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Airway management is required during general anaesthesia and is essential for life-threatening conditions such as cardiopulmonary resuscitation. Evidence from recent trials indicates a high incidence of critical events during airway management, especially in neonates or infants. It is important to define the optimal techniques and strategies for airway management in these groups. In this joint European Society of Anaesthesiology and Intensive Care (ESAIC) and British Journal of Anaesthesia (BJA) guideline on airway management in neonates and infants, we present aggregated and evidence-based recommendations to assist clinicians in providing safe and effective medical care. We identified seven main areas of interest for airway management: i) preoperative assessment and preparation; ii) medications; iii) techniques and algorithms; iv) identification and treatment of difficult airways; v) confirmation of tracheal intubation; vi) tracheal extubation, and vii) human factors. Based on these areas, Population, Intervention, Comparison, Outcomes (PICO) questions were derived that guided a structured literature search. GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to formulate the recommendations based on those studies included with consideration of their methodological quality (strong '1' or weak '2' recommendation with high 'A', medium 'B' or low 'C' quality of evidence). In summary, we recommend: 1. Use medical history and physical examination to predict difficult airway management (1C). 2. Ensure adequate level of sedation or general anaesthesia during airway management (1B). 3. Administer neuromuscular blocker before tracheal intubation when spontaneous breathing is not necessary (1C). 4. Use a videolaryngoscope with an age-adapted standard blade as first choice for tracheal intubation (1B). 5. Apply apnoeic oxygenation during tracheal intubation in neonates (1B). 6. Consider a supraglottic airway for rescue oxygenation and ventilation when tracheal intubation fails (1B). 7. Limit the number of tracheal intubation attempts (1C). 8. Use a stylet to reinforce and preshape tracheal tubes when hyperangulated videolaryngoscope blades are used and when the larynx is anatomically anterior (1C). 9. Verify intubation is successful with clinical assessment and end-tidal CO 2 waveform (1C). 10. Apply high-flow nasal oxygenation, continuous positive airway pressure or nasal intermittent positive pressure ventilation for postextubation respiratory support, when appropriate (1B)., (Copyright © 2023 British Journal of Anaesthesia, European Society of Anaesthesiology and Intensive Care. Published by Elsevier Ltd.. All rights reserved.)

Background: Receipt of recommended well-child care is lowest for children without insurance, many of whom receive care in community health centers (CHCs)., Objective: To understand if there is an association between parent preventive care and their children's well-child visits., Methods: We used electronic health record data to identify children and link them to parents both seen in an OCHIN network (CHC; n = 363 clinics from 17 states), randomly selected a child aged 3 to 17 with ≥1 ambulatory visit between 2015 and 2018. We employed a retrospective, cohort study design and used general estimating equations Poisson regression to estimate yearly rates of well-child visits based on parent preventive care adjusted for relevant covariates and stratified by child age for 3 linked samples: mother only, father only, and two parents., Results: We included 75,398 linked mother only pairs, 12,438 in our father only, and 4,156 in our 2-parent sample. Children in the mother only sample had a 6% greater rate of yearly well-child visits when their mother received preventive care (adjusted rate ratio [ARR] = 1.06; 95% CI = 1.03-1.08) compared to no preventive care. Children in the father only sample had a 7% greater rate of yearly well-child visits when their father received preventive care (ARR = 1.07; 95% CI = 1.04-1.11) versus no preventive care. Children in the two parent sample had an 11% greater rate of yearly well-child visits when both parents received preventive care (ARR = 1.11; 95% CI = 1.03-1.19) compared to neither receiving preventive care., Conclusions: These findings suggest focusing on receipt of healthcare for the whole family may improve well-child visit rates., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

One of the most prevalent sleep disorders in children and adolescents is "insomnia," which can be briefly described as problems with initiating and/or maintaining sleep with associated daytime consequences. These are typical insomnia symptoms, and when experienced for long enough and when they interfere with an important area of the young person's life (eg, schooling), then a diagnosis of an insomnia disorder may be warranted. The authors strongly urge the scientific community to conduct further controlled trials, including dismantling trials that evaluate the relative effectiveness of individual cognitive behavioral therapy for insomnia components., Competing Interests: Disclosure G. Michael has a book contract with the Little Brown Book Company on this topic and has received consultancies from the Australian Psychological Society; there are no other conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Foreign-born Latino children in the United States (US) have poor asthma outcomes, but the role of routine care utilization in these outcomes is unclear. Our objective was to compare select ambulatory care utilization measures for asthma between foreign-born Latino, US-born Latino, and non-Hispanic white children., Methods: Using a multistate network of clinics with a linked electronic health record, we compared the International Classification of Disease (ICD)-coded asthma diagnosis among those with respiratory symptoms, electronic health records documentation of diagnosis, prescriptions, and influenza vaccination of foreign-born and US-born Latino children, and non-Hispanic white children over a 10+ year study period. We also examined outcomes by country of birth in children from Mexico, Cuba, and Guatemala., Results: Among our study population (n = 155,902), 134,570 were non-Hispanic white, 19,143 were US-born Latino, and 2189 were foreign-born Latino. Among those with suspicious respiratory symptoms, there was no difference between these groups in the predicted probability of an ICD-coded asthma diagnosis. US-born Latino children with asthma were less likely to have asthma documented on their problem list, more likely to have an albuterol prescription, and less likely to have an inhaled steroid prescribed. All Latino children had higher rates of influenza vaccination than non-Hispanic white children., Conclusions: In a national network, there were few disparities between Latino (US- and foreign-born) children and non-Hispanic white comparators in many common asthma care services, except some measures in US-born Latino children. Providers should understand that their US-born Latino children may be at elevated risk for not receiving adequate asthma care., (Copyright © 2021. Published by Elsevier Inc.)

