Physical limits of flight performance in the heaviest soaring bird.

Flight costs are predicted to vary with environmental conditions, and this should ultimately determine the movement capacity and distributions of large soaring birds. Despite this, little is known about how flight effort varies with environmental parameters. We deployed bio-logging devices on the world's heaviest soaring bird, the Andean condor (Vultur gryphus), to assess the extent to which these birds can operate without resorting to powered flight. Our records of individual wingbeats in >216 h of flight show that condors can sustain soaring across a wide range of wind and thermal conditions, flapping for only 1% of their flight time. This is among the very lowest estimated movement costs in vertebrates. One bird even flew for >5 h without flapping, covering ∼172 km. Overall, > 75% of flapping flight was associated with takeoffs. Movement between weak thermal updrafts at the start of the day also imposed a metabolic cost, with birds flapping toward the end of glides to reach ephemeral thermal updrafts. Nonetheless, the investment required was still remarkably low, and even in winter conditions with weak thermals, condors are only predicted to flap for ∼2 s per kilometer. Therefore, the overall flight effort in the largest soaring birds appears to be constrained by the requirements for takeoff.

Collisions between Ultracold Molecules and Atoms in a Magnetic Trap.

We prepare mixtures of ultracold CaF molecules and Rb atoms in a magnetic trap and study their inelastic collisions. When the atoms are prepared in the spin-stretched state and the molecules in the spin-stretched component of the first rotationally excited state, they collide inelastically with a rate coefficient k_{2}=(6.6±1.5)×10^{-11} cm^{3}/s at temperatures near 100 µK. We attribute this to rotation-changing collisions. When the molecules are in the ground rotational state we see no inelastic loss and set an upper bound on the spin-relaxation rate coefficient of k_{2}<5.8×10^{-12} cm^{3}/s with 95% confidence. We compare these measurements to the results of a single-channel loss model based on quantum defect theory. The comparison suggests a short-range loss parameter close to unity for rotationally excited molecules, but below 0.04 for molecules in the rotational ground state.

Long Rotational Coherence Times of Molecules in a Magnetic Trap.

Polar molecules in superpositions of rotational states exhibit long-range dipolar interactions, but maintaining their coherence in a trapped sample is a challenge. We present calculations that show many laser-coolable molecules have convenient rotational transitions that are exceptionally insensitive to magnetic fields. We verify this experimentally for CaF where we find a transition with sensitivity below 5 Hz G^{-1} and use it to demonstrate a rotational coherence time of 6.4(8) ms in a magnetic trap. Simulations suggest it is feasible to extend this to more than 1 s using a smaller cloud in a biased magnetic trap.

Deep Laser Cooling and Efficient Magnetic Compression of Molecules.

We introduce a scheme for deep laser cooling of molecules based on robust dark states at zero velocity. By simulating this scheme, we show it to be a widely applicable method that can reach the recoil limit or below. We demonstrate and characterize the method experimentally, reaching a temperature of 5.4(7) µK. We solve a general problem of measuring low temperatures for large clouds by rotating the phase-space distribution and then directly imaging the complete velocity distribution. Using the same phase-space rotation method, we rapidly compress the cloud. Applying the cooling method a second time, we compress both the position and velocity distributions.

Magnetic Trapping and Coherent Control of Laser-Cooled Molecules.

We demonstrate coherent microwave control of the rotational, hyperfine, and Zeeman states of ultracold CaF molecules, and the magnetic trapping of these molecules in a single, selectable quantum state. We trap about 5×10^{3} molecules for almost 2 s at a temperature of 70(8) µK and a density of 1.2×10^{5} cm^{-3}. We measure the state-specific loss rate due to collisions with background helium.

Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder.

A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.

Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha.

We earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned ~432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3' untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N=1755, control N=3580 and parents of probands N=1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P=0.078 and odd ratio (OR)=1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N=710) and schizoaffective disorder (N=50) (psychosis sample: 1421 cases, 2824 controls, P=0.037 and OR=1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P=0.008 and OR=3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P=0.008 and OR=3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P=0.304 and OR=1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P=0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped across the linkage region (rs873417, allelic P=0.0004). Follow-up genotyping in samples from Ireland, Bulgaria and Germany did not show consistent replication, but meta-analysis of all samples (4116 cases and 6491 controls) remained nominally significant (meta-analysis P=0.026, OR=1.1). We conclude that, although we have obtained convergent lines of evidence implicating both rare and common schizophrenia risk variants at PRKCA, none of these is individually compelling. However, the evidence across all approaches suggests that further study of this locus is warranted.

Mutation screening of the 3q29 microdeletion syndrome candidate genes DLG1 and PAK2 in schizophrenia.

