CC16 polymorphisms in asthma, asthma subtypes, and asthma control in adults from the Agricultural Lung Health Study.

BACKGROUND: The club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects and is a potential early biomarker of lung damage. The CC16 single nucleotide polymorphism (SNP) rs3741240 risk allele (A) has been inconsistently linked to asthma; other tagging SNPs in the gene have not been explored. The aim was to determine whether CC16 tagging polymorphisms are associated with adult asthma, asthma subtypes or asthma control in the Agricultural Lung Health Study (ALHS). METHODS: The ALHS is an asthma case-control study nested in the Agricultural Health Study cohort. Asthma cases were individuals with current doctor diagnosed asthma, likely undiagnosed asthma, or asthma-COPD overlap defined by questionnaire. We also examined asthma subtypes and asthma control. Five CC16 tagging SNPs were imputed to 1000 Genomes Integrated phase 1 reference panel. Logistic regression was used to estimate associations between CC16 SNPs and asthma outcomes adjusted for covariates. RESULTS: The sample included 1120 asthma cases and 1926 controls of European ancestry, with a mean age of 63 years. The frequency of the risk genotype (AA) for rs3741240 was 12.5% (n = 382). CC16 rs3741240 was not associated with adult asthma outcomes. A tagging SNP in the CC16 gene, rs12270961 was associated with uncontrolled asthma (n = 208, ORadj= 1.4, 95% CI 1.0, 1.9; p = 0.03). CONCLUSION: This study, the largest study to investigate associations between CC16 tagging SNPs and asthma phenotypes in adults, did not confirm an association of rs3741240 with adult asthma. A tagging SNP in CC16 suggests a potential relationship with asthma control.

Pesticide use and risk of systemic autoimmune diseases in the Agricultural Health Study.

BACKGROUND: Systemic lupus erythematosus (SLE) risk has been associated with pesticide use, but evidence on specific pesticides or other agricultural exposures is lacking. We investigated history of pesticide use and risk of SLE and a related disease, Sjögren's syndrome (SS), in the Agricultural Health Study. METHODS: The study sample (N = 54,419, 52% male, enrolled in 1993-1997) included licensed pesticide applicators from North Carolina and Iowa and spouses who completed any of the follow-up questionnaires (1999-2003, 2005-2010, 2013-2015). Self-reported cases were confirmed by medical records or medication use (total: 107 incident SLE or SS, 79% female). We examined ever use of 31 pesticides and farm tasks and exposures reported at enrollment in association with SLE/SS, using Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), with age as the timescale and adjusting for gender, state, and correlated pesticides. RESULTS: In older participants (>62 years), SLE/SS was associated with ever use of the herbicide metribuzin (HR 5.33; 95%CI 2.19, 12.96) and applying pesticides 20+ days per year (2.97; 1.20, 7.33). Inverse associations were seen for petroleum oil/distillates (0.39; 0.18, 0.87) and the insecticide carbaryl (0.56; 0.36, 0.87). SLE/SS was inversely associated with having a childhood farm residence (0.59; 0.39, 0.91), but was not associated with other farm tasks/exposures (except welding, HR 2.65; 95%CI 0.96, 7.35). CONCLUSIONS: These findings suggest that some agricultural pesticides may be associated with higher or lower risk of SLE/SS. However, the overall risk associated with farming appears complex, involving other factors and childhood exposures.

Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies.

BACKGROUND: Body mass index (BMI), a measure of obesity typically assessed in middle age or later, is known to be positively associated with pancreatic cancer. However, little evidence exists regarding the influence of central adiposity, a high BMI during early adulthood, and weight gain after early adulthood on pancreatic cancer risk. DESIGN: We conducted a pooled analysis of individual-level data from 20 prospective cohort studies in the National Cancer Institute BMI and Mortality Cohort Consortium to examine the association of pancreatic cancer mortality with measures of central adiposity (e.g. waist circumference; n = 647 478; 1947 pancreatic cancer deaths), BMI during early adulthood (ages 18-21 years) and BMI change between early adulthood and cohort enrollment, mostly in middle age or later (n = 1 096 492; 3223 pancreatic cancer deaths). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. RESULTS: Higher waist-to-hip ratio (HR = 1.09, 95% CI 1.02-1.17 per 0.1 increment) and waist circumference (HR = 1.07, 95% CI 1.00-1.14 per 10 cm) were associated with increased risk of pancreatic cancer mortality, even when adjusted for BMI at baseline. BMI during early adulthood was associated with increased pancreatic cancer mortality (HR = 1.18, 95% CI 1.11-1.25 per 5 kg/m(2)), with increased risk observed in both overweight and obese individuals (compared with BMI of 21.0 to <23 kg/m(2), HR = 1.36, 95% CI 1.20-1.55 for BMI 25.0 < 27.5 kg/m(2), HR = 1.48, 95% CI 1.20-1.84 for BMI 27.5 to <30 kg/m(2), HR = 1.43, 95% CI 1.11-1.85 for BMI ≥30 kg/m(2)). BMI gain after early adulthood, adjusted for early adult BMI, was less strongly associated with pancreatic cancer mortality (HR = 1.05, 95% CI 1.01-1.10 per 5 kg/m(2)). CONCLUSIONS: Our results support an association between pancreatic cancer mortality and central obesity, independent of BMI, and also suggest that being overweight or obese during early adulthood may be important in influencing pancreatic cancer mortality risk later in life.