Aggression can have a hedonistic aspect in predisposed individuals labeled as appetitive aggression. The present study investigates the neurobiological correlates of this appetitive type of aggression in non-clinical samples from community. Applying functional magnet resonance imaging (fMRI), we tested whether 20 martial artists compared to 26 controls had a higher activation in the nucleus accumbens (NAcc), a central part of the dopaminergic, mesolimbic reward system. Subjects had to watch violent vs. neutral pictures representing appetitive aggression. The affinity towards hedonistic violence was assessed by the Appetitive and Facilitative Aggression Scale (AFAS). Furthermore, the subjects rated all the pictures with regard to how pleasant and violent they were. The martial artists reported a higher AFAS-score and a more positive perception of violent pictures. On the neural level, across all subjects, there was a significant positive correlation between the AFAS-score and the activation in the left NAcc and an inverse association with the activation of the right NAcc when watching violent compared to neutral pictures. This lateralization effect indicates a different processing of hedonistic aspects of aggression in the two hemispheres., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences., Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes., Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1-6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO 2 <90% for 60 s) was reported in 40%. No associated risk factors could be identified among co-morbidities, surgical, or anaesthesia management. Using propensity scoring to adjust for confounders, difficult anaesthesia tracheal intubation did not lead to an increase in 30 and 90 day morbidity or mortality., Conclusions: The results of the present study demonstrate a high incidence of difficult tracheal intubation in children less than 60 weeks post-conceptual age commonly resulting in severe hypoxaemia. Reassuringly, the morbidity and mortality at 30 and 90 days was not increased by the occurrence of a difficult intubation event., Clinical Trial Registration: NCT02350348., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Memory impairment in motor neuron disease (MND) is still an underrecognized feature and has traditionally been attributed to executive dysfunction. Here, we investigate the rate of memory impairment in a longitudinal cohort of MND patients, its relationship to other cognitive functions and the underlying neuroanatomical correlates. 142 patients with MND and 99 healthy controls (HC) underwent comprehensive neuropsychological testing and structural MRI at 3T up to four times over a period of 18 months. Linear-mixed effects models were fitted to identify changes at baseline and over time in episodic memory function (learning, immediate and delayed recall, recognition), composed cognitive scores (memory, verbal fluency, executive function), and memory-related structural brain regions (hippocampus, entorhinal cortex, parahippocampal gyrus). Associations between episodic memory performance and volumetric or cortical thickness changes of these regions were computed using Pearson's r. Learning, immediate and delayed recall, as well as recognition performance were significantly reduced in MND when compared to controls at baseline. Performances in these subtests improved over time although MND showed less improvement than controls. This relationship did not change when only "classical" ALS patients were considered. Patients with MND showed thinning of the right parahippocampal gyrus (PhG) in comparison to controls that was progressing over time. Bilateral hippocampal atrophy was observed in MND patients with memory impairment after splitting the group according to their overall episodic memory performance, with the right hippocampus shrinking over time. In MND patients, the bilateral hippocampal atrophy was associated with impairment in learning, recall, and recognition at baseline. In contrast, left PhG thinning was associated with a poorer learning performance. These results show that episodic memory impairment in MND is a frequent cognitive dysfunction. Since deficits are not clearly declining with disease course, an early involvement of this cognitive domain in the disease seems probable. The memory performance-dependent atrophy of the hippocampus and PhG provide evidence for a widespread involvement of these non-motor cortical areas in disease pathology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

