Presence of Newcastle disease viruses of sub-genotypes Vc and VIn in backyard chickens and in apparently healthy wild birds from Mexico in 2017.

Virulent Newcastle disease viruses (NDV) have been present in Mexico since 1946, and recently, multiple outbreaks have been reported in the country. Here, we characterized eleven NDV isolated from apparently healthy wild birds and backyard chickens in three different locations of Jalisco, Mexico in 2017. Total RNA from NDV was reverse-transcribed, and 1285 nucleotides, which includes 3/4 of the fusion gene, was amplified and sequenced using a long-read MinION sequencing method. The sequences were 99.99-100% identical to the corresponding region obtained using the Illumina MiSeq. Phylogenetic analysis using MinION sequences demonstrated that nine virulent NDV from wild birds belonged to sub-genotypes Vc and VIn, and two backyard chicken isolates were of sub-genotype Vc. The sub-genotype Vc viruses had nucleotide sequence identity that ranged from 97.7 to 98% to a virus of the same sub-genotype isolated from a chicken in Mexico in 2010. Three viruses from pigeons had 96.3-98.7% nucleotide identity to sub-genotype VIn pigeon viruses, commonly referred to as pigeon paramyxovirus, isolated in the USA during 2000-2016. This study demonstrates that viruses of sub-genotype Vc are still present in Mexico, and the detection of this sub-genotype in both chickens and wild birds suggests that transmission among these species may represent a biosecurity risk. This is the first detection and complete genome sequencing of genotype VI NDV from Mexico. In addition, the utilization of an optimized long-read sequencing method for rapid virulence and genotype identification using the Oxford nanopore MinION system is demonstrated.

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2.

We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2(V617F)-positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2(V617F)-expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.

Four-limb compartment syndrome associated with the systemic capillary leak syndrome.

Systemic capillary leak syndrome, or the Clarkson syndrome, is an extremely rare condition in which increased capillary permeability results in a massive shift of fluid into the extravascular space. This is followed rapidly by hypotensive shock, haemoconcentration, and, potentially, substantial oedema of the limbs resulting in an acute compartment syndrome. It is important for orthopaedic surgeons to be aware of this syndrome as our medical colleagues, who initially care for these patients, are less familiar with the diagnosis and the need for emergency management of the associated compartment syndrome should it develop. There have been fewer than 100 cases of this entity reported. This case report is the first to describe the subsequent development of a compartment syndrome in all four limbs. Clinical vigilance and continuous monitoring of intracompartmental pressure is necessary in these patients in order to help reduce limb-threatening complications.

Millisecond timing on PCs and Macs.

A real-time, object-oriented solution for displaying stimuli on Windows 95/98, MacOS and Linux platforms is presented. The program, written in C++, utilizes a special-purpose window class (GLWindow), OpenGL, and 32-bit graphics acceleration; it avoids display timing uncertainty by substituting the new window class for the default window code for each system. We report the outcome of tests for real-time capability across PC and Mac platforms running a variety of operating systems. The test program, which can be used as a shell for programming real-time experiments and testing specific processors, is available at http://www.cs.dal.ca/~macinnwj. We propose to provide researchers with a sense of the usefulness of our program, highlight the ability of many multitasking environments to achieve real time, as well as caution users about systems that may not achieve real time, even under optimal conditions.

High-dose therapy and autologous hematopoietic-cell transplantation for follicular lymphoma beyond first remission: the Stanford University experience.