Deletion of chromosome 3q29, which is associated with mental retardation and autism, was recently identified as being present in excess or occurring de novo in schizophrenia cases, being present in approximately 1/1,000 cases and 1/40,000 unscreened controls. Of the ∼20 genes in the commonly deleted region two are prominent candidates for involvement in the behavioral features of the microdeletion syndrome: DLG1 and PAK2. We report the result of mutation screening of the entire protein coding sequence of both genes in a sample of 234 unrelated cases and 272 unrelated controls from the UK. We find no evidence for any amino acid changing genetic variants in PAK2. We observe several rare and singleton non-synonymous genetic variations at DLG1, however there is no excess of these variants in cases when compared to controls. Our sample was underpowered to detect very rare or low-penetrance disease relevant alleles in the studied genes. Therefore very rare, low-to-moderate penetrance protein coding mutations or non-coding mutations at DLG1 and/or PAK2, or a nearby gene, may reproduce the behavioral characteristics of the 3q29 microdeletion.

Future trends in measuring physiology in free-living animals.

Thus far, ecophysiology research has predominantly been conducted within controlled laboratory-based environments, owing to a mismatch between the recording technologies available for physiological monitoring in wild animals and the suite of behaviours and environments they need to withstand, without unduly affecting subjects. While it is possible to record some physiological variables for free-living animals using animal-attached logging devices, including inertial-measurement, heart-rate and temperature loggers, the field is still in its infancy. In this opinion piece, we review the most important future research directions for advancing the field of 'physiologging' in wild animals, including the technological development that we anticipate will be required, and the fiscal and ethical challenges that must be overcome. Non-invasive, multi-sensor miniature devices are ubiquitous in the world of human health and fitness monitoring, creating invaluable opportunities for animal and human physiologging to drive synergistic advances. We argue that by capitalizing on the research efforts and advancements made in the development of human wearables, it will be possible to design the non-invasive loggers needed by ecophysiologists to collect accurate physiological data from free-ranging animals ethically and with an absolute minimum of impact. In turn, findings have the capacity to foster transformative advances in human health monitoring. Thus, we invite biomedical engineers and researchers to collaborate with the animal-tagging community to drive forward the advancements necessary to realize the full potential of both fields. This article is part of the theme issue 'Measuring physiology in free-living animals (Part II)'.

Clinical, ultrasonographic and pathological findings in a bull with segmental aplasia of the mesonephric duct.

On assessment for use in an AI stud, a 12-month-old bull was found to produce low volume ejaculates with 41% of the sperm having morphological abnormalities. No left epididymal tail was palpable and the head of the epididymis on the left was twice the size compared with the right. Ultrasound examination showed the left testis to contain a large central area of decreased echogenicity, which could be followed proximally to a 15-mm echolucent lesion at the site of the epididymal head. Postmortem examination revealed a 15-mm diameter cyst in the region of the left epididymal head, and absence of the body and tail of the epididymis. The mediastinum testis of the left testis was dilated, corresponding to the area of decreased echogenicity observed on ultrasonography. No left seminal vesicle was present and the ampulla was significantly smaller than the same structure on the right. Histological examination revealed incomplete or absent spermatogenesis involving the majority of seminiferous tubules in the left testis, and a small proportion of those of the right testis. The cystic structure at the site of the left epididymal head was lined by irregular, sometimes attenuated, epithelium and contained sparse spermatozoa. This case demonstrates the adverse impact, which segmental aplasia of the mesonephric duct had on the testicular and epididymal function of a bull, and highlights the importance of careful clinical assessment in its diagnosis.

Historical and current perspectives on the treatment, control and pathogenesis of milk fever in dairy cattle.

Milk fever has been recognised in cattle for about 215 years and its clinical signs have not changed since they were described by Victorian veterinary surgeons in the mid-nineteenth century. It was only 80 years ago that abnormal parathyroid gland function was associated with the pathogenesis of the hypocalcaemia characteristic of the disease, and the current basis for its treatment with intravenous calcium salts was established. Although this treatment is effective, most recent research has focused on preventing the disease through an understanding of the endocrine control of extracellular calcium homeostasis. In the 1970s the synthetic vitamin D analogue 1alpha-hydroxycholecalciferol was developed for intramuscular injection before a cow calved, but variable results encouraged other preventive strategies to be considered, including restricting the dietary intake of calcium, and manipulating the dietary cation-anion balance of cows before they calved. Currently, the role of extracellular calcium receptors in the parathyroid gland is under investigation as a preliminary step to devising more effective treatments and/or preventive methods for milk fever.

The investigation and management of back pain in children.