A few systematic imaging studies employing ultrasound (HRUS) and magnetic resonance imaging (MRI) have suggested tongue measures to aid in diagnosis of amyotrophic lateral sclerosis (ALS). The relationship between structural tongue alterations and the ALS patients' bulbar and overall motor function has not yet been elucidated. We here thus aimed to understand how in-vivo tongue alterations relate to motor function and motor function evolution over time in ALS. Our study included 206 ALS patients and 104 age- and sex-matched controls that underwent HRUS and 3T MRI of the tongue at baseline. Sonographic measures comprised coronal tongue echointensity, area, height, width and height/width ratio, while MRI measures comprised sagittal T1 intensity, tongue area, position and shape. Imaging-derived markers were related to baseline and longitudinal bulbar and overall motor function. Baseline T1 intensity was lower in ALS patients with more severe bulbar involvement at baseline. Smaller baseline coronal (HRUS) and sagittal (MRI) tongue area, smaller coronal height (HRUS) and width (HRUS) as well as more rounded sagittal tongue shape predicated more rapid functional impairment - not only of bulbar, but also of overall motor function - in ALS. Our results suggest that in-vivo sonography und MRI tongue measures could aid as biomarkers to reflect bulbar and motor function impairment., Competing Interests: Declaration of Competing Interests None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Essentials The utility of bleeding assessment tools regarding platelet function disorders is still elusive. We studied consecutive patients in a prospective cohort study in a tertiary hospital. Substantially higher scorings were observed in patients with platelet function disorders. Bleeding assessment tools might provide a useful screening tool., Background: Bleeding assessment tools (BATs) have been widely implemented in the evaluation of patients with suspected bleeding disorders. However, diagnostic BAT utility regarding platelet function disorders is still elusive., Aim: We aimed to assess the diagnostic value of the International Society on Thrombosis and Haemostasis BAT (ISTH-BAT) for platelet function disorders in clinical practice., Methods: The clinical characteristics and laboratory data of all consecutive patients with a suspected bleeding disorder referred between January 2012 and March 2017 to an outpatient unit of a university hospital were prospectively collected. The diagnostic evaluation was performed according to current recommendations following a prespecified protocol and platelet function was tested using light transmission aggregometry as well as flow cytometry., Results: Five hundred and fifty-five patients were assessed; 66.9% were female, median age was 43.7 years (interquartile range [IQR] 29.3, 61.7). Confirmed platelet function disorder was diagnosed in 54 patients (9.7%), possible platelet function disorder in 64 patients (11.5%), and other disorders in 170 patients (30.6%). Median scoring of the ISTH-BAT was 2 in patients without a bleeding disorder (IQR 1, 3), 4 in patients with a possible platelet function disorder (2, 7), and 7 in patients with confirmed platelet function disorder (5, 9). Area under the receiver operating characteristic curve (the area under the curve [AUC]) was 0.75 (95% CI 0.70, 0.80)., Conclusions: Presence of a platelet function disorder was associated with substantially higher BAT scorings compared to patients without. Our data suggest that the ISTH-BAT provides a useful screening tool for patients with suspected platelet function disorders., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Insomnia is one of the most prevalent sleep disorders in school-aged children and adolescents. Although cognitive behavioral therapy for insomnia (CBT-i) is the first-line treatment for adults, and existing studies show promising effects also for children and adolescents, the number of randomized controlled trials in younger age groups is rather small. CBT-i techniques for school-aged children and adolescents include bedtime shifts (including sleep restriction), stimulus control, thought challenging, psychoeducation, and relaxation techniques. The integration of parents, especially in school-aged children with insomnia, is highly recommended. More research is needed to investigate specific characteristics and models of child and adolescent insomnia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Diffusion-weighted magnetic resonance imaging (dMRI) enables the microstructural characterization and reconstruction of white matter pathways in vivo non-invasively. However, dMRI only provides information on the orientation of potential fibers but not on their anatomical plausibility. To that end, recent methodological advances facilitate the effective use of anatomical priors in the process of fiber reconstruction, thus improving the accuracy of the results. Here, we investigated the potential of anatomically constrained tracking (ACT), a modular addition to the tractography software package MRtrix3, to accurately reconstruct the optic radiation, a commonly affected pathway in multiple sclerosis (MS). Diffusion MRI data were acquired from 28 MS patients and 22 age- and sex-matched healthy controls. For each participant, the optic radiation was segmented based on the fiber reconstruction obtained using ACT. When implementing ACT in MS, it proved essential to incorporate lesion maps to avoid incorrect reconstructions due to tissue-type misclassifications in lesional areas. The ACT-based results were compared with those obtained using two commonly used probabilistic fiber tracking procedures, based on FSL (FMRIB Software Library) and MRtrix3 without ACT. All three procedures enabled a reliable localization of the optic radiation in both MS patients and controls. However, for FSL and MRtrix3 without ACT it was necessary to place an additional waypoint halfway between the lateral geniculate nucleus and the primary visual cortex to filter out anatomically implausible tracks. In the case of ACT, the results with and without an additional waypoint were virtually identical, presumably because the employed anatomical constraints already prevented the occurrence of the most implausible tracks. Irrespective of the employed tractography procedure, increased diffusivity and decreased anisotropy were found in the optic radiation of the MS patients compared to the controls., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The human optic chiasm comprises partially crossing optic nerve fibers. Here we used diffusion MRI (dMRI) for the in-vivo identification of the abnormally high proportion of crossing fibers found in the optic chiasm of people with albinism., Methods: In 9 individuals with albinism and 8 controls high-resolution 3T dMRI data was acquired and analyzed with a set of methods for signal modeling [Diffusion Tensor (DT) and Constrained Spherical Deconvolution (CSD)], tractography, and streamline filtering (LiFE, COMMIT, and SIFT2). The number of crossing and non-crossing streamlines and their weights after filtering entered ROC-analyses to compare the discriminative power of the methods based on the area under the curve (AUC). The dMRI results were cross-validated with fMRI estimates of misrouting in a subset of 6 albinotic individuals., Results: We detected significant group differences in chiasmal crossing for both unfiltered DT (p = 0.014) and CSD tractograms (p = 0.0009) also reflected by AUC measures (for DT and CSD: 0.61 and 0.75, respectively), underlining the discriminative power of the approach. Estimates of crossing strengths obtained with dMRI and fMRI were significantly correlated for CSD (R 2  = 0.83, p = 0.012). The results show that streamline filtering methods in combination with probabilistic tracking, both optimized for the data at hand, can improve the detection of crossing in the human optic chiasm., Conclusions: Especially CSD-based tractography provides an efficient approach to detect structural abnormalities in the optic chiasm. The most realistic results were obtained with filtering methods with parameters optimized for the data at hand., Significance: Our findings demonstrate a novel anatomy-driven approach for the individualized diagnostics of optic chiasm abnormalities., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Perception and practice of violence have hedonistic aspects associated with positive arousal (appetitive aggression). Earlier studies have mainly investigated the aetiology of aggressive behaviour in forensic/psychiatric patients. The present study examined structural brain characteristics in healthy people practicing violent sports (martial artists) compared to controls not showing violent behaviour. Aggressiveness was assessed in 21 male healthy martial artists and 26 age-matched male healthy controls using the aggressivity factors questionnaire (FAF). Participants underwent structural T1-weighted MRI. Grey matter (GM) differences were analysed using voxel-based morphometry. Whole-brain analyses of the main effects of group and aggressiveness and their interaction were computed. An interaction effect between group and aggressiveness was evident in a brain cluster comprising the left temporal pole and left inferior temporal gyrus. In martial artists, aggressiveness was inversely related to mean GM concentration in this cluster while in controls the opposite pattern was evident. Since these temporal brain regions are relevant for emotion/aggression regulation and threat appraisal, the increased GM concentration in aggressive controls might reflect a stronger cognitive top-down inhibition of their aggressiveness. Lower GM concentration in more aggressive martial artists may indicate a reduced need of inhibitory cognitive control because of their improved self-regulation skills., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To examine whether the distribution of prefrontal cortical thickness in patients with motor neuron disease is normal or bimodal and how it compares to the normal population., Methods: 158 patients with motor neuron disease (MND) and 86 healthy controls (HC) were enrolled in a prospective, two-center study with a common structural MRI protocol. Cortical thickness measures were extracted for the prefrontal cortex, premotor cortex, motor cortex, and occipital cortex using FreeSurfer, adjusted for age and sex, and tested for normality of distribution., Results: Cortical thickness measures of the bilateral prefrontal, premotor, motor, and occipital cortex were normally distributed in patients and healthy controls. MND-related cortical thinning was observed in the right motor cortex ( p  = 0.002), reflected in a significantly higher proportion of MND cases being worse than -1 standard deviation of the healthy control mean: 29.1% in the right motor cortex ( p  = 0.002). Cortical thinning of the left motor cortex was a function of clinical phenotype and physical disability. Left prefrontal cortical thickness was reduced in patients with additional cognitive and/or behavioural deficits compared to MND patients without cognitive deficits. Prefrontal, premotor, motor, and occipital cortical thickness was related to patients' general cognitive abilities., Conclusion: The study shows that prefrontal cortical thickness in MND is normally distributed but shifted towards thinner cortex in MND patients with cognitive and/or behavioural impairment. The distribution of thickness values did not indicate the assumption of a bimodal distribution although patients with comorbid cognitive deficits are more likely to suffer from prefrontal cortical thinning.

Purpose: Aim of the present study was to investigate potential impairment of non-motor areas in amyotrophic lateral sclerosis (ALS) using near-infrared spectroscopy (NIRS) and diffusion tensor imaging (DTI). In particular, we evaluated whether homotopic resting-state functional connectivity (rs-FC) of non-motor associated cortical areas correlates with clinical parameters and disease-specific degeneration of the corpus callosum (CC) in ALS., Material and Methods: Interhemispheric homotopic rs-FC was assessed in 31 patients and 30 healthy controls (HCs) for 8 cortical sites, from prefrontal to occipital cortex, using NIRS. DTI was performed in a subgroup of 21 patients. All patients were evaluated for cognitive dysfunction in the executive, memory, and visuospatial domains., Results: ALS patients displayed an altered spatial pattern of correlation between homotopic rs-FC values when compared to HCs ( p  = 0.000013). In patients without executive dysfunction a strong correlation existed between the rate of motor decline and homotopic rs-FC of the anterior temporal lobes (ATLs) (ρ = - 0.85, p  = 0.0004). Furthermore, antero-temporal homotopic rs-FC correlated with fractional anisotropy in the central corpus callosum (CC), corticospinal tracts (CSTs), and forceps minor as determined by DTI ( p  < 0.05)., Conclusions: The present study further supports involvement of non-motor areas in ALS. Our results render homotopic rs-FC as assessed by NIRS a potential clinical marker for disease progression rate in ALS patients without executive dysfunction and a potential anatomical marker for ALS-specific degeneration of the CC and CSTs.

