A survey of dairy goat kid-rearing practices on Canadian farms and their associations with self-reported farm performance.

Although future production of dairy goats is influenced by kid-rearing practices, little is known regarding which practices maximize kid growth, welfare, and future production success. The objectives of this survey study were to (1) identify common rearing practices of Canadian commercial dairy goat farms and evaluate their associations with 6 farm performance indicators and (2) determine if farms could be grouped by management style on the basis of the 6 performance indicators and compare rearing practices common across the different groups. A survey was sent by post or electronic media to reach dairy goat producers across Canada. The questionnaire contained 70 questions on the following areas of kid rearing: kidding management, care of newborn, colostrum management, milk and solid feeding in the preweaning period, health management, disbudding, housing conditions, weaning strategies, record keeping and growth monitoring, and farm performance data. Performance indicators, calculated on self-reported data, were 305-d milk production, preweaning mortality rate, diarrhea and respiratory disease prevalence, average daily gain from birth to weaning, herd milk production, and replacement rate. A total of 175 questionnaires were returned. After applying inclusion criteria, including herd size (≥40 goats) and completeness of surveys, 104 respondents from Ontario (n = 72, 69%), Québec (n = 23, 22%), and the Western provinces (n = 9, 9%) were retained for analysis, representing 29% of all Canadian producers. Farm sizes ranged from 42 to 2,500 (median = 190) goats. A large amount of variation in rearing practices and farm performance was found between farms. Colostrum and milk feeding management were found to be associated with all performance indicators except for kid respiratory disease prevalence, with timing of colostrum delivery and feeding method accounting for most the associations within each of the 2 areas. Replacement rate was mostly affected by whether or not kids were reared with their dam. Herds surveyed in the study could successfully be divided into 3 distinct groups (production-focused, longevity-focused, and low performance), representing different management styles on the basis of farm self-reported performance levels. Rearing practices found to be associated with higher farm performance could be targeted by advisory services to help improve management practices on Canadian dairy goat farms.

Potassium carbonate as a supplement to improve milk fat concentration and yield in early-lactating dairy goats fed a high-starch, low-fiber diet.

This study investigated the use of K2CO3 as dietary buffer to prevent or to recover from low milk fat production when early-lactating dairy goats are fed a high-starch, low-fiber (HSLF) diet. At kidding, 30 Alpine goats housed in pens with Calan gate feeders received a total mixed ration with a forage-to-concentrate ratio of 55:45 on a dry matter (DM) basis for a baseline period of 27 ± 4 d. Goats (milk yield, 4.14 ± 0.88 kg/d; milk fat, 4.28 ± 0.52%; mean ± SD) were then assigned to 1 of 10 blocks according to parity (first vs. second or more) and milk fat concentration, and fed a HSLF diet containing 45% forages and 55% concentrates for 2 experimental periods of 28 d. Treatments were identified as (1) control, in which the HSLF diet was fed throughout both periods; (2) preventive, in which the HSLF diet supplemented with K2CO3 (1.6% of DM) was fed during both periods; and (3) recovery, in which the HSLF diet was fed during the first period (P1) and the HSLF diet supplemented with K2CO3 was fed during the second period (P2). Data from P1 and P2 were analyzed separately. In P1, preplanned contrasts were used to evaluate the preventive effect of K2CO3 (control and recovery, both groups receiving the same diet during this period, vs. preventive), and in P2, to assess the potential of K2CO3 to alleviate an already existing state of low milk fat (control vs. recovery and preventive vs. recovery). Feeding the HSLF diet in P1 moderately decreased milk fat concentration (-16%) and yield (-13%) as compared with baseline. Dietary addition of K2CO3 decreased DM intake by 12 and 14% in P1 and P2, respectively. Ruminal pH was not different among treatments. There was also no significant difference in milk yield (4.13 and 3.71 kg/d on average in P1 and P2, respectively) for any tested contrasts. In P1, milk fat concentration and yield did not differ among goats fed control (3.58% and 151 g/d, respectively) and preventive (3.67% and 148 g/d, respectively) diets. In P2, milk fat concentration and yield did not differ among goats fed the control diet (3.38% and 137 g/d, respectively), and diets where K2CO3 was used as preventive (3.44% and 126 g/d, respectively) or recovery treatment (3.25% and 113 g/d, respectively). Supplementing a high-concentrate diet with 1.6% K2CO3 was therefore not effective in either preventing or suppressing already existing conditions of low milk fat production in dairy goats.

