Risk factors for infection in Malaysian patients with systemic lupus erythematosus

To determine the incidence, types and risk factors for infection in systemic lupus erythematosus (SLE) patients in Kuala Lumpur, Malaysia, we retrospectively reviewed the medical records of 102 patients with definite SLE attending a specialist clinic. Details of major infections (pneumonia or severe infection requiring intravenous therapy) and minor infections, and their time of onset in relation to immunosuppressive therapy and disease flares were recorded. There were 77 major and 163 minor infections during 564 patient-years of follow-up. In the month following a course of pulse methylprednisolone, the incidence of major infection was 20 times higher and the incidence of minor infection was 10 times higher than at other periods (p<0.0001). In the month after disease flare, the incidence of major infection was 10 times higher and the incidence of minor infection six times higher than at other times (p<0.0001). After allowing for methylprednisolone therapy and disease flares, there was no increase in the rate of infections during treatment with azathioprine, oral or intravenous cyclophosphamide. There was no effect of renal involvement on infection rate.      

Detection of fetal red cells in fetomaternal hemorrhage using a fetal hemoglobin monoclonal antibody by flow cytometry

BACKGROUND: The laboratory determination of the level of fetal cells in maternal circulation remains an important support in the obstetrical management of women with suspected uterine trauma and in the proper dose administration of anti-D for prevention of Rh hemolytic disease of the newborn. Limitations in the sensitivity and precision of the widely used manual Kleihauer-Betke test have prompted an increased utilization of flow cytometric methods for fetal cell detection in maternal blood samples. STUDY DESIGN AND METHODS: Murine monoclonal antibodies directed against fetal hemoglobin (HbF) were developed, conjugated to fluorescein isothiocyanate, and used in a multiparametric flow cytometric assay developed for the quantitation of fetal red cells. A rapid intracellular staining method using brief glutaraldehyde fixation and Triton X-100 permeabilization prior to monoclonal antibody incubation was developed, along with optimization of the flow cytometric analysis protocol for the analysis of 50,000 cells. The performance of the assay was assessed for linearity and precision and correlated with the Kleihauer-Betke acid elution method. RESULTS: The anti-HbF flow cytometric method showed good correlation with the Kleihauer-Betke method (r2 = 0.86) and superior precision with a CV < 15 percent for blood samples with > 0.1 percent fetal cells. Analysis of 150 blood samples from nonpregnant adults, including individuals with elevated HbF due to hemoglobinopathies and hereditary persistence of HbF, gave a mean value of 0.02 percent fetal cells, and all results were less than 0.1 percent. CONCLUSIONS: The anti-HbF flow cytometric method for detection of fetal cells offers a simple, reliable, and more precise alternative to the Kleihauer-Betke manual technique for the assessment of fetomaternal hemorrhage. The method has additional potential applications for the study of HbF levels or frequency of adult red cells with low levels of HbF (F cells) in individuals with hemoglobinopathies.     

Patients with osteosarcoma with a single pulmonary nodule on computed tomography: a single-institution experience

Background/PurposeThe purpose of this study is to determine if patients with osteosarcoma (OS) with metachronous metastatic pulmonary disease presenting with a single pulmonary nodule (SPN) on computed tomography (CT) were found to have other lesions at the time of thoracotomy.MethodsData were collected retrospectively on consecutive patients with OS treated at our institution from 1982 to 2007. Patients with no evidence of disease at the end of initial therapy who subsequently relapsed in the lung were identified.ResultsIn our study, 16 (8%) of 198 patients with OS with metachronous metastatic pulmonary disease presented with a SPN on CT scan. In all patients, only 1 metastatic nodule for OS was found at the time of thoracotomy. The median time between diagnosis and first lung relapse was 23.8 months (range, 4-80 months). Eleven patients (68.7%) subsequently had a second lung relapse, but only 3 patients had involvement of the ipsilateral lung (mean time interval between first and second pulmonary relapses of 17 months; range, 2-44 months). Five-year overall survival from diagnosis was 56.2%. Seven patients (43.8%) died of disease progression.ConclusionsIn our experience, patients with OS with metachronous metastatic pulmonary disease presenting with a SPN on CT were not found to have additional malignant lesions at the time of thoracotomy. Consideration should be given in this group of selected patients to use a minimally invasive approach to nodule removal with image-guided localization, if needed, rather than open thoracotomy because ipsilateral metastases are not likely to be found.     

