The impact of automated, constant incomplete milking on energy balance, udder health, and subsequent performance in early lactation of dairy cows.

Incomplete milking (IM) is one way of mitigating the negative energy balance (NEB) that is characteristic for early lactation and may increase the risk for disease. Our objectives were to test the effects of IM in early lactation on energy balance (EB), metabolic status, udder health, and subsequent performance. To facilitate the practical application, an automated system was used to remove the milking clusters once a predefined amount of milk is withdrawn. Forty-six Holstein cows were equally allocated to either the treatment (TRT, starting on 8 d in milk) or the control group (CON; conventional cluster removal at milk flow rate <0.3 kg/min). Milk removal in the TRT group was limited to the individual cow's milk yield 1 d before IM started and held constant for 14 d. Thereafter, all cows were conventionally milked and records related to EB, performance, and udder health were continued up to 15 wk of lactation. During the 14 d of IM, on average 11.1% less milk was obtained from the TRT cows than from the CON cows. Thereafter, milk yield increased in the TRT group, eliminating the group difference throughout the remaining observation period until wk 15 of lactation. The TRT cows tended to have less dry matter intake and also water intake than the CON cows. The extent of the NEB and the circulating concentrations of fatty acids, ß-hydroxybutyrate, insulin-like growth factor-1, and leptin mostly did not differ between the groups. The IM did not affect body condition. Udder health was maintained over the entire observation period in all cows. Our results demonstrate the applicability of the automated cluster removal for limiting milk withdrawal to a defined amount in early lactation. However, it remains to be determined whether the absent effect on energy metabolism was due to the relatively stable energy status of the cows or to the relatively mild IM setting used herein.

Measurement of the α-Particle Monopole Transition Form Factor Challenges Theory: A Low-Energy Puzzle for Nuclear Forces?

We perform a systematic study of the α-particle excitation from its ground state 0_{1}^{+} to the 0_{2}^{+} resonance. The so-called monopole transition form factor is investigated via an electron scattering experiment in a broad Q^{2} range (from 0.5 to 5.0 fm^{-2}). The precision of the new data dramatically supersedes that of older sets of data, each covering only a portion of the Q^{2} range. The new data allow the determination of two coefficients in a low-momentum expansion, leading to a new puzzle. By confronting experiment to state-of-the-art theoretical calculations, we observe that modern nuclear forces, including those derived within chiral effective field theory that are well tested on a variety of observables, fail to reproduce the excitation of the α particle.

Deep convolutional neural networks for the detection of diarrhea and respiratory disease in preweaning dairy calves using data from automated milk feeders.

The objective of the current study was to develop a predictive model for calf disease detection in the preweaning period using data from automated milk feeders (AMF). A deep convolutional neural network (CNN) architecture for the detection of respiratory disease and diarrhea in dairy calves was developed. German Holstein calves were fed milk replacer either ad libitum (up to 25 L/d; n = 32) or restrictively (6 L/d; n = 32) via AMF from 10 ± 3 d of life on. Concentrate, hay, and water were freely available. Calf health parameters were scored daily. The AMF measured milk replacer (MR) intake, number of rewarded visits, number of unrewarded visits, and drinking speed. A calf was considered sick if its fecal score was 3 or 4 and its respiratory score was 2 or 3. Only data from AMF up to 47 d of age were included in the analysis. This cut in the data was made to avoid data from the weaning period. Data were split in 80:20 ratios for training and testing data sets according to the Pareto principle. A minimum sensitivity of 80% was considered an appropriate requirement for the prediction models. Considering all calves in group housing, cross-validation of the test data set showed a sensitivity of 83% and a specificity of 79%, with a positive predictive value and a negative predictive value of 37 and 97%, respectively. The area under the curve of the receiver operating characteristic for the deep CNN model was 0.81 for all group-housed calves. The CNN model yielded sensitivity and specificity of 83 and 71%, respectively (for ad libitum-fed calves), and 82 and 87%, respectively (for restricted-fed calves), with good area under the curve-receiver operating characteristic (0.77 to 0.87), indicating that the CNN models can predict calf disease in both groups with different MR allowances. The permutation feature importance was measured by the decrease in model accuracy, and features (behaviors) were summarized in descending order of their relative importance to the CNN model. Drinking speed and MR intake were the main factors to predict calf disease in calves fed ad libitum. The number of unrewarded visits to the milk feeder and MR intake were the main factors to predict calf disease in restricted-fed calves. Despite the relatively small sample size, the results provide strong evidence that daily feeding behavior data from AMF can be used to identify calves at risk for disease. In conclusion, despite a very good testing performance of the CNN model, the relatively low daily prevalence of calf disease in the present study resulted in a high proportion of false-positive alarms.