Factors associated with multiple barriers to access to primary care: an international analysis.

BACKGROUND: Disparities in access to primary care (PC) have been demonstrated within and between health systems. However, few studies have assessed the factors associated with multiple barriers to access occurring along the care-seeking process in different healthcare systems. METHODS: In this secondary analysis of the 2016 Commonwealth Fund International Health Policy Survey of Adults, access was represented through participant responses to questions relating to access barriers either before or after reaching the PC practice in 11 countries (Australia, Canada, France, Germany, Norway, the Netherlands, New Zealand, Sweden, Switzerland, the United Kingdom, and United States). The number of respondents in each country ranged from 1000 to 7000 and the response rates ranged from 11% to 47%. We used multivariable logistic regression models within each of eleven countries to identify disparities in response to the access barriers by age, sex, immigrant status, income and the presence of chronic conditions. RESULTS: Overall, one in five adults (21%) experienced multiple barriers before reaching PC practices. After reaching care, an average of 16% of adults had two or more barriers. There was a sixfold difference between nations in the experience of these barriers to access. Vulnerable groups experiencing multiple barriers were relatively consistent across countries. People with lower income were more likely to experience multiple barriers, particularly before reaching primary care practices. Respondents with mental health problems and those born outside the country displayed substantial vulnerability in terms of barriers after reaching care. CONCLUSION: A greater understanding of the multiple barriers to access to PC across the stages of the care-seeking process may help to inform planning and performance monitoring of disparities in access. Variation across countries may reveal organisational and system drivers of access, and inform efforts to improve access to PC for vulnerable groups. The cumulative nature of these barriers remains to be assessed.

A controlled before-after study to evaluate the effect of a clinician led policy to reduce knee arthroscopy in NSW.

BACKGROUND: Clinical evidence shows knee arthroscopy has little benefit for degenerative conditions and considerable variation in the incidence of knee arthroscopy in Australia has been identified. This study aimed to evaluate a clinician-led evidence-based policy which was implemented in one local health district in New South Wales (NSW) in 2012 to reduce the use of knee arthroscopy for patients aged 50 years or over. METHODS: Trends in rates and volume of knee arthroscopy for patients 50 years or over in NSW between 2004 and 2015 by district were examined. Changes at four hospitals that adopted the policy were assessed by a quasi-experimental before and after study design with control groups, using the generalised estimating equations (GEE) Poisson model. Each case hospital was matched with four control hospitals in terms of the volume of knee arthroscopy surgeries performed in the five years prior to the intervention. RESULTS: Between 2004 and 2015, the number of knee arthroscopies in NSW initially increased and then decreased after 2011, with considerable variation across districts. While an overall reducing trend in NSW was observed between 2011 and 2015 (39%), a 58% reduction (95% CI: 55-62%) was found in the intervention district, including the private sector, being the greatest reduction found in all districts. The GEE Poisson results show that, compared with control hospitals, the number of knee arthroscopy was significantly reduced by 56% (95% CI: 11%-79%) at four hospitals that adopted the policy during the follow-up period (p = 0.02). CONCLUSIONS: Clinicians in one local health district initiated a policy to restrict knee arthroscopy for patients aged 50 years or over, which may explain the greater reduction seen in that district compared to all others, despite an overall decrease noted in the state. A significant reduction found at intervened hospitals proved the effect of the policy, suggesting that the implementation of a simple clinical governance process may help reduce inappropriate surgery.

Low latency optical-based mode tracking with machine learning deployed on FPGAs on a tokamak.

Active feedback control in magnetic confinement fusion devices is desirable to mitigate plasma instabilities and enable robust operation. Optical high-speed cameras provide a powerful, non-invasive diagnostic and can be suitable for these applications. In this study, we process high-speed camera data, at rates exceeding 100 kfps, on in situ field-programmable gate array (FPGA) hardware to track magnetohydrodynamic (MHD) mode evolution and generate control signals in real time. Our system utilizes a convolutional neural network (CNN) model, which predicts the n = 1 MHD mode amplitude and phase using camera images with better accuracy than other tested non-deep-learning-based methods. By implementing this model directly within the standard FPGA readout hardware of the high-speed camera diagnostic, our mode tracking system achieves a total trigger-to-output latency of 17.6 µs and a throughput of up to 120 kfps. This study at the High Beta Tokamak-Extended Pulse (HBT-EP) experiment demonstrates an FPGA-based high-speed camera data acquisition and processing system, enabling application in real-time machine-learning-based tokamak diagnostic and control as well as potential applications in other scientific domains.