Back pain in children and adolescents is probably much less common than in adults, but its true incidence is unknown. Although back pain has traditionally been considered a rare and often sinister presentation in the paediatric age group, recent literature now suggests that a relatively high number of children do experience back pain, but only a small proportion seek medical attention. For the majority of children with back pain no underlying cause is identified, but some require investigation to exclude serious underlying pathology. Laboratory and imaging investigations should be targeted towards those with "red flag" symptoms and signs. Imaging studies, particularly MRI, have an important role in diagnosis of underlying pathology such as infection or malignancy.

Association analysis of the glial cell line-derived neurotrophic factor (GDNF) gene in schizophrenia.

The glial cell line-derived neurotrophic factor (GDNF) gene is located within a region of chromosome 5 (5p14.1-q13.3) that has been highlighted as a potential schizophrenia susceptibility locus by a number of genome scans. GDNF is neurotrophic and is also thought to be involved in differentiation of dopaminergic neurones. The GDNF gene is, therefore, a positional and functional candidate gene for schizophrenia. It is of additional interest because altered GDNF mRNA and protein expression has been reported in response to antipsychotics and the psychotomimetic phencyclidine, and two previous studies, focussed on a single variant, have reported weak support for genetic association between GDNF and schizophrenia in small samples. To test the hypothesis that GDNF is a susceptibility gene for schizophrenia, we performed a detailed association study. We chose 9 SNPs that spanned a genomic region of 40 kb and fully encompassed GDNF. SNPs were genotyped in a sample of 673 schizophrenic patients and 716 matched controls, all of Caucasian origin and all collected from the UK or Ireland. Of the 9 SNPs genotyped 2 showed nominally significant genotypic association at the P< or =0.05 level (rs2973050; OR=1.11; P-value=0.007 and rs2910702; OR=1.14; P-value=0.039). Permutation testing to allow for multiple comparisons of non-independent markers gave a corrected genotypic P-value of 0.052 for rs2973050. We also genotyped an (AGG)(n) repeat located in the 3' UTR of the GDNF but this showed no evidence for association. We conclude that our sample does not provide independent statistically significant evidence for association between GDNF and schizophrenia, nor does it replicate previous specific reports of association.

Spinal cord compression by tophaceous gout with fluorodeoxyglucose-positron-emission tomographic/MR fusion imaging.

A 36-year-old woman presented with lower extremity paralysis. Her past medical history included gout. Conventional radiography and MR imaging revealed bone erosion and soft tissue lesions of the thoracic spine. Fluorodeoxyglucose-positron-emission tomographic (FDG-PET) images revealed hypermetabolic lesions of the thoracic spine. A CT-guided biopsy was diagnostic for inflammatory tophaceous gout. This case describes the CT, MR, and FDG-PET imaging characteristics of acute inflammatory gout. FDG-PET imaging characteristics of this disorder have not been previously described.

Whole-flock, metaphylactic tilmicosin failed to eliminate contagious ovine digital dermatitis and footrot in sheep: a cluster randomised trial.

The aim of this study was to evaluate the clinical success of whole-flock systemic tilmicosin and enhanced biosecurity in eliminating active contagious ovine digital dermatitis (CODD) from sheep flocks. Thirty flocks in the UK were randomly allocated to receive either treatment as usual (as per the farmer's normal routine) or whole-flock treatment with tilmicosin, together with isolation and extended treatment of clinically affected individuals and isolation and treatment of purchased sheep during the study period. All flocks were visited once at onset of the trial to examine all sheep. One year later, all sheep were re-examined to determine the presence/absence of clinical lesions. The primary outcome was the clinical elimination of CODD from flocks. Secondary outcomes were reduction in prevalence of CODD, clinical elimination of footrot and reduction in prevalence of footrot. The analysis included 11 control flocks and 13 intervention flocks, with initially 3460 and 4686 sheep, respectively. For CODD: at follow-up, in the intervention group, 6/13 (46 per cent) flocks had a prevalence of zero compared with 1/11 (9 per cent) in the control group (P=0.12). For footrot: at follow-up, no flocks had a prevalence of zero. Therefore, the intervention is not recommended for the elimination of CODD or footrot in the UK.

Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain.