Dysregulation of gastrointestinal RAGE (receptor for advanced glycation end products) expression in dogs with chronic inflammatory enteropathy.

The pathogenesis of chronic inflammatory enteropathies (CIE) in dogs involves dysregulated innate immune responses. The receptor for advanced glycation end products (RAGE), a pattern recognition receptor, plays a role in chronic inflammation. Abrogation of proinflammatory RAGE signaling by ligand binding (e.g., S100/calgranulins) to soluble RAGE (sRAGE) might also be a novel therapeutic avenue. Serum sRAGE levels are decreased in canine CIE, but gastrointestinal tissue RAGE expression has not been investigated in dogs. Thus, the study aimed to evaluate the gastrointestinal mucosal RAGE expression in dogs with CIE. Further, the potential binding of RAGE to canine S100/calgranulin ligands was investigated. Epithelial RAGE expression was quantified in gastrointestinal (gastric, duodenal, ileal, and colonic) biopsies from 12 dogs with CIE and 9 healthy control dogs using confocal laser scanning microscopy. RAGE expression was compared between both groups of dogs and was tested for an association with patient characteristics, clinical variables, histologic lesion severity, and biomarkers of extra-gastrointestinal disease, systemic or gastrointestinal inflammation, function, or protein loss. Statistical significance was set at p < 0.05. RAGE:S100/calgranulin binding was assessed by immunoassay and electrophoretic techniques. RAGE expression was detected in all 59 biopsies from diseased and healthy control dogs evaluated. Epithelial RAGE expression in the duodenum and colon was significantly higher in dogs with CIE than in healthy controls (p < 0.04). Compared to healthy controls, RAGE expression in dogs with CIE also tended to be higher in the ileum but lower in the stomach. A slight (statistically not significant) shift towards more basal intestinal epithelial RAGE expression was detected in CIE dogs. Serum sRAGE was proportional to epithelial RAGE expression in the duodenum (p < 0.04), and RAGE expression in the colon inversely correlated with biomarkers of protein loss in serum (both p < 0.04). Several histologic morphologic and inflammatory lesion criteria and markers of inflammation (serum C-reactive protein and fecal calprotectin concentration) were related to epithelial RAGE expression in the duodenum, ileum, and/or colon. in vitro canine RAGE:S100A12 binding appeared more pronounced than RAGE:S100A8/A9 binding. This study showed a dysregulation of epithelial RAGE expression along the gastrointestinal tract in dogs with CIE. Compensatory regulations in the sRAGE/RAGE axis are an alternative explanation for these findings. The results suggest that RAGE signaling plays a role in dogs with CIE, but higher anti-inflammatory decoy receptor sRAGE levels paralleled RAGE overexpression. Canine S100/calgranulins were demonstrated to be ligands for RAGE.

Long-term outcome of persons with diabetic and non-diabetic neuro-osteoarthropathy after foot correction using external fixation.

AIM: Diabetic neuro-osteoarthropathy (Charcot foot) is a serious form of diabetic foot syndrome, often leading to severe deformity of the foot and subsequently to ulcers and osteomyelitis. The aim of this retrospective study was to determine the success rate and long-term outcomes for a Charcot foot operation using external fixation in 115 individuals who underwent surgery between July 2008 and December 2012. METHODS: Some 115 consecutive persons, 78 (68%) men and 37 (32%) women, were enrolled in this study. The eligibility criterion for this retrospective study was reconstructive foot surgery using a Hoffmann II external fixator in diabetic and non-diabetic neuro-osteoarthropathy. The main examination parameters in the follow-up were walking ability, amputation and mortality. Average follow-up was 5.7 (± 3.2) years. RESULTS: Ninety-seven per cent of people were able to walk after the operation with bespoke shoes or an orthosis. At follow-up, 77% were able to walk and 51% were fully mobile even outside the home. Subsequent amputations were performed in 29 individuals (26%), with 17 (15%) minor and 12 (11%) major amputations. Forty-seven individuals died before follow-up, the majority (53%) from cardiovascular events. Average survival time post surgery was 4.5 (± 2.9) years. CONCLUSION: Reconstruction surgery using external fixation is a very useful method for maintaining walking ability in the case of conservatively non-treatable diabetic and non-diabetic neuro-osteoarthropathy. Individuals with severe Charcot foot disease had a low rate of major amputations. Osteomyelitis was the main reason for major amputations.

Effects of a partially perforated flooring system on animal-based welfare indicators in broiler housing.