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects upper and lower motor neurons. Observational and intervention studies can be tracked using clinical measures such as the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) but for a complete understanding of disease progression, objective in vivo biomarkers of both central and peripheral motor pathway pathology are highly desirable. The aim of this study was to determine the utility of structural and diffusion imaging as central nervous system biomarkers compared to the standard clinical measure, ALSFRS-R, to track longitudinal evolution using three time-point measurements. N = 34 patients with ALS were scanned and clinically assessed three times at a mean of three month time intervals. The MRI biomarkers were structural T1-weighted volumes for cortical thickness measurement as well as deep grey matter volumetry, voxel-based morphometry and diffusion tensor imaging (DTI). Cortical thickness focused specifically on the precentral gyrus while quantitative DTI biomarkers focused on the corticospinal tracts. The evolution of imaging biomarkers and ALSFRS-R scores over time were analysed using a mixed effects model that accounted for the scanning interval as a fixed effect variable, and, the initial measurements and time from onset as random variables. The mixed effects model showed a significant decrease in the ALSFRS-R score, (p < 0.0001, and an annual rate of change (AROC) of - 7.3 points). Similarly, fractional anisotropy of the corticospinal tract showed a significant decrease (p = 0.009, AROC = - 0.0066) that, in turn, was driven by a significant increase in radial diffusivity combined with a trend to decrease in axial diffusivity. No significant change in cortical thickness of the precentral gyrus was found (p > 0.5). In addition, deep grey matter volumetry and voxel-based morphometry also identified no significant changes. Furthermore, the availability of three time points was able to indicate that there was a linear progression in both clinical and fractional anisotropy measures adding to the validity of these results. The results indicate that DTI is clearly a superior imaging marker compared to atrophy for tracking the evolution of the disease and can act as a central nervous biomarker in longitudinal studies. It remains, however, less sensitive than the ALSFRS-R score for monitoring decline over time.

There is increasing appreciation of non-motor system involvement in amyotrophic lateral sclerosis (ALS), although its full extent and clinical significance remains to be established. This study tested the hypothesis that memory impairment in patients with ALS is related to hippocampal degeneration. Consecutive patients with ALS (58) and 29 matched controls participated in standardized neuropsychological assessment and magnetic resonance imaging. Patients with ALS performed worse in global cognitive functioning and executive and verbal memory tests (p < 0.05). The hippocampus was manually segmented in each hemisphere, and volumes were calculated with correction for intracranial volume. Analysis of covariance, controlled for the effect of age and education years, showed significantly smaller hippocampal volume on the right (p = 0.004) in patients with ALS. Verbal memory test performance correlated with the left hippocampal volume in patients with ALS (p < 0.05), although there was no significant correlation with tests of executive function and clinical variables underscoring the specificity of the present findings. Hippocampal volume loss and its correlation with the severity of verbal memory impairment highlight significant hippocampal involvement which can occur as a non-motor deficit in patients with ALS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Previous studies have shown that in amyotrophic lateral sclerosis (ALS) multiple motor and extra-motor regions display structural and functional alterations. However, their temporal dynamics during disease-progression are unknown. To address this question we employed a longitudinal design assessing motor- and novelty-related brain activity in two fMRI sessions separated by a 3-month interval. In each session, patients and controls executed a Go/NoGo-task, in which additional presentation of novel stimuli served to elicit hippocampal activity. We observed a decline in the patients' movement-related activity during the 3-month interval. Importantly, in comparison to controls, the patients' motor activations were higher during the initial measurement. Thus, the relative decrease seems to reflect a breakdown of compensatory mechanisms due to progressive neural loss within the motor-system. In contrast, the patients' novelty-evoked hippocampal activity increased across 3 months, most likely reflecting the build-up of compensatory processes typically observed at the beginning of lesions. Consistent with a stage-dependent emergence of hippocampal and motor-system lesions, we observed a positive correlation between the ALSFRS-R or MRC-Megascores and the decline in motor activity, but a negative one with the hippocampal activation-increase. Finally, to determine whether the observed functional changes co-occur with structural alterations, we performed voxel-based volumetric analyses on magnetization transfer images in a separate patient cohort studied cross-sectionally at another scanning site. Therein, we observed a close overlap between the structural changes in this cohort, and the functional alterations in the other. Thus, our results provide important insights into the temporal dynamics of functional alterations during disease-progression, and provide support for an anatomical relationship between functional and structural cerebral changes in ALS.

