BAY 94-9027, a PEGylated recombinant factor VIII, exhibits a prolonged half-life and higher area under the curve in patients with severe haemophilia A: Comprehensive pharmacokinetic assessment from clinical studies.

INTRODUCTION: Recombinant factor VIII (rFVIII) products with extended half-lives, such as BAY 94-9027, can potentially maintain higher FVIII levels for longer periods of time, thus providing improved bleeding protection vs standard-acting FVIII products. AIM: To characterize the pharmacokinetic (PK) profile of BAY 94-9027 from phase 1, phase 2/3 (PROTECT VIII) and phase 3 (PROTECT VIII Kids) clinical trials in adults, adolescents and children with severe haemophilia A METHODS: Patients with severe haemophilia A (FVIII <1%) with >50 FVIII exposure days (EDs) and no history of inhibitors were included in the phase 1 (18-65 years, ≥150 EDs), PROTECT VIII (12-65 years, ≥150 EDs) and PROTECT VIII Kids (<12 years, >50 EDs) trials. PK parameters were assessed following a 25-IU/kg or 60-IU/kg BAY 94-9027 dose in the phase 1 study after the first and repeated infusion, in PROTECT VIII after the first and repeated 60-IU/kg infusion and in PROTECT VIII Kids after a single 60-IU/kg infusion. The chromogenic assay was used to assess FVIII activity. RESULTS: Compared with sucrose-formulated rFVIII, BAY 94-9027 had reduced clearance that resulted in a ~1.4-fold increase in half-life and dose-normalized area under the curve (AUC). The BAY 94-9027 PK profile was comparable after single- and repeated-dose administrations. Dose-proportional increases were observed between 25- and 60-IU/kg administrations. BAY 94-9027 PK characteristics were age dependent, consistent with other FVIII products. CONCLUSIONS: BAY 94-9027 shows an extended half-life and increased AUC vs standard-acting FVIII products. These PK characteristics will result in higher FVIII levels for longer duration.

Effect of Liquid Feed-Stock Composition on the Morphology of Titanium Dioxide Films Deposited by Thermal Plasma Spray.

Titanium dioxide coatings were deposited on the surface of titanium foils by Thermal Plasma Spray (TPS) process. Three different TiO2 coatings were prepared using the commercial TiO2-P25 nanopowder and titanium isopropoxide precursor solution as feed-stocks. Structure and morphology of the TiO2-P25 powder and the plasma sprayed coatings were analyzed by X-ray diffraction (XRD), Raman spectroscopy, N2 adsorption-desorption isotherms, UV-visible spectroscopy and Scanning Electron Microscopy (SEM). XRD and Raman results indicate that the TiO2 coatings were composed of an anatase/rutile mixture that is conditioned by the suspension composition used to be sprayed. Coatings prepared from TiO2-P25 nanoparticles in water suspension (NW-P25) and titanium isopropoxide solution suspension (NSP-P25) are incorporated into the coatings without phase transformation and their anatase/rutile ratio percentage remains very similar to the starting TiO2-P25 powder. On the contrary, when titanium isopropoxide solution is used for spraying (SP), the amount of rutile increases in the final TiO2 coating. SEM analysis also reveals different microstructure morphology, coating thickness, density and porosity of the three TiO2 films that depend significantly on the type of feed-stock employed. Interestingly, we have observed the role of titanium isopropoxide in the formation of more porous and cohesive layers of TiO2. The NSP-P25 coating, prepared with a mix of titanium isopropoxide solution based on TiO2 nanoparticles, presents higher deposition efficiencies and higher coating thickness than the film prepared with nanoparticles suspended in water (NW-P25) or with titanium isopropoxide solutions (SP). This is due to the precursor solution is acting as the cement between TiO2 nanoparticles, improving the cohesive strength of the coating. In sum, NSP-P25 and NW-P25 coatings display a good photocatalytic potential, based on their light absorption properties and mechanical stability. Band gap of the nanoparticulated coatings displays a light absorption at wavelengths below 379 and 399 nm for NW-P25 and NSP-P25 respectively. On the contrary, the SP coating, despite to present lower band-gap value, has bad cohesive properties with surface crackings that makes it mechanically unstable. Therefore, mixtures of P25 nanoparticles with titanium isopropoxide as feed-stock materials can produce promising photocatalytic coatings.