High-throughput low-cost digital lickometer system for the assessment of licking behaviours in mice.

BACKGROUND: Proper hydration is essential for maintaining health and supports various biological processes, including temperature regulation, immune function, nutrient delivery, and organ function. Visual assessment has traditionally been used to quantify liquid intake, although technological advances in optical and electrical sensors now offer higher accuracy and larger potential for automatic operation with millisecond precision and individual lick resolution. NEW METHOD: We describe an inexpensive electronic sensor board to monitor mouse licking behavior. The system is equipped with integrated filtering and data preprocessing steps. It measures lick count, frequency, width and interlick intervals with high resolution, allowing the real-time monitoring of complex licking patterns in several mice in their respective home cages over prolonged periods. RESULTS: Our lickometer provides two-millisecond resolution, efficiently detecting variations in licking behaviors in mice. The system is adapted to monitor licking behaviors in up to 12 mice simultaneously. Lick count, duration and interlick intervals, along with preference for sweet water were monitored over two days, revealing variations in licking patterns across light and dark phases extended over prolonged periods. COMPARISON WITH EXISTING METHODS: Our lickometer allows for monitoring licking behaviors and dynamics. It can be adapted to conventional mouse cages using electrical circuits. It is open-source, cost-effective, efficient, and can be utilized in real-time for large cohorts, representing an ideal tool for studying ingestive dynamics in different environmental and pathological contexts. CONCLUSION: We have developed a novel, cost-effective, and efficient device to monitor ingestive behaviors in mice. The throughput of our device allows for monitoring several mice simultaneously while it can be applied directly to a conventional mouse cage, simplifying its implementation into pre-existing experimental setups.

Tangential extreme ultraviolet and soft x-ray diagnostic system for time-resolved temperature measurement on the High Beta Tokamak-Extended Pulse.

The High Beta Tokamak-Extended Pulse has recently incorporated a tangential multi-energy extreme ultraviolet and soft x-ray diagnostic system. This system enables measurements of the electron temperature and the examination of mode dynamics within the tokamak. While other systems have been built for poloidal views over similar temperature ranges, this is the first multi-energy tangential-view system designed to work in a temperature range below 200 eV in a tokamak. To facilitate these measurements, a filter wheel comprising five distinct groups of dual-filters has been developed and implemented. By employing a combination of 0.1 µm aluminum and 0.2 µm titanium filters, the system allows estimation of electron temperature profiles through reconstruction of the emission profile using the standard "double-foil" technique. The influence of impurities and filter oxide layers on measurement outcomes is examined. Results reveal that, while the absolute electron temperature values may exhibit some deviations, key characteristics like the electron temperature profile shape and inversion radius during sawtooth events remain consistent. This consistency confirms the system's suitability for core plasma studies. This system has proven effective in detecting and analyzing internal magnetohydrodynamic phenomena, such as sawteeth.

Impact of comorbidities on survival following major injury across different types of road users.