Alternative flooring designs in broiler housing have been the subject of intensive research. Research comparing different floor types with a focus on animal-based welfare indicators might be of special interest to meet the animal's needs. This case-control study investigated the effect of a partially perforated vs. a littered flooring system on health- and behavior-based welfare indicators of fast-growing Ross 308 broilers. Furthermore, production performance was assessed. The experimental barn was partially (50%) equipped with a perforated floor directly underneath the feeders and water lines accessible by perforated ramps. Conventional wood shavings were used in the control barn, as usual in practice. There were 4 fattening periods (repetitions) of 31 to 32 D performed with 500 animals per barn (final density of 39 kg m-2). Beside the flooring system, management conditions were identical. Health- and behavior-based welfare indicators were assessed weekly. Production performance indicators were measured continuously during animal control. During the avoidance distance test, animals were less fearful on day 21 (P = 0.010) and tended to be less fearful on day 28 (P = 0.083) in the barn with the partially perforated flooring system compared to the littered control barn. More animals around the novel object were also assessed in the barn with the partially perforated flooring system during the novel object test on day 1 (P < 0.001) and a tendency was found on day 28 (P = 0.064). Results showed that the partially perforated flooring system had a positive influence on foot pad dermatitis from day 14 (all P ≤ 0.007) and hock burn on day 28 (P < 0.001). With regard to the production performance, animals showed no differences in final body weight for both floor types. In this study, the partially perforated flooring system had a positive effect on animal health and behavior as indicated by welfare indicators without a reduction in production performance.

Evidence for a role of RUNX1 as recombinase cofactor for TCRß rearrangements and pathological deletions in ETV6-RUNX1 ALL.

T-cell receptor gene beta (TCRß) gene rearrangement represents a complex, tightly regulated molecular mechanism involving excision, deletion and recombination of DNA during T-cell development. RUNX1, a well-known transcription factor for T-cell differentiation, has recently been described to act in addition as a recombinase cofactor for TCRδ gene rearrangements. In this work we employed a RUNX1 knock-out mouse model and demonstrate by deep TCRß sequencing, immunostaining and chromatin immunoprecipitation that RUNX1 binds to the initiation site of TCRß rearrangement and its homozygous inactivation induces severe structural changes of the rearranged TCRß gene, whereas heterozygous inactivation has almost no impact. To compare the mouse model results to the situation in Acute Lymphoblastic Leukemia (ALL) we analyzed TCRß gene rearrangements in T-ALL samples harboring heterozygous Runx1 mutations. Comparable to the Runx1+/- mouse model, heterozygous Runx1 mutations in T-ALL patients displayed no detectable impact on TCRß rearrangements. Furthermore, we reanalyzed published sequence data from recurrent deletion borders of ALL patients carrying an ETV6-RUNX1 translocation. RUNX1 motifs were significantly overrepresented at the deletion ends arguing for a role of RUNX1 in the deletion mechanism. Collectively, our data imply a role of RUNX1 as recombinase cofactor for both physiological and aberrant deletions.

Study of Two-Photon Exchange via the Beam Transverse Single Spin Asymmetry in Electron-Proton Elastic Scattering at Forward Angles over a Wide Energy Range.

We report on a new measurement of the beam transverse single spin asymmetry in electron-proton elastic scattering, A_{⊥}^{ep}, at five beam energies from 315.1 to 1508.4 MeV and at a scattering angle of 30°<θ<40°. The covered Q^{2} values are 0.032, 0.057, 0.082, 0.218, 0.613 (GeV/c)^{2}. The measurement clearly indicates significant inelastic contributions to the two-photon-exchange (TPE) amplitude in the low-Q^{2} kinematic region. No theoretical calculation is able to reproduce our result. Comparison with a calculation based on unitarity, which only takes into account elastic and πN inelastic intermediate states, suggests that there are other inelastic intermediate states such as ππN, KΛ, and ηN. Covering a wide energy range, our new high-precision data provide a benchmark to study those intermediate states.

Changes in incidence of severe hypoglycaemia in people with type 2 diabetes from 2006 to 2016: analysis based on health insurance data in Germany considering the anti-hyperglycaemic medication.

