Entanglement distillation between solid-state quantum network nodes.

The impact of future quantum networks hinges on high-quality quantum entanglement shared between network nodes. Unavoidable imperfections necessitate a means to improve remote entanglement by local quantum operations. We realize entanglement distillation on a quantum network primitive of distant electron-nuclear two-qubit nodes. The heralded generation of two copies of a remote entangled state is demonstrated through single-photon-mediated entangling of the electrons and robust storage in the nuclear spins. After applying local two-qubit gates, single-shot measurements herald the distillation of an entangled state with increased fidelity that is available for further use. The key combination of generating, storing, and processing entangled states should enable the exploration of multiparticle entanglement on an extended quantum network.

Pharmacological evaluation of a selective bradykinin B1 antagonist in a canine model of arthritis.

The effects of a selective bradykinin 1 receptor antagonist, compound A, were evaluated in a canine model of acute inflammatory model of arthritis. Despite detection of the B1 receptor in canine type B synoviocytes using a fluorescent ligand, oral administration of compound A (9 and 27 mg/kg) did not improve weight bearing of dogs injected intra-articularly with IL-1ß in a force plate analysis. Analysis of the synovial fluid of IL-1ß-treated dogs indicated high levels of bradykinin postchallenge. Excellent exposure, coupled with evidence of the presence of the B1 receptor during an acute inflammatory model of pain, indicates an inability of the receptor to mediate inflammatory pain in canines.

Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma.

BACKGROUND: Idarubicin, a PO bioavailable anthracycline antibiotic-class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery. OBJECTIVES: The primary objective of this study was to determine the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD. ANIMALS: Client-owned dogs with measurable lymphoma. METHODS: Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines. RESULTS: The MTD in dogs > 15 kg body weight was 22 mg/m(2) . Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol. CONCLUSIONS AND CLINICAL IMPORTANCE: PO administered idarubicin was generally well-tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated-dose, randomized clinical trials.

Secretory immunoglobulin A (IgA) responses in IgA nephropathy patients after mucosal immunization, as part of a polymeric IgA response.

Secretory immunoglobulin A (SIgA), although generated at mucosal surfaces, is also found in low concentrations in the circulation. Recently, SIgA was demonstrated in mesangial deposits of patients with immunoglobulin A nephropathy (IgAN), suggesting a role in the pathogenesis. This finding is in line with the belief that high molecular weight (HMW) immunoglobulin A (IgA) is deposited in the kidney. However, there is little information on the size distribution of antigen-specific IgA in circulation upon mucosal challenge. In this study we measured antigen-specific IgA, including SIgA, in serum following challenge of IgAN patients and controls via intranasal vaccination with a neoantigen, cholera toxin subunit B (CTB). We size-fractionated serum and nasal washes to study the size distribution of total IgA, SIgA and CTB-specific IgA. Finally, we compared the size distribution of antigen-specific IgA after mucosal immunization with the distribution upon systemic immunization. A significant induction of antigen-specific SIgA was detectable in serum of both patients with IgAN and controls after mucosal immunization with CTB. Independent of the route of immunization, in both groups the antigen-specific IgA response was predominantly in the polymeric IgA fractions. This is in contrast to total IgA levels in serum that are predominantly monomeric. We conclude that mucosal challenge results in antigen-specific SIgA in the circulation, and that the antigen-specific IgA response in both IgAN patients and in controls is of predominantly HMW in nature. No differences between IgAN patients and controls were detected, suggesting that the size distribution of antigen-specific IgA in the circulation is not disturbed specifically in IgAN patients.

A novel small molecule Met inhibitor, PF2362376, exhibits biological activity against osteosarcoma.