Working-memory capacity protects model-based learning from stress

Accounts of decision-making have long posited the operation of separate, competing valuation systems in the control of choice behavior. Recent theoretical and experimental advances suggest that this classic distinction between habitual and goal-directed (or more generally, automatic and controlled) choice may arise from two computational strategies for reinforcement learning, called model-free and model-based learning. Popular neurocomputational accounts of reward processing emphasize the involvement of the dopaminergic system in model-free learning and prefrontal, central executive–dependent control systems in model-based choice. Here we hypothesized that the hypothalamic-pituitary-adrenal (HPA) axis stress response—believed to have detrimental effects on prefrontal cortex function—should selectively attenuate model-based contributions to behavior. To test this, we paired an acute stressor with a sequential decision-making task that affords distinguishing the relative contributions of the two learning strategies. We assessed baseline working-memory (WM) capacity and used salivary cortisol levels to measure HPA axis stress response. We found that stress response attenuates the contribution of model-based, but not model-free, contributions to behavior. Moreover, stress-induced behavioral changes were modulated by individual WM capacity, such that low-WM-capacity individuals were more susceptible to detrimental stress effects than high-WM-capacity individuals. These results enrich existing accounts of the interplay between acute stress, working memory, and prefrontal function and suggest that executive function may be protective against the deleterious effects of acute stress.A number of accounts of human and animal decision-making posit the coexistence of separate valuation systems that control choice (1–4), which, broadly speaking, represent automatic or habitual vs. deliberative or controlled modes. The circumstances under which one system may dominate over the other and thereby exert control over behavior has been a question of interest in both neuroscience and psychology, in part because of the implications of such differential control for disorders of compulsion such as drug abuse (5, 6). Acute stress may afford unique leverage in isolating the properties of these systems, because it is believed to prompt a shift from more cognitive or deliberative processes to more automatic processes presumed to be underpinned by phylogenetically older brain structures (7).Accordingly, a spate of recent work suggests that acute stress—indexed by changes in levels of cortisol, a neuroendocrine marker of stress response—engenders reliance on putative habitual and/or automatic processes in human decision-making (8–13), consistent with the assumption that the physiological stress response impairs central executive functions subserving more deliberative choice. However, distinguishing such processes is both experimentally and theoretically fraught, because in dual process theories, which system controls a particular behavior is typically ambiguous, and can only be recognized by characteristics (such as reaction times or conscious access) associated in different theories with either sort of control, and often only in the comparison between different tasks that promote either mode. Here we leverage a more operational version of this distinction based on reinforcement learning (RL) theory (1), which proposes that deliberative and automatic modes of decision-making arise from two distinct computationally precise and neurobiologically grounded learning strategies for evaluating actions from previous experiences. This approach allows us to characterize more precisely and within a single task the impact of physiological stress response upon trial-by-trial learning dynamics of either sort.This RL framework (1) posits that choice behavior arises from a combination of two value learning systems that operate in parallel and whose fundamental difference is whether they rely on an “internal model” of task contingencies for evaluating choices. The model-based system is computationally sophisticated and learns a model of the environment to plan candidate courses of action prospectively. In contrast, the model-free system eschews this model and merely prescribes that previously rewarded actions are repeated, akin to the Law of Effect and to prominent theories in which dopaminergic prediction error responses drive learning about action preferences at target areas such as the striatum (14, 15). Because these hypothesized modes of choice are defined quantitatively as arising from different trial-by-trial learning rules, they make clear and divergent predictions about subjects’ trial-by-trial adjustment of decision preferences in response to feedback, enabling the contributions of both approaches to be dissociated experimentally. In fact, many laboratory choice tasks cannot differentiate between the contributions of the learning strategies, because when each action is paired with a single reward, the two sorts of value learning reduce to the same learning rule. However, the strategies differ appreciably in sequentially structured choice tasks. Recent work, informed by this approach, reveals that under normal circumstances, human learning in such tasks exhibits contributions of both putative systems (16–18). The grounding of these theories in neurocomputational models (19) and work on animal learning (4) also provides a unique perspective on dual process architectures, complementary to a set of views whose roots lie more in human cognitive neuroscience.In line with the considerable computational requirements of model-based evaluation (1, 20), and with evidence that this process relies on the prefrontal cortex (PFC, 4), recent work suggests that the model-based system imposes considerable demands on central executive resources. In particular, depletion of working-memory (WM) resources abolishes model-based contributions to learning behavior but spares model-free contributions (21). At the same time, a different line of work examining central executive function under acute stress reveals how neurophysiological stress response engenders WM capacity impairment (22, 23) and reduction of WM-related activity in the PFC as assessed by neuroimaging (24).On the basis of these two lines of work, an intuitive prediction emerges: stress response—as it deleteriously impacts the PFC-dependent executive resources—should selectively reduce model-based learning, but simultaneously spare model-free learning. Closely supporting this prediction, previous investigations reveal that acute stress engenders reliance on habitual behaviors, at the expense of flexible, goal-directed responding. However, because the two forms of choice were differentiated by posttraining probe trials—testing flexible sensitivity to reinforcer devaluation (25) or to a conjunction of spatial cues (26)—it remains to be investigated how and whether stress affects either of the two sorts of trial-by-trial learning dynamics that have been hypothesized to give rise to the endpoint behaviors probed there (1).A complimentary possibility is suggested by findings that acute stress can increase firing rates of dopaminergic neurons (27) and extracellular dopamine levels in the neural structures putatively underpinning model-free RL (28). We might thus expect, alternately or additionally, that stress would modulate or even strengthen model-free learning. There is indeed recent evidence for effects of stress on probabilistic reward learning (29, 30). However, the task used does not permit differentiating model-based from model-free contributions to learning.Here we elucidate the impact of hypothalamic-pituitary-adrenal (HPA) axis stress response on the expression of model-based and model-free contributions to sequential choice behavior. In the RL task we use (16) model-based and model-free learning strategies—distinguished, respectively, by their utilization and ignorance of the full environment structure—that give rise to distinct and quantifiable behavioral signatures. Our results reveal how the physiological stress response attenuates the influence of model-based (but not model-free) learning, underlining the distinct and separable contributions of these theorized valuation systems.Further, in line with the central-executive–dependent nature of the model-based system, we shed light on how individual differences in WM capacity (often taken as a general measure of executive function and fluid intelligence, 31), modulate the effect of physiological stress response on model-based choice. Specifically, we demonstrate that subjects with more executive resources to spare find themselves less susceptible to the behavioral changes brought about by stress response, elucidating the interplay between acute stress, executive function, and dual-system accounts of decision-making.     