Investing in prospective cohorts for etiologic study of occupational exposures.

Prospective cohorts have played a major role in understanding the contribution of diet, physical activity, medical conditions, and genes to the development of many diseases, but have not been widely used for occupational exposures. Studies in agriculture are an exception. We draw upon our experience using this design to study agricultural workers to identify conditions that might foster use of prospective cohorts to study other occupational settings. Prospective cohort studies are perceived by many as the strongest epidemiologic design. It allows updating of information on exposure and other factors, collection of biologic samples before disease diagnosis for biomarker studies, assessment of effect modification by genes, lifestyle, and other occupational exposures, and evaluation of a wide range of health outcomes. Increased use of prospective cohorts would be beneficial in identifying hazardous exposures in the workplace. Occupational epidemiologists should seek opportunities to initiate prospective cohorts to investigate high priority, occupational exposures.

Risk of breast cancer according to clinicopathologic features among long-term survivors of Hodgkin's lymphoma treated with radiotherapy.

BACKGROUND: It is unknown whether breast cancer (BC) characteristics among young women treated with radiotherapy (RT) for Hodgkin's lymphoma (HL) differ from sporadic BC. METHODS: Using population-based data, we calculated BC risk following HL according to clinicopathologic features. RESULTS: Compared with BC in the general population, risks of oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive and ER-negative/PR-negative BC in young, irradiated HL survivors were increased five-fold (95% confidence interval (CI)=3.81-6.35) and nine-fold (95% CI=6.93-12.25), respectively. Among 15-year survivors, relative risk of ER-negative/PR-negative BC exceeded by two-fold (P=0.002) than that of ER-positive/PR-positive BC. CONCLUSION: Radiotherapy may disproportionately contribute to the development of BC with adverse prognostic features among young HL survivors.

Computed tomographic, magnetic resonance imaging, and cross-sectional anatomic features of the manus in a normal American black bear (Ursus americanus).

The purpose of this study was to provide a detailed description of cross-sectional anatomic structures of the manus of a black bear cadaver and correlate anatomic findings with corresponding features in computed tomographic (CT) and magnetic resonance (MR) images. CT, MR imaging, and transverse sectioning were performed on the thoracic limb of a cadaver female black bear which had no evidence of lameness or thoracic limb abnormality prior to death. Features in CT and MR images corresponding to clinically important anatomic structures in anatomic sections were identified. Most of the structures identified in transverse anatomic sections were also identified using CT and MR imaging. Bones, muscles and tendons were generally easily identified with both imaging modalities, although divisions between adjacent muscles were rarely visible with CT and only visible sometimes with MR imaging. Vascular structures could not be identified with either imaging modality.

Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study.