The receptor tyrosine kinase Met is dysregulated in several human cancers including osteosarcoma (OSA) in which overexpression is a negative prognostic indicator and enforced Met expression in normal osteoblasts leads to genomic instability and malignant transformation. Met is also known to be inappropriately expressed in canine OSA tumour samples and cell lines. The purpose of this study was to evaluate the potential utility of an orally bioavailable small molecule Met inhibitor, PF2362376, against canine OSA cell lines as a prelude to future clinical work. PF2362376 inhibited phosphorylation of Met, Gab-1, Erk and Akt, but not of Src or STAT3. Furthermore, PF2362376 inhibited proliferation of canine OSA cell lines and induced cell death at biologically achievable concentrations. Last, activities associated with Met signalling including migration, invasion, branching morphogenesis and colony formation in soft agar were blocked by PF2362376. These studies support the notion that Met is a relevant target for therapeutic intervention in OSA.

Ultraviolet-A (UVA-1) radiation suppresses immunoglobulin production of activated B lymphocytes in vitro.

Previous studies have shown that low-dose ultraviolet-A (UVA-1) total body irradiations were capable of improving disease activity in patients with systemic lupus erythematosus (SLE). We hypothesized that UVA-1-induced suppression of immunoglobulin production by activated B cells in the dermal capillaries could be (partly) responsible for this effect. Our experiments with donor skin demonstrated that approximately 40% of UVA-1 could penetrate through the epidermis. Irradiation of peripheral blood mononuclear cells (PBMCs) with 2 J/cm(2) of UVA-1 resulted in 20% cell death. This toxic effect could be prevented totally by preincubation of the cell cultures with catalase. This indicates that the generation of hydrogen peroxide plays a role in UVA-1 cytotoxicity. T cells and B cells appeared to be less susceptible to UVA-1 cytotoxicity than monocytes. With the use of a CD40-CD40L B cell activation method we measured immunoglobulin production after various doses of UVA-1 irradiation (0-2 J/cm(2)). The doses of 2 J/cm(2) caused a significant decrease of IgM, IgG, IgA and IgE production under the conditions of interleukin (IL)-10 or IL-4 (IgE) stimulation. Although UVA-1 can cause apoptosis of B lymphocytes, we show that relatively low doses of UVA-1 radiation also affect the function of these cells. Both effects may be responsible for the observed improvement of disease activity in SLE patients.

Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages.

Rapamycin (Rapa), a recently introduced immunosuppressive drug, seems to be effective in preventing acute allograft rejection. Although its antiproliferative effect on T lymphocytes has been investigated extensively, its effect on the initiators of the immune response, the dendritic cells (DCs), is not known. Therefore, the effect of Rapa on monocyte- (mo-DCs) and CD34(+)-derived DCs in vitro but also on other myeloid cell types, including monocytes and macrophages, was examined. The present study shows that Rapa does not affect phenotypic differentiation and CD40L-induced maturation of mo-DCs. However, Rapa dramatically reduced cell recovery (40%-50%). Relatively low concentrations of Rapa (10(-9) M) induced apoptosis in both mo-DCs and CD34(+)-derived DCs, as visualized by phosphatidylserine exposure, nuclear condensation and fragmentation, and DNA degradation. In contrast, Rapa did not affect freshly isolated monocytes, macrophages, or myeloid cell lines. The sensitivity to Rapa-induced apoptosis was acquired from day 2 onward of mo-DC differentiation. Rapa exerts its apoptotic effect via a reversible binding to the cytosolic receptor protein FKBP-12, as demonstrated in competition experiments with FK506, which is structurally related to Rapa. Partial inhibition of Rapa-induced apoptosis was obtained by addition of ZVAD-fmk, which implies caspase-dependent and caspase-independent processes. The fact that Rapa exerts a specific effect on DCs but not on monocytes and macrophages might contribute to the unique actions of Rapa in the prevention of allograft rejection and other immune responses.

CHOP Infant Coma Scale ("Infant Face Scale"): a novel coma scale for children less than two years of age.