BACKGROUND: While comorbidities and types of road users are known to influence survival in people hospitalised with injury, few studies have examined the association between comorbidities and survival in people injured in road traffic crashes. Further, few studies have examined outcomes across different types of road users with different types of pre-existing comorbidities. This study aims to examine differences in survival within 30 days of admission among different road user types with and without different pre-existing comorbidities. METHOD: Retrospective cohort study using data for all major road trauma cases were extracted from the NSW Trauma Registry Minimum Dataset (1 January 2013 - 31 July 2019) and linked to the NSW Admitted Patient Data Collection, and the NSW Registry of Births, Deaths and Marriages - death dataset. Pre-existing comorbidities and road user types were identified by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification (ICD-10-AM) codes and Charlson Comorbidity Index in the Trauma Registry, hospital admission, and death datasets. Logistic regression was used to assess the associations between six types of road users (pedestrian, pedal cycle, two- and three-wheel motorcycle, car and pick-up truck, heavy vehicle and bus, and other types of vehicle) and death within 30 days of hospital admission while controlling for comorbidities. All models used 'car and pick-up truck driver/passenger' as the road user reference group and adjusted for demographic variables, injury severity, and level of impaired consciousness. RESULTS: Within 6253 traffic injury person-records (all aged ≥15 years old, ISS>12), and in final models, injured road users with major trauma who had a history of cardiovascular diseases (including stroke), diabetes mellitus, and higher Charlson Comorbidity Index score, were more likely to die, than those without pre-existing comorbidities. Furthermore, in final models, pedestrians were more likely to die than car occupants (OR: 1.68 - 1.77, 95CI%: 1.26 - 2.29 depending on comorbidity type). CONCLUSIONS: This study highlights the need to prioritize enhanced management of trauma patients with comorbidities, given the increasing prevalence of chronic medical conditions globally, together with actions to prevent pedestrian crashes in strategies to reach Vision Zero.

How we mobilize haemopoietic stem cells.

Mobilization and collection of haemopoietic stem and progenitor cells (HSPC) is the cornerstone of autologous and allogeneic stem cell transplantation for a wide variety of haematological and some non-haematological malignancies. Centres providing this service face the challenge of optimizing the likelihood of successful collection of transplantable doses of cells, while maximizing the efficiency of the apheresis unit and minimizing the risk of toxicity as well as mobilization failure. Recent developments in the understanding of the molecular mechanisms of mobilization have led to the emergence of novel strategies for HSPC mobilization, which may assist in meeting these imperatives. The task for clinicians is how to incorporate the use of these strategies into practice, in the light of emerging evidence for efficacy and safety of these agents. Herein, the literature is reviewed, and a proposed algorithm for HSPC mobilization is presented.

Cytokines increase human hemopoietic cell adhesiveness by activation of very late antigen (VLA)-4 and VLA-5 integrins.

Cytokines are known to be important regulators of normal hemopoiesis, acting in concert with components of the bone marrow microenvironment. Interactions with this microenvironment are known to regulate the proliferation, differentiation, and homing of hemopoietic progenitor (CD34+) cells. Adhesive interactions with the extracellular matrix retain CD34+ cells in close proximity to cytokines, but may also provide important costimulatory signals. Thus, the functional states of adhesion receptors are critical properties of CD34+ cells, but the physiological mechanisms responsible for regulating functional properties of cell adhesion receptors on primitive hemopoietic cells are still unknown. We confirm that the integrins very late antigen (VLA)-4 and VLA-5 are expressed on the CD34+ cell lines MO7e, TF1, and on normal bone marrow CD34+ progenitor cells, but in a low affinity state, conferring on them a weak adhesive phenotype on fibronectin (Fn). Herein, we show that the cytokines interleukin (IL)-3, granulocyte-macrophage CSF (GM-CSF), and KIT ligand (KL) are physiological activators of VLA-4 and VLA-5 expressed by MO7e, TF1, and normal bone marrow CD34+ progenitor cells. Cytokine-stimulated adhesion on Fn is dose dependent and transient, reaching a maximum between 15 and 30 min and returning to basal levels after 2 h. This cytokine-dependent activation is specific for VLA-4 and VLA-5, since activation of other beta 1 integrins was not observed. The addition of second messenger antagonists staurosporine and W7 abolished all cytokine-stimulated adhesion to Fn. In contrast, genistein inhibited KL-stimulated adhesion, but failed to inhibit GM-CSF- and IL-3-stimulated adhesion. Our data suggest that cytokines GM-CSF and IL-3 specifically stimulate beta 1 integrin function via an "inside-out" mechanism involving protein kinase activity, while KL stimulates integrin activity through a similar, but initially distinct, pathway via the KIT tyrosine-kinase. Thus, in addition to promoting the survival, proliferation, and development of hemopoietic progenitors, cytokines also regulate adhesive interactions between progenitor cells and the bone marrow microenvironment by modifying the functional states of specific integrins. These data are of importance in understanding the fundamental processes of beta 1 integrin activation and cellular response to mitogenic cytokines as well as on the clinical setting where cytokines induce therapeutic mobilization of hematopoietic progenitors.