AIM: To investigate the incidence of severe hypoglycaemia over the past 10 years, taking into account changes in anti-hyperglycaemic therapy. METHODS: This retrospective population-based study used German health insurance data. All adults diagnosed with documented type 2 diabetes (extrapolated to the German population: 6.6 million in 2006; 7.9 million in 2011; 8.86 million in 2016) were screened for severe hypoglycaemia. Anti-hyperglycaemic agents were identified by Anatomical Therapeutic Chemical (ATC) code. RESULTS: The event rate for severe hypoglycaemia was 460 per 100 000 people in 2006, 490 per 100 000 in 2011 and 360 per 100 000 in 2016. The proportion of people with severe hypoglycaemia receiving sulfonylureas, as well as receiving combination therapy of metformin and sulfonylureas decreased from 2006 to 2016 (23.6% vs. 6.2%) Among those with severe hypoglycaemia in 2006, there were no prescriptions for dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists or sodium-glucose co-transporter 2 (SGLT2) agonists. The proportions of people with severe hypoglycaemia receiving DPP-4 inhibitors, GLP-1 receptor agonists or SGLT2 agonists in 2011 and 2016 were low. The proportion of people receiving human insulin also decreased (from 11.3% in 2006 to 10.3% in 2011 and 4.3% in 2016); the proportion of people receiving insulin analogues increased from 5.4% in 2006 to 11.5% in 2016. Therapy with mixed insulins was used by 19.7% of people with severe hypoglycaemia in 2006, by 14.0% in 2011 and by 7.3% in 2016. People undergoing therapy with insulin analogues have the highest risk of severe hypoglycaemia adjusted by age, gender, nephropathy diagnosis and year of survey [odds ratio (OR) 14.4, 95% confidence interval (95% CI) 13.5-15.5]. CONCLUSION: The incidence of severe hypoglycaemic events in Germany increased between 2006 and 2011, and decreased in 2016.

New Insight in the Q

Virtual Compton scattering on the proton has been investigated at three yet unexplored values of the four-momentum transfer Q^{2}: 0.10, 0.20, and 0.45 GeV^{2}, at the Mainz Microtron. Fits performed using either the low-energy theorem or dispersion relations allowed the extraction of the structure functions P_{LL}-P_{TT}/ε and P_{LT}, as well as the electric and magnetic generalized polarizabilities α_{E1}(Q^{2}) and ß_{M1}(Q^{2}). These new results show a smooth and rapid falloff of α_{E1}(Q^{2}), in contrast to previous measurements at Q^{2}=0.33 GeV^{2}, and provide for the first time a precise mapping of ß_{M1}(Q^{2}) in the low-Q^{2} region.

First Measurement of the Q

We report on the first Q^{2}-dependent measurement of the beam-normal single spin asymmetry A_{n} in the elastic scattering of 570 MeV vertically polarized electrons off ^{12}C. We cover the Q^{2} range between 0.02 and 0.05 GeV^{2}/c^{2} and determine A_{n} at four different Q^{2} values. The experimental results are compared to a theoretical calculation that relates A_{n} to the imaginary part of the two-photon exchange amplitude. The result emphasizes that the Q^{2} behavior of A_{n} given by the ratio of the Compton to charge form factors cannot be treated independently of the target nucleus.

[Tauopathies : From molecule to therapy]. / Tauopathien : Vom Molekül zur Therapie.

BACKGROUND: The microtubule-associated tau protein is the defining denominator of a group of neurodegenerative diseases termed tauopathies. OBJECTIVE: Provide a timely state of the art review on recent scientific advances in the field of tauopathies. MATERIAL AND METHODS: Systematic review of the literature from the past 10 years. RESULTS: Tau proteins are increasingly being recognized as a highly variable protein, underlying and defining a spectrum of molecularly defined diseases, with a clinical spectrum ranging from dementia to hypokinetic movement disorders. Genetic variation at the tau locus can trigger disease or modify disease risk. Tau protein alterations can damage nerve cells and propagate pathologies through the brain. Thus, tau proteins may serve both as a serological and imaging biomarker. Tau proteins also provide a broad spectrum of rational therapeutic interventions to prevent disease progression. This knowledge has led to modern clinical trials. CONCLUSION: The field of tauopathies is in a state of dynamic and rapid progress, requiring close interdisciplinary collaboration.

Evaluation of inner teat morphology by using high-resolution ultrasound: Changes due to milking and establishment of measurement traits of the distal teat canal.