The Glasgow Coma Scale (GCS) is the most frequently used tool worldwide for assessing the severity of neurologic injury after brain trauma, although applying this scale to infants and younger children can be problematic. The CHOP Infant Coma Scale, or Infant Face Scale (IFS), is a novel scale for children under 2 years of age which differs from other pediatric coma scales in the following ways: (1) it relies on objective behavioral observations; (2) it assesses cortical as well as brainstem function; (3) it parallels the GCS in scoring but is based on infant-appropriate behaviors; and (4) it can be applied to intubated patients. We report the results of a prospective study designed to compare interrater reliability between the IFS and GCS in children less than 2 years of age. Seventy-five hospitalized children less than 2 years of age were assessed simultaneously by a pair of observers, representing a spectrum of health care professionals, who scored the children using both the IFS and GCS. Interrater reliability for each pair of observers for each scale was assessed using the kappa statistic. A second series of 10 infants in the intensive care unit with specific diagnoses of acute traumatic or hypoxic/ischemic brain injury were similarly assessed. In the 75 hospitalized infants with a variety of diagnoses, interrater reliability for the GCS was in the "almost perfect," "slight," and "fair" range for the eye-opening, motor, and verbal subtests, respectively. In contrast, the IFS showed interrater reliability in the "almost perfect," "substantial," and "almost perfect" ranges for the three subtests. When applied to infants in an intensive care unit with acute traumatic brain injury or hypoxia/ischemia, the GCS interrater reliability scores were in the "fair" range, while the IFS scores were in the "almost perfect" range. The IFS demonstrates improved interrater reliability in direct comparison to the GCS, particularly in the "verbal/face" component where most pediatric coma scales are deficient. The IFS may prove to be a simple and practical bedside index of brain injury severity in children less than two years of age.

The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells.

Corticosteroids and the calcineurin inhibitors cyclosporin A (CsA) and FK506 have been studied extensively regarding their effects on T lymphocytes, but their effects on dendritic cells (DC) are relatively unknown. Monocytes are one of the precursors of DC that differentiate into CD14-CD1a+ immature DC upon culture with IL-4 and GM-CSF. The presence of CsA or FK506 during differentiation did not affect DC development. In contrast, the presence of corticosteroids, either dexamethasone (Dex) or prednisolone (Pred), for as little as the first 48 h of culture blocked the generation of immature DC. Dex-DC were unresponsive to signals inducing maturation (CD40 ligand, lipopolysaccharide), as demonstrated by the absence of CD83, CD80/CD86 and HLA-DR up-regulation and their strongly reduced T cell stimulatory capacity. Furthermore, Dex-DC showed a decreased CD40 ligand-induced IL-6 and TNF-alpha production, a complete block in IL-12p40 production, while IL-10 production was unaffected. CsA-DC and FK506-DC showed a partial reduction in the production of TNF-alpha, whereas all other functional activities appeared to be similar to control DC. These data show that, when compared to calcineurin inhibitors, corticosteroids have a unique and profound inhibitory effect on the generation and function of DC.

Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands.

Mutations in the LDL receptor are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations of the LDL receptor gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL receptor gene mutations in a population represents a prerequisite for the implementation of nation-wide genetic testing for FH. In this study, the frequency and geographical distribution of 13 known mutations were evaluated in a cohort of 1223 FH patients. We identified 358 mutation carriers, representing 29% of the FH cohort. Four mutations (N543H-2393de19, 1359--1G-->A, 313 + 1 G-->A and W23X) occurred with a relatively high frequency, accounting for 22.4% of the entire study cohort. Two of these common FH mutations (N543H-2393de19 and 1359 - 1G-->A) showed a preferential geographic distribution. Second, to further expand the array of LDL receptor gene mutations, we conducted mutation analysis by denaturing gradient gel electrophoresis (DGGE) in 141 children with definite FH. A mutation was identified in 111 patients, involving 16 new single base substitutions and four small deletions and insertions, which brings the number of different FH-causing mutations in our country up to 61. Our data indicate that an estimate of the prevalence of specific mutations, as well as the compilation of a database of all FH-causing mutations in a given country, can facilitate selection of the most appropriate molecular diagnostic approach.

Binding of beta-VLDL to heparan sulfate proteoglycans requires lipoprotein lipase, whereas ApoE only modulates binding affinity.