Although specific pesticides have been associated with wheeze in farmers, little is known about pesticides and asthma. Data from 19,704 male farmers in the Agricultural Health Study were used to evaluate lifetime use of 48 pesticides and prevalent adult-onset asthma, defined as doctor-diagnosed asthma after the age of 20 yrs. Asthma cases were categorised as allergic (n = 127) and nonallergic (n = 314) based on their history of eczema or hay fever. Polytomous logistic regression, controlling for age, state, smoking and body mass, was used to assess pesticide associations. High pesticide exposure events were associated with a doubling of both allergic and nonallergic asthma. For ever-use, 12 individual pesticides were associated with allergic asthma and four with nonallergic asthma. For allergic asthma, coumaphos (OR 2.34; 95% CI 1.49-3.70), heptachlor (OR 2.01; 95% CI 1.30-3.11), parathion (OR 2.05; 95% CI 1.21-3.46), 80/20 mix (carbon tetrachloride/carbon disulfide) (OR 2.15; 95% CI 1.23-3.76) and ethylene dibromide (OR 2.07; 95% CI 1.02-4.20) all showed ORs of >2.0 and significant exposure-response trends. For nonallergic asthma, DDT (dichlorodiphenyltrichloroethane) showed the strongest association (OR 1.41; 95% CI 1.09-1.84), but with little evidence of increasing asthma with increasing use. Current animal handling and farm activities did not confound these results. There was little evidence that allergy alone was driving these associations. In conclusion, pesticides may be an overlooked contributor to asthma risk among farmers.

Angiogenesis in the caprine caruncles in non-pregnant and pregnant normal and swainsonine-treated does.

Microvascular corrosion casts of caruncles from non-pregnant and pregnant doe goats at 4, 7, 10, 13, 16, and 18 weeks were examined with scanning electron microscopy. The internal convex surface of the caruncles of non-pregnant does was covered with capillary meshes of regular diameter and form, without crypts. As pregnancy advanced the complexity of the vasculature increased: at 4 weeks the surface showed a pattern of ridges separated by troughs. At later stages, branches of radial arteries penetrated the periphery forming an extensive mesh of capillaries on the concave surface. Capillary diameters increased significantly during pregnancy, especially after 4 weeks, when large flattened sinusoids formed. These sinusoids had a great deal of surface area for potential contact with the fetal component. The caprine placenta is usually considered to have increased interhemal distance compared with endotheliochorial and hemochorial types: our results suggest that the very extensive development of sinusoids and crypts may compensate for any negative consequences of the placental architecture. Placental angiogenesis, which is physiologically normal, may serve as a general model of this process in other circumstances, such as tumor. The effect of swainsonine (active compound of locoweed and a potential anticancer drug) on vascular development showed no differences in sinusoidal diameters at 7 weeks, but a decrease in capillary density was noted. Swainsonine caused a great distortion to the vasculature at 18 weeks. The effects of this compound on the vascular development lend credibility to its potential as an anticancer agent.

Cocaine or selective block of dopamine transporters influences multisecond oscillations in firing rate in the globus pallidus.

Previous studies have shown that direct-acting dopamine agonists modulate the multisecond oscillations which are present in globus pallidus spike trains in vivo in awake rats. To investigate possible modulation by endogenous dopamine and by other monoamines, and by drugs with abuse potential, cocaine or selective monoamine uptake blockers were injected systemically during extracellular recording of single globus pallidus neurons and the results analyzed with spectral and wavelet methods. Both cocaine and the selective dopamine uptake blocker GBR-12909 significantly shortened the period of multisecond oscillations, as well as increasing overall firing rate. Cocaine effects were blocked by dopamine antagonist pretreatment, as well as by N-methyl-D-aspartate receptor antagonist (MK-801) pretreatment. Desipramine and fluoxetine (blockers of norepinephrine and serotonin uptake, respectively) had no significant effects on multisecond oscillations. The results suggest that dopamine has a primary role among monoamines in modulating multisecond oscillations in globus pallidus activity, and that tonic dopaminergic and glutamatergic transmission is necessary for normal slow oscillatory function.

Drugs used in the treatment of attention-deficit/hyperactivity disorder affect postsynaptic firing rate and oscillation without preferential dopamine autoreceptor action.

BACKGROUND: Current theories propose that low doses of catecholaminergic stimulants reduce symptoms in patients with attention-deficit/hyperactivity disorder by acting on autoreceptors to reduce catecholaminergic transmission; few data are available that directly address this hypothesis. METHODS: We investigated the autoreceptor and postsynaptic receptor actions of systemically administered stimulants on dopaminergic systems in rats with single-unit recording in the substantia nigra pars compacta and globus pallidus, respectively. RESULTS: Dose-response curves for rate indicated that the potencies of the indirect-acting agonists methylphenidate and D-amphetamine at dopaminergic autoreceptors were not greater than at postsynaptic receptors; in fact, D-amphetamine was more potent postsynaptically. In addition to effects on firing rate, spectral/wavelet analyses indicated that these drugs had prominent effects on postsynaptic multisecond oscillations. These oscillations were shifted by stimulants from baseline periods of approximately 30 sec to periods of 5-10 sec. Effects on pattern were found at doses as low as 1.0 mg/kg (methylphenidate) and 0.2 mg/kg (D-amphetamine). At this latter dose, D-amphetamine had little effect presynaptically. CONCLUSIONS: These and prior results demonstrate that there is no autoreceptor-preferring dose range of catecholaminergic stimulants; these drugs at low doses are unlikely to reduce motor activity by this mechanism. Nonetheless, they might affect attentive and cognitive processes by modulating multisecond temporal patterns of central activity.