Relationship between in feed drugs, antibiotics and organic enrichment in marine sediments at Canadian Atlantic salmon aquaculture sites.

The presence of in-feed anti-sea lice drugs and their relationship with organic enrichment is poorly understood in sediment surrounding salmon farms. Using data from an aquaculture monitoring program (2018-2020), we describe this relationship at ten sites in four Canadian provinces. Three anti-sea lice pesticides (lufenuron, teflubenzuron, emamectin benzoate and metabolite desmethyl emamectin benzoate), and one antibiotic (oxytetracycline) were detected. Concentrations were often below limits of quantification. Values are also lower than those reported in other aquaculture salmon-producing countries. Highest concentrations, along with organic enrichment, were observed ~200 m of cages with lower concentrations detected up to 1.5 km away. Most samples had at least two drugs present: 75.2 % (British Columbia), 91.4 % (Newfoundland), and 54.8 % (New Brunswick/Nova Scotia) highlighting the potential for cumulative effects. Emamectin benzoate and oxytetracycline were detected four and three years respectively after last known treatments, demonstrating the need for research on overall persistence of compounds.

Effect of gravity-like torque on goal-directed arm movements in microgravity.

Gravitational force level is well-known to influence arm motor control. Specifically, hyper- or microgravity environments drastically change pointing accuracy and kinematics, particularly during initial exposure. These modifications are thought to partly reflect impairment in arm position sense. Here we investigated whether applying normogravitational constraints at joint level during microgravity episodes of parabolic flights could restore movement accuracy equivalent to that observed on Earth. Subjects with eyes closed performed arm reaching movements toward predefined sagittal angular positions in four environment conditions: normogravity, hypergravity, microgravity, and microgravity with elastic bands attached to the arm to mimic gravity-like torque at the shoulder joint. We found that subjects overshot and undershot the target orientations in hypergravity and microgravity, respectively, relative to a normogravity baseline. Strikingly, adding gravity-like torque prior to and during movements performed in microgravity allowed subjects to be as accurate as in normogravity. In the former condition, arm movement kinematics, as notably illustrated by the relative time to peak velocity, were also unchanged relative to normogravity, whereas significant modifications were found in hyper- and microgravity. Overall, these results suggest that arm motor planning and control are tuned with respect to gravitational information issued from joint torque, which presumably enhances arm position sense and activates internal models optimally adapted to the gravitoinertial environment.

Fibres used in the construction of car seats--an assessment of evidential value.

The evidential significance of car seat fibres has been investigated. Thirty six samples of car seat fabric were examined and the fibres catalogued according to their morphology and characteristics. The majority of car seat fibres were black or grey thick polyester fibres that were either dyed or pigmented. The MSP spectra produced were unlike those usually obtained from black or grey polyester fibres used in clothing. Tapings taken from car seats were examined for car seat fibres, various types were found showing that these fibres are expected to shed from the fabric albeit in low numbers, unless the vehicle is older. No fibres that matched the samples of the car seat fabric were found on the tapings of the car seats. One hundred garments were examined for car seat fibres, 10% of garments had populations of such fibres present and 41% had at least one car seat fibre present. None of these fibres matched the samples of the car seat fabric or those from the car seat tapings.

Assessing trace-elements as indicators of marine finfish aquaculture across three distinct Canadian coastal regions.

Several trace-elements have been identified as indicators of finfish aquaculture organic enrichment. In this study, sediment sampling at finfish farms was completed as part of an Aquaculture Monitoring Program in three distinct Canadian regions. Despite diverse datasets, multivariate analyses show a consistent clustering of known direct (Cu and Zn) and indirect (Cd, Mo and U) tracers of aquaculture activities with sediment organic matter (OM) and/or total dissolved sulfides concentrations. OM content was also a predictor of Cu, Zn, Mo and U concentrations according to decision tree analyses. Distance from cages did not emerge as a strong driver of differences among sampling points; however, a tendency towards negative associations is clear especially for Zn. Enriched stations as determined after geochemical normalization were mostly localized within 150 m of net-pens. Selected trace-elements (in particular Zn) can be useful indicators of aquaculture organic enrichment in different ecosystems and valuable tools for monitoring programs.