Clinical, genetic, and pathological findings suggest a close relationship between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We studied the patterns of cortical atrophy across the spectrum between ALS and ALS-FTD. A surface-based morphometry analysis based on an age- and sex-matched sample of 81 ALS patients and 62 healthy control subjects (HC) was conducted. In addition, we used an age-matched subsample of 57 ALS patients and 31 HC to compare cortical thickness between 3 groups of neuropsychologically characterized ALS patients: (1) cognitively unimpaired; (2) cognitively impaired; and (3) ALS-FTD patients. Compared with HC, the entire sample of patients demonstrated cortical thinning in the bilateral precentral gyrus, right precuneus, and right frontal and temporal lobes. ALS-FTD patients showed cortical thinning in regions including the frontal and temporal gyri and the posterior cingulate cortex. Cognitively impaired ALS patients showed cortical thinning in regions largely overlapping with those found in ALS-FTD, but changes were less widespread. In conclusion, the cognitive status of ALS subjects is associated with different patterns of cortical atrophy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Amyotrophic lateral sclerosis (ALS) is characterized by pronounced clinical heterogeneity in terms of onset and disease progression. Widespread changes in white matter fibres could be observed by diffusion tensor imaging (DTI), which detects alterations in the degree (diffusivity, ADC) and directedness (fractional anisotropy, FA) of proton movement. The aim of the current study was to determine whether different ALS onset types were reflected in different DTI brain patterns., Methods: Seventeen patients with a diagnosis of ALS (6 bulbar, 11 limb onset) and seventeen age-matched controls received 1.5T DTI, where FA and ADC were analyzed using statistical parametric mapping., Results: In ALS patients, an increased diffusivity in the white matter was found below the precentral gyrus and along the corticospinal tract (CST) right into the internal capsule. The FA was decreased in the posterior limb of internal capsule and in the subcortical white matter in the precentral gyrus. In bulbar onset increased diffusivity was found in the CST, whilst in limb onset, frontal subcortical areas displayed an increased diffusivity., Conclusion: DTI changes can be regarded as prominent features in ALS. Herein we were able to demonstrate discriminating brain DTI patterns due to bulbar or limb onset., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Several pathways are involved in the control of endothelial cell morphology, endothelial permeability and function in order to maintain vascular homeostasis. Here we report that protein kinase N3 (PKN3) appears to play a pivotal role in maintaining endothelial cell morphology, cell-cell junctions and motility. An RNAi-based cell biological approach in cultured human endothelial cells (HUVEC) revealed that knockdown of PKN3 expression gave rise to cells with divergent cell morphology, impaired locomotion, disturbed adherens junctions (AJ) integrity and irregular actin organization. Notably, knockdown of PKN3 cells led to improper stress fiber formation and marked adhesiveness of intercellular adherens junctions when cells became stimulated with the pro-inflammatory cytokine TNF-α. Moreover, TNF-α-induced ICAM-1 expression on the cell surface was reduced in cells with suppressed PKN3 expression. Finally, loss-of-function for PKN3 appeared to affect Pyk2 phosphorylation in endothelial cells. These observations suggest that PKN3 can be considered a novel protein implicated in remodeling the actin-adherens junction, possibly by linking ICAM-1-signaling with actin/AJ dynamics. We propose that loss of PKN3 function and concomitant aberrations in actin rearrangement may attenuate pro-inflammatory activation of endothelial cells., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Objective: Late-onset Pompe disease is a slowly progressive disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Since 2006, an intravenous enzyme replacement therapy (ERT) with Myozyme™ (alglucosidase alfa) is available but long-term experience with ERT in late-onset Pompe disease is still limited., Methods: Two adult patients with impaired walking ability and disease duration of 10 and 13 years, respectively received ERT over a period of 24 months. Clinical and functional parameters including dynamometer-based assessment of proximal muscle strength were registered longitudinally., Results: In both patients some gain in function and physical endurance could be observed which was collaborated by stable dynamometer tests. No serious adverse events occurred and no patient required de novo ventilation., Conclusion: The clinical results from our data base imply that long term enzyme replacement therapy seems to somewhat affect functionality and quality of life and can stabilize the otherwise progressive disease course in patients with late-onset Pompe disease., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: CD40 is a receptor expressed on a wide range of cells such as leukocytes and endothelial cells (EC). As a member of the tumor necrosis factor (TNF) superfamily the activation of CD40 by CD40-ligand (CD40L) plays a crucial role for the development and progression of a variety of inflammatory processes including atherosclerosis. The aim of the present study was to investigate the effect of CD40/CD40L interaction on leukocyte adhesion to the endothelium and on endothelial cell migration., Methods and Results: Human umbilical vein endothelial cells (HUVEC) were stimulated with either stable transfectants of mouse myeloma cells expressing the CD40L or wild type cells (4 h). Subsequently adhesion of leukocytes expressing Sialyl Lewis X, the counterpart for E-selectin (HL60 cells), was measured under shear stress (2-2.6 dyne/cm(2)) using a flow chamber adhesion assay. Stimulation of CD40 led to a significant increase of E-selectin dependent adhesion of leukocytes to the endothelium. Incubation of cells with either the CD40L blocking antibody TRAP-1 or the E-selectin blocking antibody BBA2 during CD40 stimulation completely abolished adhesion of leukocytes to HUVEC. Similar results were found in human cardiac microvasculature endothelial cells (HCMEC). In contrast stimulation of CD40 had no effect on adhesion of L-selectin expressing NALM6-L cells. Furthermore, CD40/CD40L interaction abrogated VEGF-induced migration of HUVEC compared to non-stimulated controls. In comparison experiments, stimulation of endothelial cells with VEGF led to a significant phosphorylation of ERK1/2, Akt, and eNOS. Stimulation of endothelial CD40 had no effect on VEGF-induced phosphorylation of ERK1/2. However, VEGF-induced activation of Akt and eNOS was reduced to baseline levels when endothelial CD40 was stimulated., Conclusion: CD40/CD40L interaction induces E-selectin dependent adhesion of leukocytes to human endothelial cells and reduces endothelial cell migration by inhibiting the Akt/eNOS signaling pathway., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Unlabelled: Macrophage migration is a key aspect in the initiation and progression of atherosclerosis. Insulin-like growth factor (IGF)-1 is highly expressed in macrophages in human atheroma. Its function in macrophage motility, however, remains to be elucidated. The aim of this study was to investigate the impact of IGF-1 on macrophage migration, its signaling pathways and the involvement of integrins and/or matrix metalloproteinases (MMPs)., Results: Migration checker-box experiments demonstrated that IGF-1 induced chemotaxis in human THP-1/macrophages. IGF-1 induced migration was inhibited by RGD-containing peptides and the alphavbeta3-blocking antibody LM609, but was unaffected by the MMP-inhibitor GM6001. Immunoblotting demonstrated that IGF-1 did not affect the activation of MMPs or TIMPs, nor did it increase alphav-integrin protein levels. However, IGF-1 induced recruitment of alphavbeta3, as well as trans-location of the integrin adaptor protein phospho-paxillin to focal adhesion sites. Pharmacological blocking experiments with specific inhibitors of Akt, PKC and p38 MAP-kinase revealed that IGF-1-dependent activation of focal adhesion kinase (FAK) and paxillin, and consecutively IGF-1 facilitated migration, required IGF-1/IGF-1R-mediated PI3-kinase/PKC/p38-dependent integrin inside-out signaling., Conclusion: IGF-1 plays a vital role in macrophage migration critically implicated in tissue inflammation. This involves activation of integrins and focal adhesion formation via inside-out PI3-kinase/PKC/p38-dependent signaling, but does not require MMP activation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Vascular smooth muscle cell (VSMC) invasion is a key element in atherogenesis and restenosis, requiring integrins for adhesion/de-adhesion as well as matrix metalloproteinases (MMPs) for focalized proteolysis. Among the MMP family, pro-MMP-2 is unique in its activation, depending on the formation of a multiprotein complex with MT1-MMP/TIMP-2 at the cell surface, in which integrin alphavbeta3 participates. Integrin alphav and MT1-MMP are synthesized from precursors via furin-dependent cleavage of their pro-peptide. Furin is the prototypical proprotein convertase highly expressed in VSMCs and human atherosclerotic lesions. Its precise role in the tight network involving MMPs/integrins and their coordination and cooperation required for VSMC invasion is unknown. We demonstrate that furin-inhibition with decanoyl-RVKR-chloromethylketone inhibits VSMC invasion in a comparable degree to MMP inhibitors, which reduce the MT1-MMP-MMP-2 proteolytic cascade. Furin-inhibition did not prevent MT1-MMP/MMP-2 maturation. In contrast, it strongly reduced pro-alphav cleavage, but did not lessen its cell membrane expression. However, inhibition of pro-alphav processing via furin-inhibition strongly reduced pro-MMP-2 binding to the cell surface, thereby lessening its full maturation and diminishing the cell surface in situ proteolysis required for invasion. Thus, our data demonstrate a novel mechanism of furin-dependent alphav cleavage that enhances pro-MMP-2 binding and activation at the cell membrane in cooperation with MT1-MMP in primary VSMCs. Processing of alphav by furin contributes to the recruitment of enzymatic energy to the cell surface, thereby providing focalized proteolysis associated with VSMC invasion.

