The worldwide problem of increasing dairy cow mortality is widespread in modern production systems, it causes economic losses, and indicates problems with herd health and welfare. Most studies on ...causes of dairy cow mortality are limited as they are based on secondary register data, or questionnaires for producers or veterinarians, and neither necropsies nor histopathologic analyses are usually performed. For this reason, no definite causes for dairy cow deaths have been determined making it difficult or impossible to implement effective preventive measures. The objectives of this study were to (1) determine the causes of on-farm mortality of Finnish dairy cows, (2) determine the usefulness of routine histopathologic analysis in bovine necropsies, and (3) assess how reliable producers' perception about the cause of death is. Underlying diagnoses of on-farm deaths were determined through necropsy of 319 dairy cows at an incineration plant. The necropsy data were combined with background information obtained from online questionnaires covering cow and herd records. Mastitis was the most common underlying diagnosis of death (26.6%), followed by digestive disorders (15.4%), other known disorders (13.8%), calving-associated disorders (12.2%), and locomotion disorders (11.9%). The underlying diagnoses of death varied during different stages of lactation and with parity. A large proportion of the study cows (46.7%) died during the first 30 d after calving, and of those, 63.6% died during the first 5 d. A routine histopathologic analysis was performed in every necropsy, and it changed the preliminary gross diagnosis in 18.2% of the cases. Producers' perception about the cause of death agreed with the necropsy-based underlying diagnosis of death in 42.8% of the cases. It was most consistent for mastitis, calving disorders, locomotion diseases, and accidents. In cases where producers had no insights about the cause of death, necropsy revealed the final underlying diagnosis in 88.2% of cases, demonstrating the usefulness of necropsy. Based on our findings, necropsies provide useful and reliable information to develop control programs for cow mortality. Including routine histopathologic analysis in necropsies, more accurate information may be obtained. Furthermore, targeting preventive measures on transitional cows may be most effective, as the number of deaths was highest at this time.
To describe unexpected sudden cardiac death (SCD) in young Leonbergers (<3 years) and to review the circumstances before death and necropsy findings; to prospectively evaluate the presence of ...possible arrhythmias in young Leonbergers; and to examine pedigrees for determining potential modes of inheritance.
Postmortem evaluations included 21 Leonbergers. Clinical evaluation consisted of 46 apparently healthy Leonbergers with and without a close family history of SCD.
Necropsy reports were reviewed retrospectively. Prospective clinical evaluation included physical examination, 5-min electrocardiogram, 24-h Holter, echocardiography, and laboratory tests. Pedigree data were examined for mode of inheritance.
Based on necropsy reports, SCD occurred at a median age of 12 months (range, 2.0–32.0 months) without any previous clinical signs and usually in rest. No evidence of structural cardiac disease was found; arrhythmia-related death was suspected. Clinical evaluation and 24-h Holter showed ventricular arrhythmia (VA) in 14 apparently healthy Leonbergers (median age, 18 months; range, 12–42 months). Severity of VA varied from infrequent couplets/triplets to frequent complexity (couplets, triplets, nonsustained ventricular tachycardias,VTs) characterized by polymorphology. During follow-up, two dogs with polymorphic VT died. Although breed specificity and high prevalence indicate a heritable disease, based on available pedigree data, the mode of inheritance could not be determined.
Sudden cardiac death in young Leonbergers is associated with malignant VA characterized by complexity and polymorphic nature. Diagnosis is based on 24-h Holter monitoring. Pedigree analysis suggests that the arrhythmia is familial.
This case series describes four cases of concomitant dermoid sinus and spina bifida in a Chinese crested dog, two Swedish vallhunds and a Burmese cat. The diagnosis was confirmed by computed ...tomography, computed tomography fistulography and pathology. Two dogs that showed abnormalities during neurological examination underwent magnetic resonance imaging. One of them had imaging findings interpreted as syringohydromyelia. All the dogs underwent surgery and the outcome was considered good in all the cases. Based on clinical and pathological examination as well as diagnostic imaging findings, two of the dermoid sinuses were classified as type IV, and two of them showed a previously unreported type of dermoid sinus. This new type is suggested here as type VI.
According to our recent necropsy-based study, mastitis is the most common underlying diagnosis of on-farm deaths in Finnish dairy cows. However, it remained unanswered to what extent mastitis has ...contributed to death of all necropsied cows. In the present study, based on histopathology we detected one third of the necropsied dairy cows having active inflammatory udder lesions (n = 110). The role of mastitis varied and was interpreted by causes of death (underlying, intermediate, immediate, other significant). Mastitis was most commonly either the underlying (28%) or both immediate and underlying cause of death (48%), and only seldom the immediate (4%) or intermediate (4%) cause of death.