Processing speed is correlated with cerebral health markers in the frontal lobes as quantified by neuroimaging.

We explored relationships between decline in cognitive processing speed (CPS) and change in frontal lobe MRI/MRS-based indices of cerebral integrity in 38 healthy adults (age 57-90 years). CPS was assessed using a battery of four timed neuropsychological tests: Grooved Pegboard, Coding, Symbol Digit Modalities Test and Category Fluency (Fruits and Furniture). The neuropsychological tests were factor analyzed to extract two components of CPS: psychomotor (PM) and psychophysical (PP). MRI-based indices of cerebral integrity included three cortical measurements per hemisphere (GM thickness, intergyral and sulcal spans) and two subcortical indices (fractional anisotropy (FA), measured using track-based spatial statistics (TBSS), and the volume of hyperintense WM (HWM)). MRS indices included levels of choline-containing compounds (GPC+PC), phosphocreatine plus creatine (PCr+Cr), and N-acetylaspartate (NAA), measured bilaterally in the frontal WM bundles. A substantial fraction of the variance in the PM-CPS (58%) was attributed to atrophic changes in frontal WM, observed as increases in sulcal span, declines in FA values and reductions in concentrations of NAA and choline-containing compounds. A smaller proportion (20%) of variance in the PP-CPS could be explained by bilateral increases in frontal sulcal span and increases in HWM volumes.

A population study of polyurethane foam fragments recovered from the surface of 100 outer-garments.

One hundred outer-garments were examined for microscopic fragments of polyurethane foam. Low power stereomicroscopy was used to classify fragments into 18 groups according to macroscopic colour. Amber, pale yellow and black were the most frequently encountered, whilst navy, pale blue, bright pink, beige, brown, pale green, peach and white were the least frequently encountered. High power comparison/fluorescence microscopy was used to discriminate 166 populations within 16 colour groupings. The majority (95.2%) of populations consisted of three fragments or less. This study demonstrates that the background population of foam fragments on an outer-garment consists of low numbers representing various colours. Therefore, finding a large population of microscopically indistinguishable fragments within a casework situation has the potential to be considered highly significant evidentially.

Safety and efficacy of duodenal stent insertion for gastric outlet obstruction: characterisation of a regional district general hospital service.

INTRODUCTION: Placement of a duodenal or pyloric stent is a recognised palliative procedure for symptomatic relief of malignant gastric outlet obstruction. This procedure can be associated with significant complications, reinterventions and poor long-term relief of obstructive symptoms. However, there may be a faster return to diet and shorter hospital stay in comparison to other palliative procedures (eg gastrojejunostomy). The aim of this study was to determine the safety and efficacy of duodenal stenting in our regional district general hospital in comparison to that of larger tertiary centres. MATERIALS AND METHODS: All patients with gastric outlet obstruction who had duodenal stent placement attempted in our region between 1 August 2013 and 31 July 2018 were identified by retrospective analysis of prospectively maintained coding databases and medical notes. Patient demographics, safety outcomes and efficacy outcomes were then extracted. Results were interpreted with respect to data from best available published evidence from larger tertiary centres. RESULTS: Of 43 duodenal stent insertion attempts, 84% had a successful return to diet, 18% underwent reintervention, 18% suffered adverse events, mean length of stay post-intervention was 8.6 days and mean survival post-intervention was 132 days. CONCLUSIONS: Patients with malignant gastric outlet obstruction in whom duodenal stent placement was attempted had similar outcomes to published data from larger tertiary centres. Duodenal stent placement remains an acceptable treatment option for these patients in our region.

Loss of cerebral white matter structural integrity tracks the gray matter metabolic decline in normal aging.