Background: Hypertension is recognized as prevalent in pediatric cardiac transplant recipients. This study investigated risk factors for this complication and, in particular, the role of immunosuppression., Methods: Results of 24-hour ambulatory blood pressure monitoring of children surviving more than 1 year after cardiac transplantation were analyzed retrospectively. Subjects were designated either hypertensive or normotensive by comparison with published normal values. To identify factors associated with hypertension, clinical data contemporaneous with 24-hour ambulatory blood pressure monitoring were collected and compared between the groups., Results: In the 51 children studied, the incidence of hypertension was 49%. Hypertensive and normotensive recipients were similar for sex, age at transplantation, time between transplantation and 24-hour ambulatory blood pressure results, and choice of calcineurin inhibitor. In contrast, hypertensive patients were taking significantly more immunosuppressive agents (2.92 vs 2.12 p < 0.01), had higher tacrolimus levels (10 vs 8.1 microg/liter, p = 0.03), and were more likely to be on maintenance prednisone therapy (64% vs 23%, p < 0.01) or regimens including sirolimus (40% vs 12%, p = 0.03). Multiple regression analysis controlling for tacrolimus level showed a combination of prednisone and sirolimus was more strongly associated with hypertension than either agent alone, with an odds ratio of 7.3 (95% confidence interval, 1.5-36.1) vs 4.1 (95% confidence interval, 0.85-26.3)., Conclusions: Hypertension after pediatric cardiac transplantation is a common problem and primarily associated with immunosuppressive regimen.

The hemostatic agent desmopressin (DDAVP) also has strong vasodilatory effects. DDAVP is a selective agonist for the vasopressin V2 receptor (V2R), which is coupled to cAMP-dependent signaling. DDAVP-induced vasodilation may be due to endothelial NO synthase (eNOS) activation. This hypothesis implies cAMP-mediated eNOS activation. It also implies wide extrarenal, endothelial V2R expression. We show that in human umbilical vein endothelial cells (HUVECs) the cAMP-raising agents forskolin and epinephrine increase NO production, as measured by a l-NMMA-inhibitable rise in cellular cGMP content. They also increase eNOS enzymatic activity, in a partly calcium-independent manner. cAMP-mediated eNOS activation is associated with phosphorylation of residue Ser1177, in a phosphatidyl inositol 3-kinase (PI3K)-independent manner. HUVECs do not express V2R. However, after heterologous V2R expression, DDAVP induces cAMP-dependent eNOS activation via Ser1177 phosphorylation. We have previously found V2R expression in cultured lung endothelial cells. By real time quantitative RT-PCR, we now find a wide V2R distribution notably in heart, lung and skeletal muscle. These results indicate that DDAVP and other cAMP-raising agents can activate eNOS via PI3K-independent Ser1177 phosphorylation in human endothelial cells. This mechanism most likely accounts for DDAVP-induced vasodilation.

The synthetic analog of vasopressin desmopressin (DDAVP) is widely used for the treatment of patients with von Willebrand disease (VWD), hemophilia A, several platelet disorders, and uremic bleeding. DDAVP induces an increase in plasma levels of von Willebrand factor (VWF), coagulation factor VIII (FVIII), and tissue plasminogen activator (t-PA). It also has a vasodilatory action. In spite of its extensive clinical use, its cellular mechanism of action remains incompletely understood. Its effect on VWF and t-PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium, via activation of endothelial vasopressin V2R receptor and cAMP-mediated signaling. This leads to exocytosis from Weibel Palade bodies where both VWF and t-PA are stored, as well as to nitric oxide (NO) production via activation of endothelial NO synthase. The mechanism of action of DDAVP on FVIII plasma levels remains to be elucidated. The hemostatic effect of DDAVP likely involves additional cellular effects that remain to be discovered.

We have investigated the molecular motions of polysaccharides of bovine nasal and pig articular cartilage by measuring the 13C NMR relaxation times (T1 and T2). Both types of cartilage differ significantly towards their collagen/glycosaminoglycan ratio, leading to different NMR spectra. As chondroitin sulfate is the main constituent of cartilage, aqueous solutions of related poly- and monosaccharides (N-acetylglucosamine and glucuronic acid) were also investigated. Although there are only slight differences in T1 relaxation of the mono- and the polysaccharides, T2 decreases about one order of magnitude, when glucuronic acid or N-acetylglucosamine and chondroitin sulfate are compared. It is concluded that the ring carbons are motion-restricted primarily by the embedment in the rigid pyranose structure and, thus, additional limitations of mobility do not more show a major effect. Significant differences were observed between bovine nasal and pig articular cartilage, resulting in a considerable line-broadening and a lower signal to noise ratio in the spectra of pig articular cartilage. This is most likely caused by the higher collagen content of articular cartilage in comparison to the polysaccharide-rich bovine nasal cartilage.

Molecular dynamics (MD) simulations on a tetrasaccharide subunit of chondroitin 4-sulfate (CS4) in aqueous solution were carried out to study its interactions with water. Pair distribution functions and diffusion coefficients were calculated from a 4 ns trajectory and the hydration of different molecular groups was analysed. The average values of the interglycosidic torsion angles found in the simulations are phi 13 = -10 degrees, psi 13 = -85 degrees and phi 13 = 80 degrees, psi 13 = 90 degrees for the beta-(1-->3) linkage, and phi 14 = -10 degrees, psi 14 = -70 degrees for the beta-(1-->4) linkage. Hydrophobic patches formed by sugar ring CH groups were found. The diffusion coefficients of the water molecules vary from 1.4 x 10(-9) to 2.3 x 10(-9) m2 s-1 depending on the distances between the water molecules and the atoms of the CS4 molecule and the type of CS4 atoms, respectively. Reorientation correlation times of the water molecules in the vicinity of different CS4 atoms were estimated to be about 1 ps at a polymer concentration of 4 wt.% CS4. The number of hydrogen bonds between the water molecules and the acceptor atoms of CS4 was determined to be about 20 per disaccharide unit, indicating a higher hydration ability of chondroitin sulfate in comparison with non-sulfated oligosaccharides. Substructures, where water molecules are involved in hydrogen bonds to different sugar rings, were found, which may be important for the stabilisation of the secondary structure of the CS4 molecule.