A retrospective analysis was performed to investigate the outcome of high-dose therapy (HDT) and autologous hematopoietic cell transplantation in patients with follicular lymphomas beyond first remission. Ninety-two patients with primary induction failure or relapsed follicular low-grade lymphoma (FLGL), follicular large cell lymphoma (FLCL), and transformed follicular lymphoma (TFL) were treated with myeloablative therapy consisting of etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and either carmustine (BCNU;15 mg/kg) or fractionated total body irradiation (FTBI; 1200 cGy) followed by transplantation of purged autologous bone marrow or peripheral blood hematopoietic cells. For the 49 patients with relapsed FLGL, the median age was 49 years and the median interval from diagnosis to HDT was 30 months. The 4-year estimate of overall survival (OS) was 60% (95% confidence interval [CI], 45%-75%) and of disease-free survival (DFS) was 44% (95% CI, 29%-59%). Treatment with the FTBI-containing HDT regimen was associated with significantly longer DFS (P = .04) and OS (P = .04) in our multivariate analysis. OS was also significantly longer among those treated with 3 or fewer chemotherapy regimens. For the 26 FLCL patients, the median age was 51 years and in 31% the indication for HDT was primary induction failure. For FLCL patients, the 4-year estimate of OS was 58% (95% CI, 37%-79%) and of DFS was 51% (95% CI, 30%-72%). Among the 17 patients with TFL, 13 (76%) transformed at first relapse, and only 6 patients (35%) achieved complete remission with salvage therapy prior to HDT. For TFL patients, the 4-year estimate of OS was 50% (95% CI, 24%-76%) and of DFS 49% (95% CI, 20%-78%). There were 3 occurrences of myelodysplasia (1 after treatment with TBI, 2 after BCNU treatment), yielding an estimated incidence of 7% (95% CI, 0%-16%) at 56 months. This analysis shows that relapsed FLGL patients treated with 3 or fewer different chemotherapy regimens show inferior survival. The HDT regimen containing FTBI appears to be superior to the BCNU-based regimen for relapsed FLGL, although longer follow-up is needed to evaluate late effects. Lastly, patients with TFL or induction failure and relapsed FLCL can achieve survival outcome comparable to those observed with the indolent follicular lymphomas.

Performance monitoring by the supplementary eye field.

Intelligent behaviour requires self-control based on the consequences of actions. The countermanding task is designed to study self-control; it requires subjects to withhold planned movements in response to an imperative stop signal, which they can do with varying success. In humans, the medial frontal cortex has been implicated in the supervisory control of action. In monkeys, the supplementary eye field in the dorsomedial frontal cortex is involved in producing eye movements, but its precise function has not been clarified. To investigate the role of the supplementary eye field in the control of eye movements, we recorded neural activity in macaque monkeys trained to perform an eye movement countermanding task. Distinct groups of neurons were active after errors, after successful withholding of a partially prepared movement, or in association with reinforcement. These three forms of activation could not be explained by sensory or motor factors. Our results lead us to put forward the hypothesis that the supplementary eye field contributes to monitoring the context and consequences of eye movements.

Visual and motor effects in inhibition of return.

Inhibition of return (IOR) refers to slowed reaction times (RTs) when a target appears in the same rather than a different location as a preceding stimulus. The present study tested the hypothesis that IOR reflects a motor bias rather than a perceptual deficit. Two signals (S1 and S2) were presented on each trial. These signals were peripheral onsets or central arrows. The responses required to S1 and S2 were, respectively, no response-manual, manual-manual, saccadic-manual, no response-saccadic, manual-saccadic, and saccadic-saccadic. Uniting perceptual and motor bias views of IOR, the results demonstrated inhibition for responding to (a) peripheral signals when the eyes remained fixed (slowed visual processing) and (b) both peripheral and central signals when the eyes moved (slowed motor production). However, the results also emphasized that the nature of IOR depends fundamentally on the response modality used to reveal its influence.

Neural control of behavior: countermanding eye movements.

Understanding the self-control of action entails knowledge about how actions are initiated, how planned actions are canceled and how the consequences of actions are registered. We have investigated neural correlates of these processes using the countermanding paradigm--a task that required subjects to occasionally cancel a planned speeded response, and an analysis that provides an estimate of the time needed to cancel a planned movement. By monitoring the activity of single neurons in the frontal cortex of macaque monkeys performing this task we have distinguished signals responding to the visual stimuli, other signals that control the production of movements, and still other signals that seem to monitor behavior.

Pulmonary toxicity syndrome in breast cancer patients undergoing BCNU-containing high-dose chemotherapy and autologous hematopoietic cell transplantation.