Alterations in equine guttural pouch morphology with head position: observations using a new technique for producing accurate casts.

BACKGROUND: An improved technique for preparing casts of the equine guttural pouch is described. The new technique is simplified and inexpensive in comparison to previous techniques and produces highly accurate anatomic models which are both durable and flexible. METHODS: Silicone rubber bathtub caulk was injected into the guttural pouches of horse cadavers. The silicone was allowed to cure overnight, and casts were removed by dissection. The new technique was then used to evaluate changes in the shape of the guttural pouch with changes in head position. RESULTS: With flexion of the atlanto-occipital joint, the lateral compartment of the guttural pouch in particular was found to change considerably in size in shape. The angle of inclination of the ventral border of this pouch increased with flexion, as did the depth of the impression made by the rostral portion of the stylohyoid bone. In addition, the lateral compartment diminished in thickness rostrally in casts from flexed animals. CONCLUSIONS: The viscous silicone caulk resulted in superior casts of the equine guttural pouch. Observations of changed pouch shape with head position agree well with previous reports of increased difficulty in draining the lateral compartment of the horse's guttural pouch when the head is held in the flexed position.

Axial pattern flap based on the caudal auricular artery in dogs.

An axial pattern flap that was based on the sternocleidomastoideus branches of the caudal auricular artery and vein was developed. Control flaps, which included ligation and division of the caudal auricular artery and vein, were similarly developed on the contralateral aspect of the neck. Mean survival of caudal auricular artery axial pattern flaps (85.2%), compared with control flaps (63.9%), was significantly different (P less than 0.05). On the basis of results of this study, an axial pattern flap based on the sternocleidomastoideus branches of the caudal auricular artery and vein may be a source of skin for reconstructive procedures of the head and neck.

Observations about the normal and abnormal embryogenesis of the canine lip and palate.

Twenty-three puppies with cranofacial and limb abnormalities from a family of Australian shepherd dogs were studied anatomically. Limb abnormalities included lumbar scoliosis, short malformed tibias and fibulas, and polydactyly. Craniofacial abnormalities consisted of retronathia, cleft palate, and cleft lip. The clefts can be separated into three categories: group I, cleft of the secondary palate associated with a midline cleft lip; group II, unilateral cleft of the lip and primary and secondary palate; and group III, complete bilateral cleft of the lip and primary and secondary palate. Comparing human clefts with the canine clefts suggests that the development of the secondary palate is similar whereas the development of the upper lip is different. In the dog, the maxillary processes fuse in the midline to produce the majority of the upper lip, whereas in the human the upper lip is composed of fused maxillary and medial nasal processes.

Lymph drainage of the conjunctiva: topographic anatomic study in calves.

The topographic pattern of lymph drainage from the conjuctiva was ascertained in 1- to 2-week-old calves. Multiple, small lymph vessels within and on the surface of the orbicularis oculi muscle converged to form fewer vessels which followed the course of the superficial temporal artery and vein or crossed the zygomatic arch in a more rostral position to reach the primary site of lymph collection, the parotid lymph node. Marker dye, injected into the subconjunctiva, was collected in the midrostral and rostroventral parts of the node. Drainage from the parotid node passed via multiple lymph vessels into the lateral retropharyngeal node, where marker dye concentrated in the rostrodorsal aspect of the node. Single or multiple lymph vessels carried drainage from the lateral retropharyngeal node indirectly by way of the cranial deep cervical lymph node or directly into the tracheal lymph trunk.

Ectopia cordis thoracoabdominalis in a piglet.

A congenital anomaly characterised by displacement of the heart through a ventral body wall fissure involving the thoracic and cranial abdominal regions was recorded in a female Yorkshire-cross piglet. Dissection to assess the morphology of the developmental defect and a summary review of the literature on ectopia cordis were made. This case appears to be one of only three of ectopia cordis thoracoabdominalis reported in swine.