Release of early human hematopoietic progenitors from quiescence by antisense transforming growth factor beta 1 or Rb oligonucleotides.

We have used antisense oligonucleotides to study the roles of transforming growth factor beta (TGF-beta) and the two antioncogenes, retinoblastoma susceptibility (Rb) and p53, in the negative regulation of proliferation of early hematopoietic cells in culture. The antisense TGF-beta sequence significantly enhanced the frequency of colony formation by multi-lineage, early erythroid, and granulomonocytic progenitors, but did not affect colony formation by late progenitors. Single cell culture and limiting dilution analysis indicated that autocrine TGF-beta is produced by a subpopulation of early progenitors. Antisense Rb but not antisense p53 yielded similar results in releasing multipotential progenitors (colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte) from quiescence. Rb antisense could partially reverse the inhibitory effect of exogenous TGF-beta. Anti-TGF-beta blocking antibodies, antisense TGF-beta, or Rb oligonucleotides all had similar effects. No additive effects were observed when these reagents were combined, suggesting a common pathway of action. Our results are consistent with the model that autocrine production of TGF-beta negatively regulates the cycling status of early hematopoietic progenitors through interaction with the Rb gene product.

Tomographic imaging of molecular orbitals.

Single-electron wavefunctions, or orbitals, are the mathematical constructs used to describe the multi-electron wavefunction of molecules. Because the highest-lying orbitals are responsible for chemical properties, they are of particular interest. To observe these orbitals change as bonds are formed and broken is to observe the essence of chemistry. Yet single orbitals are difficult to observe experimentally, and until now, this has been impossible on the timescale of chemical reactions. Here we demonstrate that the full three-dimensional structure of a single orbital can be imaged by a seemingly unlikely technique, using high harmonics generated from intense femtosecond laser pulses focused on aligned molecules. Applying this approach to a series of molecular alignments, we accomplish a tomographic reconstruction of the highest occupied molecular orbital of N2. The method also allows us to follow the attosecond dynamics of an electron wave packet.

Transient reductions in milk fat synthesis and their association with the ruminal and metabolic profile in dairy cows fed high-starch, low-fat diets.

Sub-acute ruminal acidosis (SARA) is sometimes observed along with reduced milk fat synthesis. Inconsistent responses may be explained by dietary fat levels. Twelve ruminally cannulated cows were used in a Latin square design investigating the timing of metabolic and milk fat changes during Induction and Recovery from SARA by altering starch levels in low-fat diets. Treatments were (1) SARA Induction, (2) Recovery and (3) Control. Sub-acute ruminal acidosis was induced by feeding a diet containing 29.4% starch, 24.0% NDF and 2.8% fatty acids (FAs), whereas the Recovery and Control diets contained 19.9% starch, 31.0% NDF and 2.6% FA. Relative to Control, DM intake (DMI) and milk yield were higher in SARA from days 14 to 21 and from days 10 to 21, respectively (P < 0.05). Milk fat content was reduced from days 3 to 14 in SARA (P < 0.05) compared with Control, while greater protein and lactose contents were observed from days 14 to 21 and 3 to 21, respectively (P < 0.05). Milk fat yield was reduced by SARA on day 3 (P < 0.05), whereas both protein and lactose yields were higher on days 14 and 21 (P < 0.05). The ruminal acetate-to-propionate ratio was lower, and the concentrations of propionate and lactate were higher in the SARA treatment compared with Control on day 21 (P < 0.05). Plasma insulin increased during SARA, whereas plasma non-esterified fatty acids and milk ß-hydroxybutyrate decreased (P < 0.05). Similarly to fat yield, the yield of milk preformed FA (>16C) was lower on day 3 (P < 0.05) and tended to be lower on day 7 in SARA cows (P < 0.10), whereas yield of de novo FA (<16C) was higher on day 21 (P < 0.01) in the SARA group relative to Control. The t10- to t11-18:1 ratio increased during the SARA Induction period (P < 0.05), but the concentration of t10-18:1 remained below 0.5% of milk fat, and t10,c12 conjugated linoleic acid remained below detection levels. Odd-chain FA increased, whereas branched-chain FA was reduced during SARA Induction from days 3 to 21 (P < 0.05). Sub-acute ruminal acidosis reduced milk fat synthesis transiently. Such reduction was not associated with ruminal biohydrogenation intermediates but rather with a transient reduction in supply of preformed FA. Subsequent rescue of milk fat synthesis may be associated with higher availability of substrates due to increased DMI during SARA.