A large-scale longitudinal study was undertaken to investigate the effects of a strategic treatment of gastrointestinal nematodes on the mortality and fertility of N'Dama cattle under village conditions. Initially, 1046 animals from 26 private N'Dama cattle herds, were monitored from October 1989 to December 1994. Each herd was stratified by age and the animals were randomly allocated to two groups with a similar average age. One group received a single anthelmintic treatment of fenbendazole (Panacur, 7.5 mg/kg BW, Hoechst Veterinä AG) in October 1989, whereas the other group remained untreated. In July 1990, the herds were subdivided into two different treatment schemes. In the herds of scheme 1, the treated animals (Treatment group I) were treated once (in August), whereas in the herds of scheme 2, the treated animals (Treatment group II) were treated twice (in July and September). The same treatment schedule was used in the subsequent rainy seasons until December 1994. One group in every herd of both schemes served as control (Treatment group 0) and received no anthelmintic treatment throughout the study. The average annual cumulative incidence mortality between 0-1 year was more than two times higher in treated animals compared to their controls (21% against 7.5%). No differences were found in older age categories. Survival analysis confirmed differences in mortality from 0-1 year, but were not significant in proportional hazard models. The 25% quantiles of age at first calving was used to quantify differences between twice treated animals (50.2 months) and its controls (58.3 months) which represents a decrease of 8 months in twice treated animals. Annual calving rates of twice treated animals were 52.2% compared to 43.6% in the control group (P < 0.001), which is an increase of 8.6% to the control rate. Possible causes of increased mortality in 0-1 year old treated calves are discussed. We can conclude that in the present epidemiological situation and the given parasite spectrum, gastro-intestinal nematodes mainly affect host fertility. Strategic control of gastro-intestinal nematodes is thus recommended for young heifers up to their age of first calving provided the overall financial analysis of the intervention is beneficial.

From October 1989 to December 1994, a longitudinal study on the control of gastrointestinal nematodes was done on 1000 N'Dama cattle in 20 private herds in Gambia. Each herd was divided into two groups with an even distribution of age and sex. One group received a single anthelmintic treatment of Fenbendazole, Panacur Hoechst Veterinär GmbH, 7.5 mg kg-1 BW in October 1989, whereas the other group served as an untreated control. In July 1990, the herds were subdivided into two different treatment schemes. In the herds of the first scheme the treated animals (Treatment group I) were treated once (in August), whereas in the herds of the second scheme the treated animals (Treatment group II) were treated twice (in July and September). The same treatment schedule was used in the subsequent rainy seasons until December 1994. One group in every herd served as control (Treatment group 0) and received no anthelmintic treatment throughout the study. One annual fenbendazole treatment had no significant effect on liveweights, whereas two annual treatments significantly increased liveweights of the age group 12-24 and 24-36 months by 9.4%, and 17.5%, respectively. Animals less than 12 months old had 6.3% higher liveweights after two treatments, the difference was statistically not significant (P < 0.06). Average weights of 3- and 4-year-old, twice-treated animals were 13.1% and 8.2%, respectively, higher compared with their controls. No effect of anthelminthic treatment on liveweights was found in 5-year-old and older animals. Herd structure analysis demonstrated that overall male offtake rates ranged from 12 to 28% in the 3-, 4- and 5-year-old age categories. The age categories within which deworming improves liveweights thus coincides with the age at which males are mainly sold. These results suggest that biannual metaphylactic treatments (end of July and beginning of September) of all animals from birth to an age of 4 years should be recommended, provided that the financial analysis demonstrates the profitability of this intervention.

The early days of oral contraceptives showed some evidence that these medications may have caused undesirable side effects on the voice, mainly in terms of virilization. In a random study carried out at the university hospitals of Jena and Berlin (Charité), two more recent drugs were tested in this regard, one containing cyproterone acetate (Diane-35) and the other one levonorgestrel (Microgynon), both from Schering. Ninety-one patients took part in extensive clinical and instrumental phoniatric investigations of voice function over a period of one year. No significant side effects on the voice could be proven for the two preparations. Gynecological and clinical effects of both Diane-35 and Microgynon were similar during the one-year study period. Women taking Diane-35 had less intracyclic bleedings and amenorrhea. Also, acne was more favorably influenced by Diane-35.

Gambian village cattle herds were treated with a single dose of ivermectine (Ivomec, MSD-AGVET Inc. 1 ml/50 kg body weight) during the dry season. This treatment suppressed the trichostrongyle egg rise prior to the rains and led to delayed egg production for at least 6 months after the onset of the rainy season, compared to untreated animals from neighbouring villages. However, the results clearly indicate that a single treatment with ivermectine during the dry season does not lead to complete suppression of the gastrointestinal strongyle infections, since a worm population still gradually built up. During the second year the ranked level of the egg excretion was significantly lower than that of the control group throughout the year until December, except in August. The results further support the hypothesis that trichostrongyle reinfection is unimportant during the dry season in this climatic zone.

The effects of trypanosome and helminth infections on health and production parameters in 2000 village N'Dama cattle were assessed periodically. Blood examination showed Trypanosoma congolense and Trypanosoma vivax to be prevalent, while strongylid-type eggs were those most frequently encountered in faecal samples. A distinct seasonal fluctuation was detected for both blood levels of trypanosomes and helminth egg output. Strongylid burden and trypanosome infection had significant negative effects on packed red cell volume levels and body weights mainly in animals of 2-3 years old. Clear indications of an increased susceptibility to trypanosomosis were found in animals affected by helminths. Similarly, animals infected with trypanosomes were more frequently infested with strongyles and egg counts were higher than in cattle in which no trypanosomes were detected.

Chloride contamination is a major source of concrete deterioration. Previous studies of chloride transport use weight-vs.-time analysis on immersed samples to deduct related concrete water exchange properties, based on the assumptions of strictly capillary flow and a well defined transport front. The calculations yield substantially higher penetration depths than are found empirically. MRI was used to tomographically follow the water uptake and check the validity of these model assumptions. To eliminate background signal from enclosed water, we worked with deuterated water in combination with deuterium MRI. This approach provides evidence for a reduced water exchange depth and for its dependence on prestorage conditions, and suggests refinements to the previously used concrete model.