We performed a retrospective review to investigate pulmonary toxicity syndrome (PTS) in a cohort of breast cancer patients undergoing BCNU-containing high-dose chemotherapy (HDC). Our aim was to characterize presentation, identify risk factors, determine outcome following therapy, and find any association with differences in survival. We reviewed the data of 152 patients with stage II or III or metastatic breast cancer treated with cyclophosphamide 5625 mg/m2, cisplatin 165 mg/m2, and BCNU 600 mg/m2 followed by autologous peripheral blood hematopoietic cell transplantation. During follow-up, PTS was diagnosed when the following criteria were met: (1) presentation with typical clinical symptoms of PTS, (2) an absolute carbon monoxide diffusion capacity (DLCO) decline of 10% compared with pre-HDC DLCO, and (3) no clinical evidence of active pulmonary infection. Patients were then treated with a course of corticosteroid therapy. The incidence of PTS for all 152 patients was 59%, with a median onset at 45 days (range, 21-149 days) post-HDC. The median absolute DLCO decrement was 26% (range, 10%-73%) at diagnosis of PTS. There was no significant correlation between patient age, stage of breast cancer, pre-HDC chemotherapy regimen, pre-HDC chest wall radiotherapy, tobacco use, prior lung disease, or baseline pulmonary function test results and the development of PTS. We did observe an interesting association between PTS and the development of a noncholestatic elevation of transaminases. Of PTS patients treated with prednisone therapy for a median of 105.5 days (range, 44-300 days), 91% achieved resolution of their PTS without pulmonary sequelae. At 3 years, the overall survival (OS) of stage II or III patients who developed PTS was 84% (95% confidence interval [CI], 73%-95%); of metastatic breast cancer patients with PTS, the OS was 58% (95% CI, 38%-78%). These values were not significantly different from those of patients who did not develop PTS (91% [95% confidence interval [CI], 81%-100%] and 53% [95% CI, 32%-74%], respectively). No significant differences in disease-free or event-free survival were observed between patients with and without PTS. The incidence of PTS in breast cancer patients treated with a BCNU-containing HDC regimen can be remarkably high. Treatment with a course of corticosteroid therapy is successful in the vast majority.

Parental alcoholism, child abuse, and adult adjustment.

Parallel findings in the adult children of alcoholics (ACOA) and child abuse literatures are integrated and extended by assessing long-term adjustment and childhood histories of parental alcoholism and sexual, physical, and emotional abuse in college students (N = 333). Abuse histories were most strongly related to adult symptom distress and social maladjustment. Parental alcoholism had no independent effects when controlling for abuse history. Parental alcoholism interacted with abuse history in relation to social adjustment, exacerbating the effects of emotional abuse. This study adds to a growing literature calling for more complex models of ACOA development that can account for the diversity of this population.

American Indian and Alaska Native health behavior: findings from the behavioral risk factor surveillance system, 1992-1995.

OBJECTIVE: The purpose of this study was to evaluate differences between American Indian and white adults in behavioral risk factors for chronic disease and injury. METHODS: Data were drawn from the 1992-1995 Behavioral Risk Factor Surveillance System, an ongoing telephone survey of health behaviors of adults. Prevalence estimates by sex were calculated for American Indian and white respondents in 15 states and the significance of their differences evaluated by chi-square tests. RESULTS: American Indians were found to be at significantly higher risk than whites for fair to poor general health status, medical cost difficulties, binge drinking, cigarette smoking, not always using safety belts, being diagnosed as diabetic, and obesity. CONCLUSIONS: To reduce the gap in behavioral risk factors between American Indians and whites, more resources need to be dedicated to American Indian health. Note. The term "American Indian" henceforth refers to those who identify themselves as American Indian or Alaska Native.

Influence of previous visual stimulus or saccade on saccadic reaction times in monkey.