Mode rotation control in a tokamak with a feedback-driven biased electrode.

Rotation of the plasma and MHD modes in tokamaks has been shown to stabilize resistive wall and tearing modes as well as improve confinement through suppression of edge turbulence. In this work, we control mode rotation with a biased electrode inserted into the plasma of the High Beta Tokamak-Extended Pulse's facility in conjunction with its active GPU (Graphical Processing Unit) feedback system. We first characterize a negative linear relationship between the electrode voltage and mode rotation. Using this relationship, we design, simulate, and implement a proof-of-concept, GPU-based active-control system, which shows consistent success in controlling mode rotation in both feedforward and feedback operation. Controllability is limited by operating conditions, the electrode's voltage range, and by the electrode's proximity to the vessel's walls. The final control system has a 15 µs cycle time, but the addition of various signal filters results in a full cycle latency of 200 µs.

Association between multimorbidity and undiagnosed obstructive sleep apnea severity and their impact on quality of life in men over 40 years old.

BACKGROUND: Multimorbidity is common but little is known about its relationship with obstructive sleep apnea (OSA). METHODS: Men Androgen Inflammation Lifestyle Environment and Stress Study participants underwent polysomnography. Chronic diseases (CDs) were determined by biomedical measurement (diabetes, dyslipidaemia, hypertension, obesity), or self-report (depression, asthma, cardiovascular disease, arthritis). Associations between CD count, multimorbidity, apnea-hyponea index (AHI) and OSA severity and quality-of-life (QoL; mental & physical component scores), were determined using multinomial regression analyses, after adjustment for age. RESULTS: Of the 743 men participating in the study, overall 58% had multimorbidity (2+ CDs), and 52% had OSA (11% severe). About 70% of those with multimorbidity had undiagnosed OSA. Multimorbidity was associated with AHI and undiagnosed OSA. Elevated CD count was associated with higher AHI value and increased OSA severity. CONCLUSION: We demonstrate an independent association between the presence of OSA and multimorbidity in this representative sample of community-based men. This effect was strongest in men with moderate to severe OSA and three or more CDs, and appeared to produce a greater reduction in QoL when both conditions were present together.

Mobilization of bone marrow-derived progenitors.

Bone marrow (BM) is a source of various stem and progenitor cells in the adult, and it is able to regenerate a variety of tissues following transplantation. In the 1970s the first BM stem cells identified were hematopoietic stem cells (HSCs). HSCs have the potential to differentiate into all myeloid (including erythroid) and lymphoid cell lineages in vitro and reconstitute the entire hematopoietic and immune systems following transplantation in vivo. More recently, nonhematopoietic stem and progenitor cells have been identified that can differentiate into other cell types such as endothelial progenitor cells (EPCs), contributing to the neovascularization of tumors as well as ischemic tissues, and mesenchymal stem cells (MSCs), which are able to differentiate into many cells of ectodermal, endodermal, and mesodermal origins in vitro as well as in vivo. Following adequate stimulation, stem and progenitor cells can be forced out of the BM to circulate into the peripheral blood, a phenomenon called "mobilization." This chapter reviews the molecular mechanisms behind mobilization and how these have led to the various strategies employed to mobilize BM-derived stem and progenitor cells in experimental and clinical settings. Mobilization of HSCs will be reviewed first, as it has been best-explored--being used extensively in clinics to transplant large numbers of HSCs to rescue cancer patients requiring hematopoietic reconstitution--and provides a paradigm that can be generalized to the mobilization of other types of BM-derived stem and progenitor cells in order to repair other tissues.

Enhanced activity of peritoneal cells after aclacinomycin injection: effect of pretreatment with superoxide dismutase on aclacinomycin-induced cytological alterations and antitumoral activity.