Mastitis occurred either as the only cause leading to death (mastitis only, MO, 39%), or with many other contributing diseases (multiple diseases, MD, 61%) which were interacting with mastitis and together leading to death. Between these groups (MO vs. MD), time of mastitis occurrence during lactation, producer-reported duration of illness, clinical signs, and medication differed, as well the histopathological severity of mastitis. The cases, where mastitis was the only initial insult, occurred evenly throughout the entire lactation, but the cases with many interacting diseases clustered in early lactation. In multiple diseases -cases mastitis occurred concurrently with metritis (31%), aspiration pneumonia (24%), acute trauma/dystocia (15%), or with other diseases, such as ketosis, hepatic lipidosis, rumenitis, and abomasal diseases.
For a pathologist, the gross mastitis diagnosis was most challenging at the beginning of the lactation, especially if inflammation was mild to moderate, suggesting the value of histopathological examination being highest at that time. Also, producers reported mastitis signs less frequently if cow had many simultaneously occurring diseases. Therefore, even if clinical signs of other diseases are present, the udder should be considered a potential cause of illness, and it should be examined, especially in dry and transition period cows.
Bay scallops (Argopecten irradians) were once abundant in the nearshore marine environment of western Florida. In recent years, however, many of the local populations that comprise the purported bay ...scallop metapopulation in Florida have collapsed, resulting in closure of the commercial fishery and implementation of severe restrictions on recreational harvest. Hypothesized causes of that collapse include overfishing, habitat degradation and increased prevalence of red tide, but the exact cause is unknown. We are attempting to restore scallop populations in Florida by planting cultured scallops in selected areas, but we are taking a stepwise approach to scallop restoration by first assessing the feasibility of this strategy before initiating a full-blown restoration effort. This experimental approach consists of first developing a thorough baseline of information concerning the local abundance and relative rates of recruitment in natural populations. We then spawn small groups of scallops for which we identify a unique mitochondrial marker. The resultant (genetically identifiable) broods are planted in cages within the location from which the parent stock was collected. We monitor the growth, survival, and reproductive development of each brood. Additionally, we employ artificial collectors to obtain juvenile scallops that are returned to the laboratory for genetic analysis. This allows us to estimate the proportional representation of cultured scallops in the recruiting population. Finally, we sample adult populations both at the planting site and at other sites throughout western Florida, to estimate the proportional representation of cultured scallops in the following adult year-class. If cultured scallops comprise a significant proportion of the subsequent year-class, or if we observe increased scallop abundance relative to background levels, then we will consider implementing a large scale restoration effort. If experimental enhancement fails, then we must assume that the causative factors of the collapse remain and must be mitigated before initiating full-scale restoration.
A new methods for controlling leakage power in handheld device was proposed. This paper presents the use of a MEMS switch as a replacement for the sleep transistor method to reduce leakage current ...allowing for significant improvement in the battery life of portable electronic systems.
Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study ...(NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.
Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5-3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.
DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.
Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.
Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. ...Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.
Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that ...binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that CC-122, a new chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or short hairpin RNA–mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)–stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell lines. Our results provide mechanistic insight into the cell-of-origin independent antilymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide.
•CC-122 is a novel agent for DLBCL with antitumor and immunomodulatory activity.•CC-122 binds CRBN and degrades Aiolos and Ikaros resulting in a mimicry of IFN signaling and apoptosis in DLBCL.
Theia: an advanced optical neutrino detector Askins, M.; Bagdasarian, Z.; Barros, N. ...
The European physical journal. C, Particles and fields,
05/2020, Letnik:
80, Številka:
5
Journal Article
Recenzirano
Odprti dostop
New developments in liquid scintillators, high-efficiency, fast photon detectors, and chromatic photon sorting have opened up the possibility for building a large-scale detector that can discriminate ...between Cherenkov and scintillation signals. Such a detector could reconstruct particle direction and species using Cherenkov light while also having the excellent energy resolution and low threshold of a scintillator detector. Situated deep underground, and utilizing new techniques in computing and reconstruction, this detector could achieve unprecedented levels of background rejection, enabling a rich physics program spanning topics in nuclear, high-energy, and astrophysics, and across a dynamic range from hundreds of keV to many GeV. The scientific program would include observations of low- and high-energy solar neutrinos, determination of neutrino mass ordering and measurement of the neutrino CP-violating phase
δ
, observations of diffuse supernova neutrinos and neutrinos from a supernova burst, sensitive searches for nucleon decay and, ultimately, a search for neutrinoless double beta decay, with sensitivity reaching the normal ordering regime of neutrino mass phase space. This paper describes
Theia
, a detector design that incorporates these new technologies in a practical and affordable way to accomplish the science goals described above.
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