Relationships between structural MRI-based markers of declining cerebral integrity, and regional PET measurements of (18)FDG uptake have not been studied well in normal aging. In this manuscript we relate changes in cerebral morphology to regional cerebral glucose uptake for 14 major cortical areas in 19 healthy older individuals (age 59-92 years). Measurements of cerebral integrity included gray matter (GM) thickness, sulcal and intergyral spans, fractional anisotropy (FA) of water diffusion and volume of hyperintense WM (HWM) lesions. (18)FDG-PET measurements were converted to standard uptake values and corrected for partial volume artifact. Following this, cortical FDG uptake was significantly correlated with several indices of WM integrity that we previously observed to be sensitive to cognitive decline in executive function, including intergyral span and HWM volumes. Our findings suggest that the age-related decline in white matter integrity, observed as increases in HWM lesions, intergyral spans and reduction in FA, correlated with a decline in the global and regional cerebral glucose uptake. Our findings support the emerging consensus that WM integrity indices are sensitive predictors of declining cerebral health in normal aging. Specifically, age-related WM degradation in the thinly myelinated association tracts appears to track the decreases in global and regional rates of glucose uptake.

Radiology cases from the Royal Hospital for Sick Children, Glasgow: biloma as a complication of hepatic transection due to a handlebar injury.

Handlebar type injuries are well documented in the paediatric population. We describe a case complicated by a biloma, which was successfully treated with percutaneous drainage, guided radiologically. The imaging findings including CT, MRI and nuclear medicine techniques are presented.

Phantom hand and wrist movements in upper limb amputees are slow but naturally controlled movements.

After limb amputation, patients often wake up with a vivid perception of the presence of the missing limb, called "phantom limb". Phantom limbs have mostly been studied with respect to pain sensation. But patients can experience many other phantom sensations, including voluntary movements. The goal of the present study was to quantify phantom movement kinematics and relate these to intact limb kinematics and to the time elapsed since amputation. Six upper arm and two forearm amputees with various delays since amputation (6months to 32years) performed phantom finger, hand and wrist movements at self-chosen comfortable velocities. The kinematics of the phantom movements was indirectly obtained via the intact limb that synchronously mimicked the phantom limb movements, using a Cyberglove® for measuring finger movements and an inertial measurement unit for wrist movements. Results show that the execution of phantom movements is perceived as "natural" but effortful. The types of phantom movements that can be performed are variable between the patients but they could all perform thumb flexion/extension and global hand opening/closure. Finger extension movements appeared to be 24% faster than finger flexion movements. Neither the number of types of phantom movements that can be executed nor the kinematic characteristics were related to the elapsed time since amputation, highlighting the persistence of post-amputation neural adaptation. We hypothesize that the perceived slowness of phantom movements is related to altered proprioceptive feedback that cannot be recalibrated by lack of visual feedback during phantom movement execution.

Mechlorethamine, vincristine, and procarbazine chemotherapy for recurrent high-grade glioma in adults: a phase II study.

We undertook a phase II study of combination chemotherapy with mechlorethamine (nitrogen mustard) 6 mg/m2 intravenously day 1 and day 8, vincristine 2 mg intravenously day 1 and day 8, and procarbazine 100 mg/m2 orally days 1 through 14 (MOP) in adults with recurrent high-grade glioma. There were 31 patients entered and 27 patients assessable for response. The median age was 49 years old. All patients had prior maximal radiotherapy, and eight had previous chemotherapy. Responses were determined based on clinical and computed tomographic (CT) scan/magnetic resonance imaging (MRI) criteria. The response rate (partial response [PR] plus objective qualitative response [OQR] plus complete response [CR]) was 52% with one CR. The response rate was higher in patients with anaplastic astrocytoma as compared with glioblastoma multiforme (P less than .05). The median duration of response was 42 weeks. Median survival for all assessable patients was 30 weeks, and for responders, it was 60 weeks. Response was correlated with ability to decrease dexamethasone doses and improved performance status. Toxicity was mainly hematologic with leukopenia being common. There was one treatment-related death from listeria meningitis, and two patients developed Pneumocystis carinii pneumonia. There were three episodes of neutropenic fever. We conclude that MOP is active and merits further investigation in adult high-grade glioma.

Anticonvulsant usage is associated with an increased risk of procarbazine hypersensitivity reactions in patients with brain tumors.