The binding of beta-VLDL to heparan sulfate proteoglycans (HSPG) has been reported to be stimulated by both apoE and lipoprotein lipase (LPL). In the present study we investigated the effect of the isoform and the amount of apoE per particle, as well as the role of LPL on the binding of beta-VLDL to HSPG. Therefore, we isolated beta-VLDL from transgenic mice, expressing either APOE*2(Arg158-->Cys) or APOE*3-Leiden (E2-VLDL and E3Leiden-VLDL, respectively), as well as from apoE-deficient mice containing no apoE at all (Enull-VLDL). In the absence of LPL, the binding affinity and maximal binding capacity of all beta-VLDL samples for HSPG-coated microtiter plates was very low. Addition of LPL to this cell-free system resulted in a 12- to 55-fold increase in the binding affinity and a 7- to 15-fold increase in the maximal binding capacity (Bmax). In the presence of LPL, the association constant (Ka) tended to increase in the order Enull-VLDL

Intra-articular pressure, elastance and range of motion in healthy and injured racehorse metacarpophalangeal joints.

The objective of this study was to determine if intraarticular pressure, elastance of the soft tissue forming the dorsal pouch, and range of motion in flexion measurements are significantly different in Thoroughbred metacarpophalangeal joints with clinical evidence of idiopathic synovitis, primary synovitis, synovitis/capsulitis, or osteoarthritis relative to clinically normal joints. Forty-two metacarpophalangeal joints, in 25 active or retired Thoroughbred racehorses, were categorised by palpation and visual inspection of the palmar pouch into one of 4 increasing grades of distention. Intra-articular pressures were then measured using 2 pressure transducers attached to 22-gauge needles from both the dorsal and palmar pouches simultaneously while the horses stood squarely under mild sedation. After obtaining baseline pressure measurements, a third needle was inserted into the dorsal pouch, and 0.5 ml increments of saline solution were added every 10 s to perform a pressure/volume (elastance) study of the dorsal pouch. The elastance study for each joint ended when leakage into the palmar pouch was detected by the pressure transducer placed in that region. A lateral radiographic view was taken of each metacarpophalangeal joint in maximal flexion. The maximum angle of flexion was measured from the radiograph, and this angle was subtracted from 180 degrees to acquire the range of motion in flexion. In this study, all Thoroughbreds with clinical evidence of lameness and/or sensitivity to flexion, referable to the metacarpophalangeal joint region, had fluid distention of the palmar pouch (grade 2 or 3 distention). The 16 metacarpophalangeal joints with no clinical abnormalities had a mean palmar pouch pressure of -1.25 mmHg. Joints afflicted with synovitis/capsulitis had the highest intraarticular pressures (mean +51.00 mmHg); however, joints with idiopathic synovitis (mean +15.71 mmHg), primary synovitis (mean +28.33 mmHg) and osteoarthritis (mean +26.20 mmHg) also had significantly elevated intraarticular pressures relative to the clinically normal group. Thoroughbred metacarpophalangeal joints diagnosed with synovitis/capsulitis, or osteoarthritis, had significantly increased elastance (stiffness) of the soft tissue forming the dorsal pouch relative to the normal group and, probably, as a result significantly decreased range of motion in flexion. The presence of primary synovitis alone did not have a significant immediate effect on elastance of the dorsal pouch and range of motion in flexion. The 16 Thoroughbred metacarpophalangeal joints assessed as having no clinical abnormalities had a mean range of motion in flexion of 60.81 degrees. The mean range of motion in flexion of Thoroughbred metacarpophalangeal joints with a clinical diagnosis of primary synovitis was 53.67 degrees; idiopathic synovitis 52.14 degrees; synovitis/capsulitis 44.20 degrees; and those with radiographic evidence of moderate to marked osteoarthritis 30.80 degrees. This study demonstrated that, as the severity of the clinical evidence of metacarpophalangeal joint injury/disease increased, the range of motion in flexion decreased.