The teat canal is important in the defense against invading pathogens, but its functional features can be impeded by the milking process. The objective of our study was to compare teat morphology before and after a standard milking procedure using high-resolution ultrasonography. Tissue changes were determined by measuring inner traits of teat morphology: teat width, teat end width, teat cistern width, diameter of the lower and upper teat wall, teat canal length, and teat canal diameter. Additionally, 3 traits describing the distal teat canal and its external orifice were established: diameter of the distal teat canal orifice, distal teat canal perimeter, and distal teat canal surface. In the first trial, we verified the repeatability of scanning over time with a mixed model. During the second trial, significant changes after milking were observed for all measured traits of teat morphology except teat end width. The traits from the distal teat canal and its orifice were remarkably changed by milking: distal teat canal orifice, +28.9%; distal teat canal perimeter, +25.0%; and distal teat canal surface, +41.5%. Comparing multiparous versus primiparous cows, higher values of teat width, teat end width, and teat canal length were observed in the older animals. Testing the effect of milk yield on teat dimensions, cows with milk yields >11.0 kg/afternoon milking were found to have larger teat widths, teat end widths, and cistern widths before attachment of the cluster. Furthermore, we observed associations of inner teat morphology toward bacterial counts in the appropriate milk. Regarding this udder health-related parameter especially, the newly established traits showed a connection. Teats in which milk showed bacterial growth had larger distal teat canal perimeters and distal teat canal surfaces. High-resolution ultrasonographic scanning of dairy teats allowed a detailed visualization of the inner morphology. The applied procedure can therefore serve as a useful tool for comparison and evaluation of different milking techniques by analyzing the resulting changes of the morphological traits. The thorough description of teat tissue can also be applied for drawing conclusions on the status of the teat canal's physical and mechanical defense function.

Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models.

The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1+/- knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1+/- mice. STEP61 protein is also increased in cortical lysates from the central nervous system-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons, from two independent SZ patient cohorts. In these selected SZ models, increased STEP61 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61 dysfunction in SZ.

Beam-Recoil Polarization Measurement of π

The helicity-dependent recoil proton polarizations P_{x}^{'} and P_{z}^{'} as well as the helicity-independent component P_{y} have been measured in the p(e[over →],e^{'}p[over →])π^{0} reaction at four-momentum transfer Q^{2}≃0.1 GeV^{2}, center-of-mass proton emission angle θ_{p}^{*}≃90°, and invariant mass W≃1440 MeV. This first precise measurement of double-polarization observables in the energy domain of the Roper resonance P_{11}(1440) by exploiting recoil polarimetry has allowed for the extraction of its scalar electroexcitation amplitude at an unprecedentedly low value of Q^{2}, establishing a powerful instrument for probing the interplay of quark and meson degrees of freedom in the nucleon.

Specific Immunotherapy in Hymenoptera Venom Allergy and Concomitant Malignancy: A Retrospective Follow-up Focusing on Effectiveness and Safety.

BACKGROUND: Malignancies are often considered a contraindication for allergen-specific immunotherapy. Consequently, patients with severe Hymenoptera venom allergy and cancer require specific care. The aim of this retrospective study was to assess patients with Hymenoptera venom allergy and cancer undergoing venom immunotherapy (VIT). METHODS: The study population comprised all patients referred for evaluation of Hymenoptera venom allergy or for a routine check-up during VIT from January 1, 2004 to December 31, 2008. RESULTS: Of the patients assessed, 2% (51 of 2594) had a documented Hymenoptera venom allergy and cancer (25 female, 26 male; mean age 58 years). Of these, 42 patients received VIT (82%): 25 patients had a previously diagnosed malignancy, 16 were diagnosed with malignancy during VIT, and 1 patient was diagnosed with cancer after completion of VIT. The most frequent type of tumor was breast cancer in female patients (60%) and prostate cancer in male patients (39%). Systemic allergic reactions during VIT were recorded in 7% of patients. A total of 19 patients experienced a field sting or underwent a sting challenge test during VIT: 95% tolerated the sting well. VIT was halted definitively in 9 patients (new diagnosis of cancer in 7 patients, reactivation of cancer in 1, and progressive polyneuropathy in 1). CONCLUSIONS: The effectiveness and adverse effects of VIT in patients with Hymenoptera venom allergy and cancer in remission are comparable to those of patients without malignancy. Our findings show that patients with Hymenoptera venom allergy and cancer are eligible for VIT.

New Measurements of the Beam Normal Spin Asymmetries at Large Backward Angles with Hydrogen and Deuterium Targets.

New measurements of the beam normal single spin asymmetry in the electron elastic and quasielastic scattering on the proton and deuteron, respectively, at large backward angles and at ⟨Q^{2}⟩=0.22 (GeV/c)^{2} and ⟨Q^{2}⟩=0.35 ( GeV/c)^{2} are reported. The experimentally observed asymmetries are compared with the theoretical calculation of Pasquini and Vanderhaeghen [Phys. Rev. C 70, 045206 (2004).PRVCAN0556-281310.1103/PhysRevC.70.045206]. The agreement of the measurements with the theoretical calculations shows a dominance of the inelastic intermediate excited states of the nucleon, πN and the Δ resonance. The measurements explore a new, important parameter region of the exchanged virtual photon virtualities.