OBJECTIVES: The purpose of this investigation was to evaluate the practicality and short-term predictive value of acute myocardial perfusion imaging with technetium-99m sestamibi in emergency room patients with typical angina and a normal or nondiagnostic electrocardiogram (ECG). BACKGROUND: Accuracy of emergency room chest pain assessment may be improved when clinical and ECG variables are used in conjunction with acute thallium-201 myocardial perfusion imaging. Technetium-99m sestamibi is a new radioisotope that is taken up by the myocardium in proportion to blood flow, but unlike thallium-201, it redistributes minimally after injection. Technetium-99m sestamibi can thus be injected during chest pain, and images acquired 1 to 2 h later (when patients have been clinically stabilized) will confirm whether abnormalities of perfusion were present at the time of injection. METHODS: One hundred two emergency room patients with typical angina (on the basis of a standardized angina questionnaire) and a normal or nondiagnostic ECG had a technetium-99m sestamibi injection during symptoms and were followed up for occurrence of adverse cardiac events (cardiac death, nonfatal myocardial infarction, coronary angioplasty, coronary surgery or coronary thrombolysis). RESULTS: Univariate predictors of cardiac events included the presence of three or more coronary risk factors (p = 0.009, risk ratio 3.3) and an abnormal or equivocal acute technetium-99m sestamibi scan (p = 0.0001, risk ratio 13.9). Multivariate regression analysis identified an abnormal perfusion image as the only independent predictor of adverse cardiac events (p = 0.009). Of 70 patients with a normal perfusion scan, only 1 had a cardiac event compared with 15 patients with equivocal scans or 17 patients with abnormal scans, with a cardiac event rate of 13% and 71%, respectively (p = 0.0004). CONCLUSIONS: Initial myocardial perfusion imaging with technetium-99m sestamibi when applied in emergency room patients with typical angina and a normal or nondiagnostic ECG appears to be highly accurate in distinguishing between low and high risk subjects.

Methotrexate in rheumatoid arthritis. Impact on quality of life assessed by traditional standard-item and individualized patient preference health status questionnaires.

In a double-blind, randomized trial of methotrexate vs placebo in rheumatoid arthritis, the effect of treatment on physical, social, and emotional function was measured in two different ways: the same, standard measurements in all patients, and individualized measurements selected by the patients at the start of the trial as representing the functions they most wanted to have improved by treatment. On the standard measurements, methotrexate-treated patients fared better than placebo-treated patients in their physical, social, and emotional function by 11%, 5%, and 6%, respectively, results that, although statistically significant, were small. However, methotrexate-treated patients were 29% better in the individualized measures, a result that was both highly statistically significant and greater than the differences in the standard measurements or in joint counts, grip strength, proximal interphalangeal joint circumference, morning stiffness, or walking time. Because the individualized measurements were as efficient as the best direct joint examination measures, yet reflected functional outcomes of greatest importance to individual patients, they constitute useful measures for such trials.

Husbandry, health and biosecurity of the smallholder and pet pig population in England.

Three hundred and thirteen pet and smallholder pig owners in England responded to an online questionnaire regarding husbandry and healthcare of their pigs. There was a lack of knowledge of the legislation regarding Department for Environment, Food and Rural Affairs (DEFRA) registration, animal movements and feeding of domestic food waste. Only 83.8 per cent of respondents had registered their pigs with DEFRA, while 17.7 per cent were not familiar with the movement regulations, and 23.9 per cent were feeding their pigs with household scraps. Contact with veterinary surgeons may be positively associated with DEFRA registration, legal feeding practices and knowledge of vaccination. Furthermore, the veterinary surgeon was considered to be the primary source of husbandry and healthcare knowledge. This paper identifies the pet and smallholder pig population as a potential risk for the incursion and spread of infectious disease, while highlighting the need for improved owner education.

Screening the human protocadherin 8 (PCDH8) gene in schizophrenia.

Abnormalities in synaptic connectivity and plasticity have been implicated in the pathophysiology of schizophrenia. Molecules involved in the development and maintenance of neural circuitry include the recently cloned protocadherins. Human protocadherin 8 (PCDH8) is homologous to 'arcadlin', a molecule shown to play a role in hippocampal synaptic function in the rat. The gene encoding PCDH8 maps to a region on chromosome 13 where linkage to schizophrenia has been reported. In this study, the entire expressed sequence of the PCDH8 gene and over 800 bp of the 5' flanking region were screened for polymorphisms in 30 DSM-IV schizophrenia individuals using Denaturing High Performance Liquid Chromatography (DHPLC). A total of nine single nucleotide polymorphisms were identified, including three in the first exon that are predicted to change the amino acid sequence. One polymorphism, causing the Trp7Arg change in the putative signal peptide, showed a trend towards excess of the arginine encoding allele in a case-control sample consisting of 520 DSM-IV schizophrenia patients and 535 matched controls from the UK (chi2=3.72, P [1 df]= 0.054). However, this polymorphism did not show preferential transmission to schizophrenic individuals in a separate sample of 203 proband-parent trios from Bulgaria. A second, rare single nucleotide variation, predicting the non-conservative amino acid change Glu39Ala, was found in one schizophrenic individual and their affected sibling but not in a further 352 affected individuals, nor 357 controls. These results suggest that any contribution of PCDH8 polymorphisms to schizophrenia susceptibility is likely to be weak, although the existence of rare variations of stronger effect cannot be excluded.