The T705I mutation of the low density lipoprotein receptor gene (FH Paris-9) does not cause familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disease caused by mutations in the low-density lipoprotein receptor gene. Among the more than 200 mutations so far identified, the T705I substitution in exon 15, designated FH-Paris 9, has been previously described as an FH-causing mutation. During the course of denaturing gradient gel electrophoretic screening of exon 15 we have identified the T705I single-base substitution not only in an FH family but also in a control, normocholesterolemic population. Therefore, we conclude that FH-Paris 9 is a missense mutation not associated with FH.

Mechanism of exercise-induced augmentation of lymphokine activated killer (LAK) cell activity in the horse.

Intense exercise affects various parameters of the immune system. The overall effect of exercise on immune function is dependent upon the physical condition of the subject, the intensity and duration of the exercise period, and the immune parameter assessed. Unconditioned horses subjected to a single bout of intensive exercise exhibit multiple alterations in immune function, including an augmentation of lymphokine activated killer (LAK) cell function. This increase in LAK cell activity is not due to an increase in circulating LAK precursors. While peripheral blood mononuclear cells from exercising horses exhibit greater responsiveness to IL-2, this is not due to an increase in IL-2 receptor expression. LAK cell generation in vitro is augmented by those catecholamines and neuropeptides which are produced during exercise, suggesting a direct effect of these compounds on LAK cell generation at a step post IL-2 receptor binding.

Evaluation of detomidine-induced analgesia in horses with chronic hoof pain.

Detomidine (10, 20 and 40 micrograms/kg i.v.) and saline were administered to eight adult horses with hoof pain and lameness associated with chronic laminitis. Mechanical noxious stimulation was applied to 16 loci over the solar surface of each forefoot by means of an electronic hoof tester to determine chronic pain thresholds. Horses were evaluated before and at 25, 55 and 120 min after treatment for lameness and to determine hoof compression thresholds (HCTs), the percentage of responsive loci and the subjective grade of hoof withdrawal response at each responsive locus. Detomidine produced a dose-dependent increase in HCT and a decrease in the subjective grade of hoof withdrawal response through 55 min after treatment. At 25 and 55 min postdose, the 40 micrograms/kg dose produced maximal elevation of the HCT. The percentage of responsive loci was decreased by detomidine at 25 min in a dose-dependent manner. The lameness grade was decreased by 40 and 20 micrograms/kg of detomidine at 25 min postdose. These data support previous studies demonstrating detomidine-induced analgesia in equine models of acute nociception.

Effects of pretreatment with ketoprofen and phenylbutazone on experimentally induced synovitis in horses.

OBJECTIVE: To compare the analgesic and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs (NSAID), ketoprofen (2.20 and 3.63 mg/kg of body weight) and phenylbutazone (4.40 mg/kg), in an acute equine synovitis model. DESIGN: 4 groups of 6 horses received NSAID or saline solution in a randomized design. ANIMALS: 24 clinically normal mares and geldings. PROCEDURE: Left intercarpal joints were injected with sterile carrageenan to induce synovitis at the same time as IV administration of NSAID or saline solution. Clinical assessments were made and synovial fluid was withdrawn at 0, 1, 3, 6, 9, 12, 24, and 48 hours. RESULTS: The eicosanoids, prostaglandin E2 (PGE2) and leukotriene B4, increased in synovial fluid after synovitis induction in all horses then returned to near baseline by 48 hours. All NSAID-treated horses had decreased PGE2, compared with saline-treated horses. This effect lasted longer in phenylbutazone-treated horses than in ketoprofen-treated horses. There were no treatment effects on leukotriene B4. In saline-treated animals, lameness, joint temperature, and synovial fluid volume, protein concentration, and nucleated cells increased 3 to 12 hours after induction, with marked reduction by 48 hours. Only phenylbutazone treatment reduced lameness, joint temperature, and synovial fluid volume. CONCLUSION: Phenylbutazone was more effective than ketoprofen in reducing lameness, joint temperature, synovial fluid volume, and synovial fluid PGE2. Results do not support lipoxygenase inhibition by either NSAID. CLINICAL RELEVANCE: This reversible model induced synovial fluid alterations similar to those observed in horses with septic arthritis. Results indicate that phenylbutazone may be more useful than ketoprofen in treating acute joint inflammation.