Influence of previous visual stimulus or saccade on saccadic reaction times in monkey. Saccadic reaction times (SRTs) to suddenly appearing targets are influenced by neural processes that occur before and after target presentation. The majority of previous studies have focused on how posttarget factors, such as target attributes or changes in task complexity, affect SRTs. Studies of pretarget factors have focused on how prior knowledge of the timing or location of the impending target, gathered through cueing or probabilistic information, affects SRTs. Our goal was to investigate additional pretarget factors to determine whether SRTs can also be influenced by the history of saccadic and visual activity even when these factors are spatially unpredictive as to the location of impending saccadic targets. Monkeys were trained on two paradigms. In the saccade-saccade paradigm, monkeys were required to follow a saccadic target that stepped from a central location, to an eccentric location, back to center, and finally to a second eccentric location. The stimulus-saccade paradigm was similar, except the central fixation target remained illuminated during presentation of the first eccentric stimulus; the monkey was required to maintain central fixation and to make a saccade to the second eccentric stimulus only on disappearance of the fixation point. In both paradigms, the first eccentric stimulus was presented at the same, opposite, or orthogonal location with respect to the final target location in a given trial. We measured SRTs to the final target under conditions in which all parameters were identical except for the location of the first eccentric stimulus. In the saccade-saccade paradigm, we found that the SRT to the final target was slowest when it was presented opposite to the initial saccadic target, whereas in the stimulus-saccade paradigm the SRT to the final target was slowest when it was presented at the same location as the initial stimulus. In both paradigms, these increases in SRTs were greatest during the shortest intervals between presentation of successive eccentric stimuli, yet these effects remained present for the longest intervals employed in this study. SRTs became faster as the direction and eccentricity of the two successive stimuli became increasingly misaligned from that which produced the maximal SRT slowing in each paradigm. The results of the stimulus-saccade paradigm are similar to the phenomenon of inhibition of return (IOR) in which human subjects are slower to respond to stimuli that are presented at previously cued locations. We interpret these findings in terms of overlapping representations of visuospatial and oculomotor activity in the same neural structures.

Saccadic performance as a function of the presence and disappearance of auditory and visual fixation stimuli.

Relative to when a fixated stimulus remains visible, saccadic latencies are facilitated when a fixated stimulus is extinguished simultaneously with or prior to the appearance of an eccentric auditory, visual, or combined visual-auditory target. In a study of nine human subjects, we determined whether such facilitation (the "gap effect") occurs equivalently for the disappearance of fixated auditory stimuli and fixated visual stimuli. In the present study, a fixated auditory (noise) stimulus remained present (overlap) or else was extinguished simultaneously with (step) or 200 msec prior to (gap) the appearance of a visual, auditory (tone), or combined visual-auditory target 10 degrees to the left or right of fixation. The results demonstrated equivalent facilitatory effects due to the disappearance of fixated auditory and visual stimuli and are consistent with the presumed role of the superior colliculus in the gap effect.

"Central" auditory gap detection: a spatial case.

Normal listeners were tested for their temporal auditory gap detection thresholds using free-field presentation of white-noise stimuli delivered from the left (L) and right (R) poles of the interaural axis. The noise bursts serving as the leading and trailing markers for the silent period were presented in either the same (LL,RR) or different (LR,RL) auditory locations. The duration of the leading marker was a second independent variable. Gap thresholds for stimuli in which the markers had the same location were low, and usually were independent of the duration of the leading marker. Gap thresholds for the LR and RL conditions were longer. These gap thresholds were sensitive to the duration of the leading marker, and increased as the leading marker duration decreased. This finding is consistent with the hypothesis that a relative timing operation mediates gap detection when the markers activate different perceptual channels. The present data suggest that this timing process can operate on perceptual channels emerging from central nervous system processing.

Heteroatom- and carbon-linked biphenyl analogs of Brequinar as immunosuppressive agents.

Structure-activity relationships were explored for some analogs of Brequinar having a linking atom between the 2-biphenyl substituent and the quinoline ring. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction were related to the overall shape and lipophilicity of the 2-substituent.

Prepartum protein restriction does not alter norepinephrine-induced thermogenesis or brown adipose tissue function in newborn calves.

We examined the effect of prepartum protein restriction on thermogenesis and several aspects of perirenal (brown) adipose tissue (BAT) in newborn calves. Lipid synthesis and morphology also were compared between BAT and sternum (white) adipose tissue. During the last 140 d of gestation, heifers were fed isocaloric diets containing adequate (10.4%) or restricted (average of 6.8%, dry matter basis) levels of protein. Body condition scores and weight gain during gestation were significantly lower in heifers fed the restricted-protein diet. However, newborn calf birth weight, calf BAT weight and composition, and calf thermoneutral metabolic rates were not affected by prepartum protein restriction. Similarly, visceral organ weights, except for lung plus trachea, were not affected (P > 0.10) by prepartum protein treatment. Peak metabolic rates were not affected (P > 0.10) by prepartum protein treatment and on average were twice the thermoneutral metabolic rates. Consistent with this, BAT of calves from heifers fed adequate- or restricted-protein diets did not differ in lipid synthesis, cellularity, or uncoupling protein mRNA:28S rRNA ratios. Although both perirenal and sternum adipocytes were mostly unilocular, perirenal adipocytes contained numerous large mitochondria with well-differentiated cristae; sternum adipocytes contained a small number of mitochondria with poorly developed cristae. Fatty acid biosynthesis from acetate was high in BAT (55-57 nmol acetate incorporated.100 mg-1.h-1) but barely detectable in sternum adipose tissue. Conversely, fatty acid biosynthesis from glucose was 80-110% higher in sternum adipose tissue than in BAT (4.5 vs 2.1-2.5 nmol glucose incorporated.100 mg-1.h-1). Thus maternal protein restriction severely affected heifers but had no effect on neonatal calf thermogenesis or BAT function.