BACKGROUND: Procarbazine usage in brain tumors has a high incidence of hypersensitivity reactions compared with its use in other malignancies. Procarbazine oxidation to a reactive intermediate is enhanced by phenobarbital. Patients with primary brain tumors would have a preferential exposure to anticonvulsants compared to patients with other malignancies. OBJECTIVE: To determine whether anticonvulsant exposure is associated with procarbazine hypersensitivity reactions in patients with primary brain tumors. METHODS: This retrospective cohort study included 83 patients with primary brain tumors who were treated with procarbazine between 1981 and 1996 at a university hospital-based regional oncology center. Data were extracted by chart review. The data collected included age, sex, race, tumor type, smoking, alcohol usage, and all concomitant medications, as well as creatinine, aspartate aminotransferase, total bilirubin, and anticonvulsant serum levels. Anticonvulsant exposure was determined by the presence of detectable serum levels. Cases of procarbazine hypersensitivity reactions were identified through a review of progress notes. RESULTS: There were 20 patients with procarbazine hypersensitivity reactions. A significant association between the exposure to anticonvulsants and the development of procarbazine hypersensitivity reactions was found (p = 0.05). In addition, there was a significant dose-response association between the development of procarbazine hypersensitivity and the presence of therapeutic anticonvulsant serum levels (p = 0.03). CONCLUSIONS: Concomitant exposure to anticonvulsants is associated with procarbazine hypersensitivity reactions, possibly though a reactive intermediate generated by CYP3A isoform induction. All patients in this cohort received enzyme-inducing anticonvulsants. New anticonvulsants devoid of this property are available. These data support trials that use these newer agents for the prophylaxis of seizures in patients with brain tumors who are to receive procarbazine.

Prototypical HTLV-I/II infection is rare in LGL leukemia.

The etiology of LGL leukemia is not known; however, we recently detected HTLV-II in a patient with LGL leukemia. In this study, we found that sera from 6 of 28 patients with LGL leukemia were positive for HTLV-I/II using a whole virus ELISA; moreover, the ELISA-negative sera were near the positive cut-off value. Therefore, we performed additional studies on these sera using commercially available assays which can confirm and distinguish HTLV-I from HTLV-II infection. Serum from only one patient was confirmed positive using conventional criteria (HTLV-II+). Sera from 25 patients (89%) had indeterminate reactivity on Western blot assays. Of these, sera from 21 (84%) reacted to gag protein p24; 12 (48%) reacted with recombinant env protein p21e, and 10 (40%) reacted with both. We could not detect HTLV-I/II pol or pX gene sequences in these patients using polymerase chain reaction analyses, with the exception of the HTLV-II-infected patient described previously. These data show that most patients with LGL leukemia are not infected with prototypical HTLV-I or HTLV-II. The frequent reactivity of patient sera to HTLV-I/II gag protein p24 and to env protein p21e, however, suggests that a deleted or variant form of HTLV-I/II may be associated with LGL leukemia.

Stress controllability influences the ataxic properties of both ethanol and midazolam in the rat.

Rats were administered either 80 escapable shocks or yoked inescapable shocks, were then injected with saline or several ataxic doses of either ethanol or midazolam, and then had their motoric impairment assessed by Rotarod performance. No motoric impairment was observed following saline injection. However, inescapable shock impaired Rotarod performance in response to both ethanol and midazolam at 2 hr, but not immediately poststress. Conversely, escapable shock reduced the ataxic potency of ethanol, although it had no influence on midazolam-induced ataxia. These results indicate functional alterations in behavioral reactivity to low doses of several classes of central nervous system depressants by psychological dynamics of stress exposure. Our findings demonstrate the impact of stress controllability on behavioral reactivity to two classes of drugs of abuse.

Transformation of polycythemia vera to acute nonlymphocytic leukemia accompanied by t(1;3)(p36;q21) karyotype.

The case of a patient with a history of polycythemia vera and 46,XX karyotype who transformed into acute nonlymphocytic leukemia with 46,XX,t(1;3)(p36;q21) rearrangement is reported. Significant percentages of the circulating blasts in the peripheral blood were positive on immunocytochemical stains for megakaryocyte markers, anti-Factor VIII, and antiglycoprotein IIb/IIIa. On the basis of our studies and published reports, trilineage hematopoietic abnormalities and a poor response to therapy may represent typical features of patients with t(1;3).

Adenosine kinase inhibitors attenuate opiate withdrawal via adenosine receptor activation.

