition, immunohistochemical evaluation revealed an increase in the oxidative stress marker, 3-nitrotyrosine and in nerve terminal protein, alpha-synuclein that colocalised in the pars intermedia of horses with disease. These findings suggest a role for nitration of overexpressed alpha-synuclein in the pathogenesis of neurodegeneration in PPID.

Febrile and plasma iron responses of rabbits injected with endogenous pyrogen from malnourished patients.

The ability of human endogenous pyrogen (EP) harvested from malnourished patients (marasmic or kwashiorkor-like) to induce fever and a simultaneous hypoferremia in rabbits is described. Human peripheral blood leukocytes were obtained from malnourished adult patients before total parenteral nutrition support, and after 1 and 7 days on this therapeutic regime; the leukocytes were stimulated to produce EP in vitro and EP was injected into each rabbit. EP obtained from the leukocytes of patients with predominant protein deprivation syndromes (kwashiorkor) before nutritional support produced an attenuated fever (0.23 degrees C over 4 h) and a relatively unchanged plasma iron concentration (delta Fe = -15 microgram/100 ml over 4 h) in the rabbits. When EP was harvested from these same patients after 7 days of nutritional support therapy and was injected into rabbits, normal 4 h fevers (1.10 degrees C) and reduction in plasma iron levels (delta Fe = -97 micrograms/100 ml) occurred in the rabbits. Human EP obtained from patients with marasmus (predominant calorie deprivation syndromes) produced relatively normal fevers and changes in plasma iron levels in the rabbits, regardless of whether the samples were taken pre-total parenteral nutrition or after 1 and 7 days of total parenteral nutrition. These observations suggest that the synthesis of endogenous pyrogen by human peripheral leukocytes is sensitive to the availability of key substrates and that nutritional support therapy restores the capacity of these cells to produce EP in vitro.

The multicellular spheroid as a model tumor allograft. II. Characterization of spheroid-infiltrating cytotoxic cells.

Alloimmune lymphoid cells infiltrating multicellular spheroids of EMT6 mammary sarcoma cells (a solid tumor allograft model) have been characterized according to their morphological and functional properties. Both lymphocytes and macrophages were found within spheroids at the time of peak tumor cell damage. Cytotoxic cells specific for allograft antigens were also present. Using a short-term 51-Cr release assay, the cells responsible for cytotoxicity were characterized as a nonadherent, nonphagocytic T cell population. Velocity sedimentation cell separation further demonstrated that these cytotoxic cells had the physical properties of small lymphocytes. Some evidence for selective spheroid infiltration by specifically alloimmune cells was also obtained. The possible relationship of this cellular infiltrate to graft damage is discussed.

The role of the reference radiologist. Estimates of inter-observer agreement and potential delay in cancer detection in the national breast screening study.

The Canadian National Breast Screening Study (NBSS) is a randomized controlled trial to assess the effect of screening on breast cancer mortality. The NBSS designated a single reference radiologist who blindly reviewed over the course of the study 5200 randomly selected two-view mammographic examinations of women not known to have breast cancer. He also reviewed 575 screening-detected breast cancer (SBC) cases and 102 interval breast cancer (IBC) cases. All cancers were histologically proven. As a result of the reviews, comments on inter-observer agreement, interpretation, and technical quality were conveyed on an ongoing basis to radiologists appointed to 15 NBSS screening centers. Agreement of the reference radiologist with center radiologists was better for breast cancer cases (kappa = 0.511, P less than .002) than for those not known to have breast cancer (kappa = 0.307, P less than .002). Observer error and technical problems led to delayed detection in 22% of SBCs and 35% of IBCs. Another 11% of SBCs and 58% of IBCs were probably mammographically occult. No similarly comprehensive review of mammography during a screening program has been published. Suggestions arising from the NBSS review were sometimes resisted by center radiologists. Measures are suggested which might facilitate acceptance of recommendations arising from audit mechanisms in mammography screening programs, thereby enhancing opportunities for mammographic excellence.

Resurrection of the amputations of Lisfranc and Chopart for diabetic gangrene.

When a patient with neuropathic diabetic gangrene of the foot has sepsis, it is not always necessary to do a below-knee guillotine amputation or a Syme's amputation. In more than six years we have done 18 successful open Lisfranc's and Chopart's amputations. Improved ambulation has been achieved in three months using simple shoe prostheses. All flaps are fashioned immediately and never sutured. No equinus deformities have developed.

Fluoride supplementation status, fractures and osteopenia in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) experience fractures on the basis of osteopenia related to chemotherapy administered for the maintenance of remission. It is likely that corticosteroids are the main cause of bone mineral loss in this circumstance. Because fluoride has been used as a therapeutic intervention in osteoporosis, including that induced by corticosteroid therapy, we explored the prospect that children with ALL who received fluoride supplementation (in drinking water or from other sources) may be relatively protected from iatrogenic skeletal morbidity. Children who completed therapy according to the Dana Farber Cancer Institute protocol 87-01 (n=35) were assessed by skeletal radiology and bone densitometry every 6 months from diagnosis. In addition, their families completed a questionnaire relating to fluoride supplementation. There was no correlation between such fluoride supplementation and either the prevalence of fractures or the severity of osteopenia. This outcome may reflect the mainly appendicular location of the fractures in this group of children. These findings, together with a consideration of the risk benefit ratio of fluoride administration to children at large, suggest that such intervention is unlikely to be beneficial in limiting skeletal morbidity during the treatment of ALL in childhood.

Spatial frequency tuning of orientation selective units estimated by oblique masking.

Threshold elevations were measured as a function of the spatial frequency of high contrast cosine masks using spatially localized test stimuli with a 1.0 octave bandwidth. The cosine masks were oriented at 14.5 degrees relative to the vertical test patterns in order to average out spatial phase effects. The experiment was repeated for each of 14 test frequencies spanning the range 0.25-22.0 c/deg in 0.5 octave steps. The resulting threshold elevation curves fell into a small number of distinct groups, suggesting the existence of discrete spatial frequency mechanisms in human central vision. The data are shown to be consistent with a model having just six distinct classes of spatial frequency mechanisms in the fovea. Spatial frequency bandwidths of these mechanisms ranged from 2.5 octaves at low frequencies to as narrow as 1.25 octaves at high spatial frequencies. These results require revision of the Wilson and Bergen (1979) [Vision Res. 19, 19-32] model for spatial vision.

Differences in mortality between patients attending the emergency room services for asthma and chronic obstructive pulmonary disease.

Asthma has a more favourable prognosis than chronic obstructive pulmonary disease (COPD), based on studies including few asthmatics and few women with COPD. We assessed differences in mortality between people attending the emergency room for asthma and for COPD in a population-based cohort. We recruited all the men and women, who were residents of Barcelona (Spain) over 14 years of age, who attended emergency room services for an obstructive lung disease during the period 1985-1989. Vital status was followed up to the end of 1995. A total of 15,517 individuals (including 4555 asthmatics and 2194 females with COPD) were studied. Mortality was ascertained using a record linkage with the regional Mortality Registry. Overall, 43.6% people died during the follow-up period. Mortality was higher among individuals with COPD than with asthma, in males and females, for all causes of death, as well as for cancer, cardiovascular and respiratory causes. After adjusting for age, the relative risk (RR) of dying of a male attending for COPD and discharged home was 1.50 (1.29-1.74) in comparison with a male attending for asthma, and 3.06 (2.66-3.51) for a male attending for COPD and admitted into the hospital. Similar figures were found for females. The increased risk for patients with COPD was significantly higher than for asthma in all age groups. Both males and females with asthma have a more favourable prognosis than patients with COPD, for all age groups.