Detection of silent intervals between noises activating different perceptual channels: some properties of "central" auditory gap detection.

This article describes four experiments on gap detection by normal listeners, with the general goal being to examine the consequences of using noises in different perceptual channels to delimit a silent temporal gap to be detected. In experiment 1, subjects were presented with pairs of narrow-band noise sequences. The leading element in each pair had a center frequency of 2 kHz and the trailing element's center frequency was parametrically varied. Gap detection thresholds became increasingly poor, sometimes by up to an order of magnitude, as the spectral disparity was increased between the noise bursts that marked the gap. These data suggested that gap-detection performance is impoverished when the underlying perceptual timing operation requires a comparison of activity in different perceptual channels rather than a discontinuity detection within a given channel. In experiment 2, we assessed the effect of leading-element duration in within-channel and between-channel gap detection tasks. Gap detection thresholds rose when the duration of the leading element was less than about 30 ms, but only in the between-channel case. In experiment 3, the gap-detection stimulus was redesigned so that we could probe the perceptual mechanisms that might be involved in stop consonant discrimination. The leading element was a wideband noise burst, and the trailing element was a 300-ms bandpassed noise centered on 1.0 kHz. The independent variable was the duration of the leading element, and the dependent variable was the smallest detectable gap between the elements. When the leading element was short in duration (5-10 ms), gap thresholds were close to 30 ms, which is close to the voice onset time that parses some voiced from unvoiced stop consonants. In experiment 4, the generality of the leading-element duration effect in between-channel gap detection was examined. Spectrally identical noises defining the leading and trailing edges of the gap were presented to the same or to different ears. There was a leading-element duration effect only for the between channel case. The mean gap threshold was again close to 30 ms for short leading-element durations. Taken together, the data suggest that gap detection requiring a temporal correlation of activity in different perceptual channels is a fundamentally different task to the discontinuity detection used to execute gap detection performance in the traditional, within-channel paradigm.

Storage pool disease in chronic lymphocytic leukemia: abnormal aggregation and secretion without bleeding.

Although bleeding complications are relatively common in patients with chronic lymphocytic leukemia, they tend to be related to thrombocytopenia or an acquired clotting factor inhibitor. Chronic lymphocytic leukemia-associated thrombocytopenia, which may also contribute to the hemorrhagic risk, is generally caused by decreased production and immune-mediated destruction. This is the case of a 56-year-old man with longstanding chronic lymphocytic leukemia who developed thrombocytopenia (platelet counts of approximately 50,000/microL) with an associated abnormal platelet morphology. Although the patient did not suffer clinically significant bleeding, several tests of platelet function were grossly abnormal. Electron microscopic examination of the platelets revealed virtually complete absence of dense granules. Platelet aggregation did not occur with adenosine diphosphate (10 microM), collagen (2 micrograms/mL), or ristocetin (1 mg/mL). Doubling the agonist concentrations produced only minimal agglutination with ristocetin. The bleeding time was mildly prolonged at 9.0 and 10.5 minutes. Von Willebrand antigen and ristocetin cofactor levels were normal. Collagen-induced adenosine triphosphate secretion was less than 10% that of a matched normal control. In contrast, platelet force development was virtually normal, reaching 4,800 dynes at 1,200 seconds compared with 5,800 dynes for the healthy control. The patient's clots demonstrated enhanced clot modulus 44,000 dynes/cm2 versus 22,400 dynes/cm2 for the healthy control. The latter finding was primarily because of high fibrinogen concentration. This third report of storage pool disease in a patient with chronic lymphocytic leukemia demonstrates that dense granule release is not required for normal platelet-mediated force development.