One hundred and four post mortem examinations of randomly selected sheep (52) and goats (52) were carried out weekly from March 1990 to February 1991. Gastrointestinal parasites were identified and counted. A large spectrum of 16 helminth species was found in 101 (97%) infected animals. The nematodes infecting small ruminants were, in order of predominance: Trichostrongylus colubriformis (96% of all animals), Oesophagostomum columbianum (82%), Haemonchus contortus (67%), Strongyloides papillosus (55%), Gaigeria pachyscelis (38%), Cooperia spp. (49%) and Trichuris ovis (12%). Forty-five (43%) necropsies revealed an infection with Moniezia benedeni, Avitellina centripunctata or Stilesia globulosa. Infections with Schistosoma bovis and Paramphistomum spp. were rarely seen. Goats carried significantly lower worm burdens than sheep and were less often infected by tapeworms. Nematode worm burdens followed a similar seasonal pattern in both host species. While Trichostrongylus colubriformis was also recovered in high numbers in the mid dry season, other species such as H. contortus, Strongyloides papillosus and Oesophagostomum columbianum reached distinct peaks in the rainy season (July-October). Different survival strategies for the prolonged dry season were observed. Haemonchus contortus outlived the unfavourable climatic conditions as inhibited larvae in the abomasal mucosa, while the other nematode species survived as adults with a reduced fecundity. Egg production per adult worm specimen was found to depend heavily on the season and egg counts in the dry season (November-June) did not correspond to the size of worm burdens. Unexpectedly high worm burdens were recovered from adult and old animals. Investigations of young animals indicated that no reinfection can occur during the dry season. The findings are discussed with regard to their relevance for strategic control of gastrointestinal nematodes in small ruminants.

The interactions between Trypanosoma congolense and Haemonchus contortus infections were studied in N'Dama calves. A total of 38 N'Dama bulls was divided into four groups and each group infected either with H. contortus 1 week after infection with T. congolense or with T. congolense 4 weeks after infection with H. contortus, or with either infection singly. Parasitological (faecal egg counts, parasitaemia), haematological (packed cell volume, white blood cell counts, albumin) and clinical parameters (body weight change, mortality rate) were compared among the various groups. The results showed a reduced prepatent period and a markedly increased pathogenicity of H. contortus infections in animals with a concurrent T. congolense infection. The most harmful combination was a H. contortus infection 1 week after the T. congolense infection which resulted in a progressive and severe anaemia, accompanied by hypoalbuminaemia, increased weight loss and high mortality. The anaemia induced by dual infections showed a low responsiveness to chemotherapy and in several cases supportive treatment did not help recovery. The results also showed that animals with a concurrent T. congolense and H. contortus infection ran a higher risk of succumbing during the infection, and also during 10 weeks following treatment. Although infections with T. congolense alone produced no clinical signs, they were found to significantly reduce the ability of infected animals to mount a normal response to a subsequent H. contortus infection. It was concluded that the increased H. contortus egg excretion observed in animals infected with both parasites might significantly increase the risk of nematode infections and that the reduced prepatent period might necessitate more frequent anthelmintic treatments. These interactions should, therefore, be considered wherever attempts are made to control these two diseases.

An immunocytochemical study was performed to examine the cellular localization and the subcellular distribution of kininogens in human blood cells. Kininogens were visualised using the immunogold-silver staining method and confocal scanning laser microscopy. We confirmed the existence of high molecular weight kininogen in human neutrophils and describe for the first time the presence of low molecular weight kininogen on these cells. Both high and low molecular weight kininogens were restricted to the neutrophils where they localized as clusters of immunogold particles on the cell membrane. No labeling was observed intracellularly in organelles such as mitochondria, endoplasmic reticulum, and azurophilic or specific granules after permeabilization of the neutrophils with Triton X-100, a procedure that permitted the visualization of elastase in the azurophilic granules. Clusters of high molecular weight kininogen molecules attached to the neutrophil surface could serve as receptors for plasma kallikrein and/or be the source of substrate for a discrete and circumscribed formation of kinins that may in turn facilitate the local diapedesis of neutrophils and the transudation of plasma constituents during acute inflammation.

Norethisterone enanthate (NET-EN) 50 mg combined with estradiol valerate (EV) 5 mg was studied as a once-a-month injectable contraceptive with regard to effectiveness, cycle control, adverse events and acceptability. In eight Family Planning Centres from 5 Latin American countries, 652 fertile women were followed-up for a period of 24 months, providing a total of 10,689 woman-months of experience. Only 1 pregnancy occurred, in the first treated month a few days before the second injection (failure rate 0.11 per 100 woman-years). Under treatment, the first cycle was drastically shortened in most cases, but thereafter cycles tended to recover to pre-treatment patterns. There was a significant decrease of hypermenorrhea and dysmenorrheic cycles. Intracyclic bleeding and spotting appeared in 1.2% and 2.4%, respectively, and amenorrhea in 2.5% of cycles. Incidence of other adverse events was very low with the exception of weight gain of 2 Kg (28%). Continuation rate at 12 months was 64.7%. The cumulative discontinuation rate due to bleeding problems was 7.4% and 10.7% due to adverse events at 24 months.

Mononuclear phagocytes adhere to and penetrate the vessel wall endothelium and contact the subendothelial space prior to the development of the atherosclerotic plaque. In an attempt to model the early events of plaque development we used an elastin-rich, multicomponent, cell-derived matrix from neonatal rat aortic smooth muscle cells as a substratum for monocytes. Using this model, we show that human monocyte morphology and metabolism are markedly altered by the matrix substratum. When a mixed mononuclear cell population is seeded on matrix or plastic, only monocytes adhere to the matrix surface. In contrast, lymphocytes as well as monocytes adhere to the plastic surface. The matrix-adherent monocytes develop large intracellular granules and form extensive clusters of individual cells. Metabolically, these cells develop sodium fluoride resistant non-specific esterase activity and their media contain more growth factor activity and PGE2. Although total protein synthesis is equivalent in both cultures, the matrix contact induces an increase in specific proteins in the media. We also show that a purified alpha-elastin substratum induces some, but not all, of the monocyte changes seen when using the matrix substratum. Using the alpha-elastin substratum, there is selective adhesion of monocytes and increased growth factor activity, however, the cells are morphologically different from the matrix-adherent cells. Thus, the use of the smooth muscle cell-derived matrix, in conjunction with purified matrix components, serves as a model that can provide insight into the mechanisms of monocyte adhesion and stimulation by the matrix environment that exists in vivo. Such mechanisms may be particularly important in atherogenesis.