Previous studies have demonstrated a role for adenosine in mediating opiate effects. This study examines the effects of indirect activation of adenosine receptors, via treatment with adenosine kinase inhibitors, on the expression of opiate withdrawal in mice. Mice receive chronic morphine treatment via implantation of subcutaneous morphine pellets (75 mg) for 72 h. Mice then receive parenteral treatment with adenosine kinase inhibitors, either 5'-amino-5'-deoxyadenosine (2, 5, 20, 40 mg/kg, intraperitoneal or i.p.) or iodotubericidin (1, 2, 5 mg/kg, i.p.), followed by naloxone injection and opiate withdrawal signs are measured over 20 min. Both adenosine kinase inhibitors significantly reduce the following opiate withdrawal signs in a dose-dependent manner compared to vehicle: withdrawal jumps, teeth chattering, forepaw tremors, and forepaw treads. Additionally, 5'-amino-5'-deoxyadenosine significantly reduces withdrawal-induced diarrhea and weight loss. Effects of 5'-amino-5'-deoxyadenosine (40 mg/kg) on opiate withdrawal signs appear to be mediated via adenosine receptor activation as they are reversed by pretreatment by adenosine receptor antagonist caffeine (20 mg, i.p.) but not by selective phosphodiesterase inhibitor Ro 20-1724 (10 mg/kg, i.p.). Adenosine receptor activation via adenosine kinase inhibitor treatment attenuates opiate withdrawal and these agents may be generally useful in the treatment of drug withdrawal syndromes.

A dynamic pattern analysis of coordination between breathing and rhythmic arm movements in humans.

We investigated the behavioral dynamics of human breathing-wrist movement coordination in a 1:1 frequency locking task. A pronation-supination wrist movement and a short trial duration were chosen to limit both mechanical and metabolic constraints on the respiratory system. Subjects voluntarily controlled their breathing rhythm to follow the metronome. We found that pronation-expiration and pronation-inspiration patterns coexisted as the (sole) stable fixed-point attractors of the coordination system. The pronation-expiration pattern was more stable than the pronation-inspiration pattern. Depending on the oscillation frequency, this differential stability gave rise to both absolute and relative coordination. These results show that simple behavioral laws of coordination encapsulate neural coupling dynamics evidenced from experimental research in human beings and animals. They challenge the classical view that such a coupling is not present for all imposed movement frequencies. Rather, relative coordination emerges as a result of the modification of coupling strength with frequency. These results can be accommodated by the asymmetric version of the HKB model of coordination dynamics. Thus, our data suggest that the principles and models of coordination dynamics may be taken as a reference to study the coupling of the motor and physiological subsystems involved in breathing-movement coordination.

Hematologic complications of human immunodeficiency virus infection and the acquired immunodeficiency syndrome.

The hematologic manifestations of HIV infection and AIDS are common and may cause symptoms that are life-threatening and impair the quality of life of these patients. The most important of these manifestations are cytopenias. Anemia and neutropenia are generally caused by inadequate production because of suppression of the bone marrow by the HIV infection through abnormal cytokine expression and alteration of the bone marrow microenvironment. Thrombocytopenia is caused by immune-mediated destruction of the platelets, in addition to inadequate platelet production. The incidence and severity of cytopenia are generally correlated to the stage of the HIV infection. Other causes of cytopenia in these patients include adverse effects of drug therapy, the secondary effects of opportunistic infections or malignancies, or other preexisting or coexisting medical problems that may be prevalent in the HIV-infected population. Diagnosis of the mechanism and cause of the cytopenia may allow for specific management. Optimal management of the underlying HIV infection is essential, and mild cytopenia in asymptomatic patients may need no specific management. Supportive care for anemia includes the use of erythropoietin in addition to the judicious use of red blood cell transfusions. Therapy for neutropenia includes the use of the myeloid growth factors G-CSF and GM-CSF. Immune-mediated thrombocytopenia may be treated with a combination of zidovudine, corticosteroids, IVGG, and splenectomy. Platelet transfusions are sometimes needed for the treatment of thrombocytopenia caused by decreased production. Other hematologic manifestations such as hypergammaglobulinemia and lupus anticoagulants are commonly asymptomatic and usually require no specific therapy, but they can rarely cause morbidity and require specific interventions.