Peritoneal macrophages from mice injected with aclacinomycin (ACM) (4 mg/kg, i.p.) showed increased functional activity, as assessed by increased antitumoral activity in vitro and in vivo and zymosan-triggered chemoluminescence. They also showed ultrastructural signs of activation (increased number of cytoplasmic organelles), and atypical alterations (giant vacuoles and giant lysosomes containing heterogenous myelinoid bodies, lipofuscine-like substance, cytoplasmic debris, and a fine granular material). As these atypical alterations could be due to the generation of superoxide following ACM injection, superoxide dismutase (SOD) was injected 1 h prior to ACM administration. Neither the morphological characteristics of activation, nor the enhanced metabolic and antitumoral activities induced by ACM were affected by SOD pretreatment, but the atypical alterations were inhibited in a dose-dependent manner. Heat-inactivated SOD did not prevent their appearance. The atypical alterations were not found in peritoneal macrophages from talc or lipopolysaccharide-injected mice, but they were present in Adriamycin-treated mice and were also prevented by SOD pretreatment, indicating that the alterations are due to anthracycline treatment. Finally, [125I]SOD was phagocytized by peritoneal macrophages in vitro and in vivo and not by L1210 tumoral cells, explaining why the atypical alterations induced by ACM were no longer seen after SOD pretreatment. The unchanged direct oncostatic activity of ACM following SOD pretreatment suggests that this combination may have some wider perhaps clinical, potential.

c-fos mRNA constitutive expression by mature human megakaryocytes.

By in situ hybridization with a c-fos probe, we have shown that human bone marrow megakaryocytes cultured in the presence of 20% aplastic anemia plasma constitutively express c-fos mRNA. At day 0, megakaryocytes are mostly immature and only 3% of them are labeled. The number of labeled cells reached 23% after 12 days of culture. Interleukin 3 (IL-3) and IL-6 added together at day 10 further increased this number to 31% 2 days later. Mature labeled megakaryocytes were more numerous and more strongly labeled than immature ones. These results suggest that c-fos could play a role in megakaryocytic terminal differentiation, either in the polyploidization or in the thrombopoietic function unique to these cells.

Neural correlates of conscious self-regulation of emotion.

A fundamental question about the relationship between cognition and emotion concerns the neural substrate underlying emotional self-regulation. To address this issue, brain activation was measured in normal male subjects while they either responded in a normal manner to erotic film excerpts or voluntarily attempted to inhibit the sexual arousal induced by viewing erotic stimuli. Results demonstrated that the sexual arousal experienced, in response to the erotic film excerpts, was associated with activation in "limbic" and paralimbic structures, such as the right amygdala, right anterior temporal pole, and hypothalamus. In addition, the attempted inhibition of the sexual arousal generated by viewing the erotic stimuli was associated with activation of the right superior frontal gyrus and right anterior cingulate gyrus. No activation was found in limbic areas. These findings reinforce the view that emotional self-regulation is normally implemented by a neural circuit comprising various prefrontal regions and subcortical limbic structures. They also suggest that humans have the capacity to influence the electrochemical dynamics of their brains, by voluntarily changing the nature of the mind processes unfolding in the psychological space.

Additive effects of steel factor and antisense TGF-beta 1 oligodeoxynucleotide on CD34+ hematopoietic progenitor cells.

We previously demonstrated that TGF-beta 1 antisense oligodeoxynucleotides can release early CD34+ bone marrow progenitors from quiescence, and increase the numbers of mixed and large erythroid colonies. As Steel Factor (SF) has a similar effect on colony formation by CD34+ cells, we tested whether this factor acts by blocking the inhibitory effects of TGF-beta. That this is not generally the case was demonstrated by the finding that the combination of TGF-beta 1 antisense with SF in cultures of CD34+ bone marrow cells yielded enhanced colony formation that was more than additive when compared to cultures containing the single agents. This combination also yielded enhanced colony formation by CD34+ umbilical cord blood cells, but in this case, the effect was slightly less than additive. Thus in cord blood, some, but not all, of the progenitors that are maintained in quiescence by TGF-beta can be triggered into cycle by SF. However, the absolute number of CFU-GEMMs found in the antisense TGF-beta plus SF cultures of cord blood was 4-fold higher than that found in comparable bone marrow cultures. These data correlate well with our previous observations that umbilical cord blood contains 4-fold more CD34+ CD38- cells, the population found to respond to TGF-beta 1 antisense oligodeoxynucleotides.