The lowest effective dose of botulinum A toxin in adult patients with upper limb spasticity

Objective: To define the lowest effective dose of botulinum toxin type A (Dysport®) and safety in the treatment of adult patients with upper limb spasticity.

Design: This was a prospective, randomized, double-blind, dose-ranging study. Patients received either a placebo or one of three doses of Dysport® (350, 500, 1000?U) into five muscles of affected arm by anatomical and electromyography guidance. Efficacy was assessed periodically throughout the 6-month study period by the Modified Ashworth Scale (MAS), the Action Research Arm Test (ARA), the Barthel Index (BI) and the Visual Analogue Pain Scale (VAS).

Results: Fifty patients were recruited. The four study groups were comparable at baseline with respect to their demographical characteristics and severity of spasticity. All doses of Dysport® studied showed a significant reduction from baseline of muscle tone and pain compared to placebo. However, the effect of functional disability was best at a dose of 500?U and the peak improvement was at week 8 after injection. A dose of 1000?U Dysport produced such an excess degree of muscle weakening that the number of randomized patients was reduced to five. BI and ARA of all patients were decrease after injection. No other adverse event was considered related to the study medication.

Conclusion: This study suggests that treatment with Dysport® reduces muscle tone in adult patients with upper limb spasticity. The optimal dose for treatment of patients with residual voluntary movement in the upper limb appears to be 500?U.     

Early life and later determinants of adult disease: a 50 year follow-up study of the Newcastle Thousand Families cohort

The relative contribution of socioeconomic, behavioural and biological factors operating in fetal and infant life, childhood and adulthood to risk for cardiovascular disease, respiratory diseases and non-insulin-dependent diabetes in middle age has become an important research issue. All 1142 babies born in Newcastle upon Tyne in May and June 1947 were recruited into a prospective cohort study of child health (the ‘Thousand Families’ study) and followed in great detail to the age of 15 y, with a brief further follow up at age 22 y. Children from poorer families were at greatest risk of severe respiratory tract infection in infancy. Children from professional and managerial families were on average taller and heavier throughout childhood than those from semi- and unskilled manual social classes. Repeated infections in early childhood greatly increased the risk of developing chronic respiratory disease by age 15 y. This paper outlines a new investigation designed to trace surviving members of this cohort and to chart the relationships between their socioeconomic circumstances, lifestyles, experiences and health from birth through to the present day. Existing data on socioeconomic circumstances and infections in infancy and childhood, infant nutrition, birthweight and physical development to age 22 y will be linked to information gained from a new study. This comprises a postal questionnaire survey of study members' adult health, socioeconomic circumstances and lifestyle, and a hospital based clinical examination including heart and lung function, glucose tolerance, blood lipids and anthropometric measurements at age 49–51 y. Out of a target sample of 979 people for whom sufficient data are available on the first year of life, 866 (88%) have been traced and 649 are still resident in the North of England. Those study members who have been traced are highly representative of the original cohort. The Thousand Families cohort provides a unique opportunity for detailed epidemiological study because of the wealth of data available on infant and childhood socioeconomic and family circumstances, all of which was collected prospectively. In addition, there has been comparatively little loss to follow-up since 1948.     

Cat colour vision: evidence for more than one cone process

1. The ability of cats to distinguish colours was investigated at mesopic and photopic levels to test the hypothesis that cats discriminate wavelength by using rods in conjunction with a single type of cone.2. Cats were trained to distinguish red from cyan, and orange from cyan at the mesopic level. They retained the ability to make this discrimination when the coloured stimuli were placed against a background bright enough to saturate the rods.3. One cat was also tested after being exposed to a bright white light of 9000 cd/m(2) for a period of 5 min, and found able to distinguish red from cyan.4. These results suggest that cats have more than one type of cone. Subsequent recordings from single units in the lateral geniculate nucleus showed that there are rare opponent colour units in layer B with input from a green-absorbing cone and a blue-absorbing cone.